Metal ion-promoted activation of amino acid esters of carbohydrates in the synthesis of peptides

Abstract Carbohydrate esters 1 and 2 of N-protected amino acids are activated by coordination of metal ions and subjected to aminolysis by amino acid esters 3 to form peptides 4 .

Der (2-Phenyl-2-trimethylsilyl)ethyl(PTMSEL)-Linker - ein neuer, mit Fluorid spaltbarer Anker für die Festphasensynthese von geschützten Peptiden und Glycopeptiden

ChemInform Abstract: Synthesis of Glycopeptides Containing Carbohydrate and Peptide Recognition Motifs

Reaktive Metabolite cancerogener polycyclischer Kohlenwasserstoffe: Synthese und Abfangreaktion von 9-Hydroxybenzo[a]pyren-4,5-oxid

Le compose du titre est prepare a partir de l'acetate-9 de benzo [a] pyrene et piege par l'ethanethiol. Mecanismes

ChemInform Abstract: Chemoenzymatic-Chemical Synthesis of a (2-3)-Sialyl T Threonine Building Block and Its Application to the Synthesis of the N-Terminal Sequence of Leukemia-Associated Leukosialin (CD 43).

Protection of all functional groups of the carbohydrate portion of the chemoenzymatically synthesized sialyl T threonine ester 1 (R=R1 =H, R2 =tBu, Fmoc=9-fluorenylmethoxycarbonyl) and subsequent acidolysis of the tert-butyl ester afforded the building block 2 (R=Ac, R1 =Me, R2 =H). The latter is a useful tool in the solid-phase synthesis of the N-terminal sequence 3 of the leukemia-associated leukosialin.

ChemInform Abstract: Synthesis of Active Principles from the Leaves of Moringa oleifera Using S-Pent-4-enyl Thioglycosides.

Abstract α - l -Rhamnosides of 4-hydroxy-benzyl compounds with nitrile, carbamate, and thiocarbamate groups occurring in Moringa oleifera leaf extracts and the α - l -rhamnoside of anisaldehyde derivatives were synthesised. Electrophilic activation of S -pent-4-enyl thiorhamnosides was applied for the construction of glycosidic linkages.

Stereocontrolled synthesis of D-α-hydroxy carboxylic acid from L-amino acids

Abstract Optically active D-α-hydroxy carboxylic acids are obtained from L-amino acids via L-α-halocarboxylic acids and their stereoselective reaction with cesium p-nitrobenzoate.

Synthetic Glycopeptides for the Development of Tumor-Selective Vaccines

ChemInform Abstract: (2-Phenyl-2-trimethylsilyl)ethyl (PTMSE) Esters - A Novel Carboxyl Protecting Group.

Self-adjuvanting synthetic antitumor vaccines from MUC1 glycopeptides conjugated to T-cell epitopes from tetanus toxoid.

The T-helper epitope peptide P30 (green in the scheme) from tetanus toxoid was used as the immunostimulant in MUC1 glycopeptide antitumor vaccines and apparently also acts as a built-in adjuvant. P30-conjugated glycopeptide vaccines containing three glycans in the immunodominant motifs PDTRP and GSTAP induced much stronger immune responses and complement dependent cytotoxicity mediated killing of tumor cells when applied in plain PBS solution without complete Freund's adjuvant.

ChemInform Abstract: Stereoselective Syntheses of Chiral Heterocycles and Alkaloids Using Carbohydrate Auxiliaries

Stereoselective solid-phase synthesis of chiral piperidine derivatives by using an immobilized galactose auxiliary.

Carbohydrates as Stereodifferentiating Auxiliaries

Carbohydrates are inexpensive natural products. Although they contain numerous functional groups and stereogenic centers in one molecule, carbohydrates were recognized as stereodifferentiating auxiliaries much later than other classes of natural products as for example amino acids or terpenes. Apart from their polyfunctional nature carbohydrates are characterized by the anomeric and exo-anomeric effects which have distinct influence of the spatial orientation of substituents linked to the anomeric position. Based on these stereochemical properties carbohydrates were used as stereodifferentiating auxiliaries in numerous diastereoselective reactions, such as aldol addition, alkylation reactio…

ChemInform Abstract: Glycoside Synthesis via Electrophile-Induced Activation of N-Allyl Carbamates.

Abstract O-Benzyl-, O-acyl-, N-acyl- and isopropylidene-protected glycosyl N-allylcarbamates, obtained from anomerically unprotected monosaccharides and allyl isocyanate, are activated by an electrophile-induced cyclisation and react with hydroxyl compounds to form the corresponding glycosides.

Glycopeptide Synthesis in Solution and on the Solid Phase

Effects of glycosylation on fragments of tumour associated human epithelial mucin MUC1.

The glycodecapeptide AcPAPGS(alpha GalNAc)T(alpha GalNAc)APPA and the C-terminal glycohexapeptide AcS(alpha GalNAc)T(alpha GalNAc)APPA have been synthesized by applying the N-terminal Fmoc group in combination with the heptyl ester cleavable by lipase-catalyzed hydrolysis at pH 7. The solution conformation of these MUC1-related synthetic glycopeptides and the control, non-glycosylated decapeptide AcPAPGSTAPPA have been investigated using NMR spectroscopy. The structural studies indicate that the glycohexapeptide has a folded structure in solution. For this molecule, unrestrained molecular dynamics has been used to confirm the presence of the observed solution through-space connections. The …

ChemInform Abstract: Carbohydrates as Chiral Templates in Stereoselective (4 + 2) Cycloaddition Reactions

Stereoselektive Synthese von Benzomorphan-Derivaten an perpivaloylierter Galactose als chiralem Auxiliar

Protecting Groups

There is hardly any area of preparative organic chemistry in which the proper use of protecting groups is not a prerequisite for the successful achievement of the goals aimed at. For this reason such blocking functions have been developed for nearly 100 years by numerous researchers from all disciplines of organic chemistry, and consequently solutions to the existing problems have been devised, making use of various synthetic transformations. It was Fischer who, among his many important contributions to chemistry, first realized that the application of protecting functions is often a necessity for a successful synthesis. Thus, he introduced the isopropylidene ketal in carbohydrate chemistry…

Stereoselective Synthesis of Bromopiperidinones and their Conversion to Annulated Heterocycles

N-Galactopyranosyl- and N-glucopyranosyl imines of aliphatic, aromatic and heteroaromatic aldehydes react with 1-methoxy-3-trimethylsilyloxy-1,3-butadiene in a domino Mannich-Michael reaction cascade to give 2-substituted 5,6-dehydro-piperidin-4-ones with high diastereoselectivity. Treatment of these cyclic enaminones with N-bromo-succinimide yields the corresponding 2-substituted 5-bromo-5,6-dehydropiperidinones which react with L-SelectrideⓇ or methylcuprate to afford the saturated bromo-piperidinones with high diastereoselectivity. Condensation reactions of these products with thioamides afford thiazolopiperidines

Synthetische Antitumor-Vakzine aus MUC1-Glycopeptiden mit zwei immundominanten Domänen - Induktion einer starken Immunreaktion gegen Brusttumorgewebe

Synthetic Antitumor Vaccines from Tetanus Toxoid Conjugates of MUC1 Glycopeptides with the Thomsen-Friedenreich Antigen and a Fluorine-Substituted Analogue

Stereoselective synthesis of C-glycosyl compounds via Michael addition of trimethylsilyl enol ethers and enamines to hex-1-enopyran-3-uloses

Abstract The titanium(IV)-catalyzed addition of trimethylsilyl enol ethers to 2,4,6-tri- O -acylhex - 1 - enopyran - 3 - uloses ( 3 and 4 ) gave stereoselectively 3,6 - di - O - acyl - 4 - deoxy - β - d - glycero -hex-3-enopyranosyl-2-ulose derivatives. The formation of the C -glycosyl bond was accompanied by a 2→3 acyl shift, followed by the elimination of the 4-acyloxy substituent. Similarly, the reaction of 1-pyrrolidinocyclohexene with 3 and 4 also led stereoselectively to 2-(2,4,6-tri- O -acyl-β- d - ribo -hexopyranosyl)cyclohexanones. In this Michael addition, among the eight possible diastereomers, only one was formed. The high stereocontrol of both C -glycosyl compound syntheses is …

ChemInform Abstract: Oligosaccharide Synthesis via Electrophile-Induced Activation of Glycosyl-N-allylcarbamates.

Abstract Glycosyl-N-allyl carbamates, obtained by reaction of anomerically unprotected saccharides with allyl isocyanate, can be activated by an electrophile-induced cyclisation and reacted with glycosyl acceptors to form the corresponding oligosaccharides By this method the mucin core 2 trisaccharide2 has successfully been synthesized. Due to the mild glycosylation conditions even 1-O-acetyl protected glycosyl acceptors can be used. This was demonstrated in the synthesis of a 1,6-linked glucosyl trisaccharide whereby a reptitious glycosylation strategy could be applied. 1. Dedicated to the memory of Professor Akira Hasegawa.

Stereoselective Synthesis of β-1-O-Acyl Derivatives of Carbohydrates: An Application of the Cesium Effect.

Abstract The stereoselective formation of anomerically pure 1-O-acyl derivatives of protected carbohydrates is achieved by reaction of the α-glycosyl halogenoses with cesium caboxylates.

Synthesis of cyclic dipeptide templates, their incorporation into peptides and studies on their conformational and biological properties.

This study investigated the diastereoselective synthesis of three dipeptide templates 1, 2 and 3, which may be regarded as conformationally restricted analogs of H-Gly-Xaa-OH, in which Xaa constitutes an aromatic amino acid. Bond formation between α-C of Gly and the aromatic moiety was achieved by proton-catalyzed intramolecular electrophilic aromatic substitution. The absolute configuration of the dipeptide templates was determined by single-crystal X-ray crystallography or by nuclear Overhauser enhancement measurements. A protective group strategy was elaborated to allow their incorporation into peptide sequences by liquid phase as well as by solid-phase peptide synthesis. The templates w…

Solid-Phase Synthesis of Biologically Important Glycopeptides

Die 2-(Triphenylphosphonio)isopropyloxycarbonyl-(Ppoc-)-Gruppe und am Phosphoniumzentrum modizifierte analoge Reste als Aminoschutzgruppen bei der Peptidsynthese

Die Einfuhrung in Aminosauren, die Stabilitat bei Peptidsynthesen und die selektive Abspaltung der 2-(Triphenylphosphonio)isopropyloxycarbonyl-(Ppoc-)-Aminoschutzgruppe sowie ihrer Varianten mit (Methyl)(diphenyl)phosphonium- und (Dimethyl)(phenyl)phosphoniumkopfen werden beschrieben. Der Ppoc-Rest ist in etwa um den Faktor 4 basenstabiler als der entsprechende 2-(Triphenylphosphonio)ethoxycarbonyl-(Peoc-)Rest. Er kann dennoch bereits bei pH = 8 in wasrig-methanolischer Hydrogencarbonatlosung von der blockierten Aminofunktion abgelost werden. Im Gegensatz zur Peoc-Abspaltung treten dabei keine storenden Nebenreaktionen des entstehenden Propenylphosphoniumsalzes mit der freigesetzten Aminofu…

Solid-Phase Synthesis of a Sialyl-Tn-Glycoundecapeptide of the MUC1 Repeating Unit

The synthesis of glycopeptides carrying tumour-associated antigens is of interest for cancer diagnosis and treatment. Here, a very efficient route lo disaccharide threonine building block 8 is presented which allows the introduction of the sialyl-Tn antigen into a peptide. The syntheses of the undecapeptide and the sialyl-Tn-containing glycoundecapeptide, which are a part of the repeating unit of MUC1, were performed by solid-phase synthesis with an allylic anchor cleavable under neutral conditions. After detachment from the resin, the peptide and the glycopeptide arc completely deprotected giving the target compounds 13 and 15, respectively.

A fully synthetic glycopeptide antitumor vaccine based on multiple antigen presentation on a hyperbranched polymer.

For antitumor vaccines both the selected tumor-associated antigen, as well as the mode of its presentation, affect the immune response. According to the principle of multiple antigen presentation, a tumor-associated MUC1 glycopeptide combined with the immunostimulating T-cell epitope P2 from tetanus toxoid was coupled to a multi-functionalized hyperbranched polyglycerol by "click chemistry". This globular polymeric carrier has a flexible dendrimer-like structure, which allows optimal antigen presentation to the immune system. The resulting fully synthetic vaccine induced strong immune responses in mice and IgG antibodies recognizing human breast-cancer cells.

Towards a fully synthetic MUC1-based anticancer vaccine: efficient conjugation of glycopeptides with mono-, di-, and tetravalent lipopeptides using click chemistry.

Abstract The membrane-bound tumor-associated glycoprotein MUC1 is aberrantly glycosylated in cancer cells compared with normal cells, and is therefore considered an attractive target for cancer immunotherapy. However, tumor-associated glycopeptides from MUC1 do not elicit a sufficiently robust immune response. Therefore, antitumor vaccines were developed, which consist of MUC1 glycopeptides as the B epitopes and immune-stimulating toll-like receptor 2 (TLR 2) lipopeptide ligands. These fully synthetic vaccine candidates were prepared by solid-phase synthesis of the MUC1 glycopeptides. The Pam(3) Cys lipopeptide, also synthesized on solid-phase, was C-terminally coupled to oligovalent lysine…

Vom E-Selektin-Liganden 1 abgeleitete Glycopeptide mit variierter Sialyl-Lewisx-Struktur als Zelladhäsionsinhibitoren für E-Selektin

Stereoselective synthesis of glycosides and anomeric azides of glucosamine

The β-azide of O-acetyl protected N-acetyl glucosamine is efficiently accessible via a phasetransfer-catalyzed reaction of the corresponding glycosyl chloride with sodium azide. The azido group revealed to be a useful anomeric protection for modifications of the protecting group pattern of the glucosamine unit. Exchange of the O-acyl groups by 4-methoxybenzylidene and 4-methoxybenzyl (Mpm) protection delivered regioselectively blocked glucosaminyl azide derivatives. In contrast, the N-phthaloyl protected glucosaminyl azide was obtained quantitatively from the corresponding glycosyl fluoride via a boron trifluoride-promoted reaction with trimethylsilyl azide. N-Phthaloyl glucosaminyl fluorid…

Phosphororganische Verbindungen, 68. Darstellung und Eigenschaften von Tetrakis(diphenylphosphin)‐nickel(0)

Die Titelsubstanz 1 wurde durch Einwirkung von Diphenylphosphin auf Bis-π-allyl-nickel, Tetrakis(triphenylphosphin)-nickel(0) (2), Nickelpulver oder Nickel(II)-bromid dargestellt. Ihre Struktur wurde durch Zerewitinoff-Bestimmung, IR- und NMR-Spektren abgesichert. Eine Alkylierung von metalliertem 1 gelang nicht. Organic Phosphorus Compounds, 68. Preparation and Properties of Tetrakis(diphenylphosphine)nickel(0) The title compound, 1, was prepared by reacting of diphenylphosphine with bis(π-allyl)nickel, tetrakis(triphenylphosphine)nickel(0) (2), nickel-powder, or nickel(II) bromide. The structure of 1 was elucidated by Zerewitinoff method, i. r. and n. m. r. spectra. The alkylation of meta…

Multivalente synthetische Glycopeptid-Lipopeptid-Antitumorvakzine: Auswirkung des Cluster-Effekts auf das Abtöten von Tumorzellen

Multivalente synthetische Vakzine wurden durch Festphasensynthese von tumorassoziierten MUC1-Glycopeptidantigenen und deren Kupplung an ein Pam3Cys-Lipopeptid durch Klick-Reaktion gewonnen. Diese Vakzine losen in Mausen Immunreaktionen aus, ohne dass externe Adjuvantien angewendet werden. Die vier MUC1-Sialyl-TN-Antigene enthaltende Vakzine zeigte einen signifikanten Cluster-Effekt. Sie induzierte in Mausen vorwiegend IgG2a-Antikorper, die an MCF-7-Brusttumorzellen binden und diese Tumorzellen durch Aktivierung des Complement-abhangigen Cytotoxizitatskomplexes (CDC) abtoten.

Cyclodextrin-assisted Glycan Chain Extension on a Protected Glycosyl Amino Acid

By the use of cyclodextrins, we have enhanced the solubility of the protected amino acid glycan Fmoc-Thr(GalNAcα1)-OtBu (1b) up to 100-fold. This improvement enabled us to carry out an enzymatic glycosylation employing a β-galactosidase in combination with an α2,3-sialyltransferase without the aid of organic cosolvents. After optimization of the one-pot reaction, the sialylated core 1 structure Fmoc-Thr[Neu5Ac(α2-3)Gal(β1-3)GalNAcα1]-OtBu (3b) could be obtained with 50% yield.

Total Synthesis of the Antifungal Natural Product Mollisin

Mollisin, a bioactive polyketide secondary metabolite of the fungus Mollisia caesia, was synthesized in nine linear steps from commercially available 2,6-dimethyl-γ-pyrone. A key transformation in this first total synthesis of mollisin was the ipso substitution of an arylstannane, which permitted the otherwise cumbersome introduction of the characteristic dichloroacetyl moiety. The fungal fungicide was obtained in an overall yield of 9 %.

ChemInform Abstract: Carbohydrates as Chiral Templates: Diastereoselective Synthesis of N- Glycosyl-N-homoallylamines and β-Amino Acids from Imines.

Complexing properties and chirality of carbohydrates were utilized in diastereoselective reactions of 0-pivaloylated N-galactosylimines with allylsilanes and -stannaries. With dyltrimethylsilane in the presence of SnCl4, imines 2 of aromatic and heteroaromatic aldehydes were converted to homdylamines 3, giving ratios of diastereomers higher than 7:1. No addition products derived from α-anomeric aromatic imines were formed. Aliphatic homdylamines 3 were synthesized by using allyltributylstannane in the presence of SnCl4. Both α- and β-anomeric aliphatic imines reacted with the allylstannane. They gave the same ratio of diastereomers and showed the same sense of asymmetric induction.

Specificity of human natural antibodies referred to as anti-Tn

International audience; To understand the role of human natural IgM known as antibodies against the carbohydrate epitope Tn, the antibodies were isolated using GalNAcα−Sepharose affinity chromatography, and their specificity was profiled using microarrays (a glycan array printed with oligosaccharides and bacterial polysaccharides, as well as a glycopeptide array), flow cytometry, and inhibition ELISA. The antibodies bound a restricted number of GalNAcα-terminated oligosaccharides better than the parent monosaccharide, e.g., 6-O-Su-GalNAcα and GalNAcα1−3Galβ1−3(4)GlcNAcβ. The binding with several bacterial polysaccharides that have no structural resemblance to the affinity ligand GalNAcα was…

ChemInform Abstract: Modified Trityl Ester Protecting Groups in Peptide Synthesis.

Auxiliary-controlled stereoselective enolate protonation: Enantioselective synthesis of cis and trans annulated decahydroquinoline alkaloids

Abstract The diastereoselective synthesis of the octahydroquinoline enone precursor of pumiliotoxin C is achieved via tandem Mannich-Michael reaction on N-galactosyl imines. Conjugate cuprate addition to the bicyclic enone stereoselectively forms the trans annulated 4a- epi -pumiliotoxin C skeleton in the presence of the carbohydrate auxiliary, and the cis annulated pumiliotoxin C skeleton in its absence.

N-Glycosyl Amides as Glycosyl Donors in Stereoselective Glycosylation Reactions

Due to their high stability, N-glycosyl amides have so far not been considered as glycosyl donors for glycosylation reactions. Two new procedures for the cleavage of the anomeric amide functionality under mild reaction conditions and further stereoselective in situ conversions of the activated glycosyl donors with alcohols and amines to give β-configured O- and N-glycosides are described in this article.

Total Synthesis of the Glycopeptide Recognition Domain of the P-Selectin Glycoprotein Ligand 1

Mixed Dialkylaluminum Chlorides and Mixed Trimethylorganoaluminates in Chemoselective 1,4 Addition Reactions to Alkylidene Malonic Acid Diethyl Ester

Mixed alkyl-methyl- and aryl-methylorganoaluminum chlorides 6 were formed by reaction of methylaluminum dichloride with organolithium or Grignard compounds and used for chemoselective 1,4 addition of higher alkyl, aryl, alkenyl and alkinyl groups to alkylidine malonic esters 1 and 2. As an alternative, mixed trimethylorganoaluminates 7 can also be applied for these Michael addition reactions. For conjugate addition of alkenyl groups to alkylidene malonates 1 and 2, alkenyl diisopropylalanes 10 obtained from alkynes and diisopropylaluminum hydride proved the most efficient reagents. Using these novel mixed organoaluminum compounds, β-branched malonic (carboxylic) acid derivatives 3c, 8, 9 an…

Synthese von Desoxy-Sialyl-Lewisx-Analoga, potentiellen Selectin-Antagonisten

Enantioselektive Strecker-Reaktion mit einem Organokatalysator ohne Wasserstoffbrückendonor-Funktion

Book Review: Protective Groups in Organic Synthesis. 2nd Edition. Edited by T. W. Greene and P. G. M. Wuts

Chemistry of glycopeptides

For a long time, peptides and proteins on the one hand and carbohydrates on the other have been considered separate classes of natural products. The rather strict distinction between these major fields of natural product chemistry is still apparent not only in the organisation of chemistry text books but also in the different approaches to immunological and cell biological recognition phenomena.

Archaea-analoge Thiolipide für gestützte Lipiddoppelschichtmembranen auf ultraglatten Goldoberflächen

A Synthetic Vaccine Consisting of a Tumor-Associated Sialyl-TN-MUC1 Tandem-Repeat Glycopeptide and Tetanus Toxoid: Induction of a Strong and Highly Selective Immune Response

Isomerisierung von 2‐Alkoxycyclopropancarbonsäuren – Eine effektive Synthese von 4‐Oxocarbonsäuren

(Z/E)-2-Alkoxycyclopropansaureester 2/3 werden aus Enolethern 1 und Diazoessigester hergestellt. Durch Verseifen entstehen die (Z/E)-2-Alkoxycyclopropancarbonsauren 4/5, welche in Wasser/Methanol Stereomutation zeigen. Diese Isomerisierung wird an (E)-2-Methoxy-2-phenyl-cyclopropancarbonsaure (5a) in deuterierten Losungsmitteln untersucht und mechanistisch interpretiert. Beim Erwarmen in Wasser/Methanol offnen sich die Verbindungen 4/5 quantitativ zu den entsprechenden 4-Oxocarbonsauren 6. Isomerisation of 2-Alkoxycyclopropanecarboxylic Acids – An Effective Synthesis of 4-Oxo Carboxylic Acids (Z/E)-2-2-Alkoxycyclopropanecarboxylic esters 2/3 were prepared from enol ethers 1 and ethyl diazoa…

ChemInform Abstract: Stereoselective Synthesis of β-1-O-Acyl Derivatives of Carbohydrates: An Application of the Cesium Effect.

Abstract The stereoselective formation of anomerically pure 1-O-acyl derivatives of protected carbohydrates is achieved by reaction of the α-glycosyl halogenoses with cesium caboxylates.

Synthese von 2-Acyloxy- und 2-Alkyloxy-3-ketoglycalen und ihren Bromaddukten

Die an den Hydroxygruppen acetyl-, pivaloyl- und methylgeschutzten 2-Hydroxy-3-ketoglycale 5a, 5b bzw. 11 werden durch Oxidation der entsprechenden 1-O-Acylglucopyranosen 3a, 3b bzw. 9 an der freien 3-Hydroxygruppe mit Dimethylsulfoxid/Acetanhydrid oder Chlorsulfonylisocyanat hergestellt und charakterisiert. Nur beim Acetylderivat 3a verlaufen die Oxidation und die Eliminierung des 1-Acetyloxysubstituenten in einem Schritt. Beim Pivaloylderivat 3b und beim Methylderivat 9 mus die Eliminierung aus der 3-Ulose 4 bzw. 10 mit Diazabicycloundecen (DBU) vervollstandigt werden. – Die geschutzten Hex-1-enopyran-3-ulosen 5a, 5b und 11 addieren Brom stereoselektiv unter Bildung der D-ribo-konfigurier…

ChemInform Abstract: Synthetic O-Glycopeptides as Model Substrates for Glycosyltransferases.

Abstract A new approach to O-glycopeptides of the glucosamine type is described. N-Urethane protected, peracetylated glucosamine is converted into its 1-thio (1-bromo) derivative and used for glycosylation of a variety of protected serine or threonine derivatives as acceptors. The urethane group is easily exchanged for the natural N-acetyl moiety and O-deacetylation is achieved with hydrazine/methanol. The resulting O-GlcNAc derivatives are subjected to an enzymatic galactosylation procedure using β-1,4-galactosyltransferase (EC 2.4.1.22) to furnish O-glycopeptides of the neolactosamine type.

Synthese von Giycopeptiden: Selektive C-terminale Deblockierung und Peptidkettenverlängerung an Glucosylserin-Derivaten

Benzyloxycarbonyl-(Z-)serin-2-bromethylester (3b) wird mit 2,3,4,6-Tetra-O-benzoyl-α-D-gluco-pyranosylbromid (14) zum Glucosylserinester 15 verknupft. Nach Umwandlung in den entsprechenden 2-Iodethylester 23 wird die Carboxygruppe durch Eliminierung mit Zink selektiv deblockiert. Dabei bleiben die Z- und die Kohlenhydrat-Schutzgruppen sowie die empfindliche O-glycosidische Bindung unverandert erhalten. Das Glycosyl-Z-serin 24 reagiert mit Aminosaure-2-bromethylestern 2 zu geschutzten Glycodipeptid-2-bromethylestern 18, die nach selektiver Carboxydeblockierung zu Glycotripeptidestern 25 C-terminal verlangert werden. Wahrend geschutzte Serin-Dipeptide 5 mit 14 zu Konjugaten 18 glycosyliert we…

ChemInform Abstract: Syntheses of Sialyl Lewis A Glycopeptides - A Partial Sequence of the P-Selectin Ligand PSGL-1.

Immunogenicity of a Fully Synthetic MUC1 Glycopeptide Antitumor Vaccine Enhanced by Poly(I:C) as a TLR3-Activating Adjuvant.

Fully synthetic MUC1 glycopeptide antitumor vaccines have a precisely specified structure and induce a targeted immune response without suppression of the immune response when using an immunogenic carrier protein. However, tumor-associated aberrantly glycosylated MUC1 glycopeptides are endogenous structures, “self-antigens”, that exhibit only low immunogenicity. To overcome this obstacle, a fully synthetic MUC1 glycopeptide antitumor vaccine was combined with poly(inosinic acid:cytidylic acid), poly(I:C), as a structurally defined Toll-like receptor 3 (TLR3)-activating adjuvant. This vaccine preparation elicited extraordinary titers of IgG antibodies which strongly bound human breast cancer…

ChemInform Abstract: Total Synthesis of the Antifungal Natural Product Mollisin.

The title compound is synthesized in nine steps from commercially available 2,6-dimethyl-γ-pyrone in an overall yield of 9%.

Ein synthetischer Impfstoff aus einem tumorassoziierten Sialyl-TN-MUC1-Tandem-Repeat-Glycopeptid und Tetanustoxoid zur Induktion einer starken, hochselektiven Immunantwort

Solid-phase synthesis of a glycopeptide from the homophilic recognition domain of epithelial cadherin 1 using a O-pentafluorophenyluronium salt

Abstract The β-turn forming glycopeptide 6 from the homophilic recognition domain of mouse epithelial cadherin 1 carrying a T N -antigen side chain was synthesised on solid phase using an allylic anchor and the new coupling reagent N , N - N ′, N ′-bis(tetramethylene)- O -pentafluorophenyluronium hexafluorophosphate 3 .

Synthetic Glycopeptides from the E-Selectin Ligand 1 with Varied Sialyl Lewisx Structure as Cell-Adhesion Inhibitors of E-Selectin.

Der 2-(4-pyridyl)Ethoxycarbonyl-(4-Pyoc)-rest - eine hydrophile, säure- und basenstabile aminoschutzgruppe für die peptidsynthese

Abstract The title amino blocking function is stable under basic and acidic conditions frequently used in the peptide synthesis. Its hydrophilicity permits an effective peptide synthesis in water. After the easy conversion to the pyridinium form the 4-Pyoc group can be removed by morpholine.

ChemInform Abstract: Enantioselective Allylic Substitution Using a Novel (Phosphino-α-D-glucopyrano-oxazoline)palladium Catalyst.

Carbohydrate Auxiliaries in Stereoselective Syntheses of Decahydroquinoline Alkaloids

Using tetra-O-pivaloyl-β-D-galactopyranosylamine as the chiral auxiliary, both trans- and cis-annelated decahydroquinoline alkaloids can be synthesized stereoselectively. This methodology of asymmetric synthesis is based on the effect that both enantiomers of 2,6-disubstituted piperidin-4-ones are selectively and alternatively accessible using the auxiliary as the identical stereodifferentiating tool. In addition, the carbohydrate auxiliary controls the stereoselective protonation of enolates formed by conjugate addition of cuprates to N-galactosyl octahydroquinolin-4-ones. The syntheses of trans-4a-epi-pumiliotoxin C and cis-4a-epi-perhydro-219A illustrate this concept of asymmetric synthe…

Combinatorial solid-phase synthesis using D-galactose as a chiral five-dimension-deversity scaffold

Abstract All five hydroxy groups of galactose as the scaffold are used for selective coupling of side chains in a combinatorial methodology by application of a set of orthogonally stable protecting groups in combination with a thioglycoside anchor.

ChemInform Abstract: Stereoselective Synthesis of 2-Substituted Pyrrolidines.

Using O -pivaloyl protected D-galactopyranosylamine and D-arabinopyranosylamine, ( S ) or ( R ) configured α-substituted homoallylamines are synthesized with high diastereoselectivity by reaction of the corresponding aldimines with allyltributylstannane. Electrophile-induced endo -trig-cyclization of these N -glycosylhomoallylamines gave the 2-substituted pyrrolidines of high diastereomeric purity.

A facile cleavage of allyl ethers on solid phase

Abstract A simple and efficient protocol for the cleavage of allyl ethers on solid phase using a palladium(0)-catalyzed allyl transfer reaction is reported.

Stereoselektive kombinatorische Ugi-Mehrkomponenten-Synthese an fester Phase

ChemInform Abstract: A Novel Synthesis of Chain-Extended Amino Sugar Derivatives Through Aza-Cope Rearrangement of N-Galactosyl-N-homoallylamines.

Abstract Chain-extended amino sugars are synthesized via stereocontrolled Lewis acid-catalyzed aza-Cope rearrangement of N-glycosyl homoallylamines in high yield and stereoselectivity.

ChemInform Abstract: Carbohydrates as Chiral Templates in the Stereoselective Synthesis of . beta.-Amino Acids

Veresterung und Veretherung sterisch gehinderter Kohlenhydrat‐Hydroxylfunktionen mit dem System Triphenylphosphan/Azodicarbonsäureester

Die 6-0-Benzoyl-3-0-Benzyl-1,2-0-isopropyliden-α-D-glucofuranose (11) reagiert unter der Einwirkung von Azodicarbonsaure-diethylester (2) (DEAD) und Triphenylphosphan (1) mit p- Nitro benzoesaure, Benzoesaure, p-Toluolsulfonsaure- und Mesitylensulfonsaure-methylester sterisch nicht einheitlich. Es bildet sich das erwartete Substitutions-(L-ido)-Produkt (unter Inversion an C-5), aber daneben auch das D-gluco-Epimere; fur dessen Bildung wird ein Acylierungsmechanismus diskutiert. – Die Reaktion der 1,2:5,6-Di-O-isopropyliden α-D-glucofuranose(7) mit dem Reagenzsystem 1/2 und Arylsulfonsaure-methylesters bleibt auf der Alkoxyphosphoniumsalze 8 stehen. Durch Umsetzung mit Alkoholat erhalt man a…

ChemInform Abstract: SYNTHESIS OF THE GLYCOPEPTIDE PARTIAL SEQUENCE A80-A84 OF HUMAN FIBROBLAST INTERFERON

The glycopentapeptide H-(GlcNAcβ1-)Asn-Glu-Thr-Ile-Val-OH (10) representing the partial sequence A80–A84 of human fibroblast interferon was synthesized using the newly developed allyl-ester protection of carboxy functions. The allyl esters, which are stable to acids and to bases, can be cleaved under very mild, neutral conditions using tris(triphenylphosphine)rhodium(I) chloride or tetrakis(triphenylphosphine)palladium(0) as a catalyst. This synthetic method opens up a preparative route to glycopeptide model structures of glycoproteins of high biological interest.

Stereoselektive Glycosylierung von Steroidalkoholen mit 2,3,4,6-Tetra-O-privaloyl-α-D-glucopyranosylbromid (Pivalobromglucose) und 2,3,4,6-Tetra-O-(o-toluoyl)-α-D-glucopyranosylbromid

Steroidalkohole verschiedener Struktur, deren Hydroxyfunktionen aus elektronischen und sterischen Grunden in ihrer Reaktivitat differieren und die daruber hinaus empfindliche Gruppierungen enthalten, werden mit 2,3,4,6-Tetra-O-pivaloyl-α-D-glucopyranosylbromid (1) selektiv und effektiv in β-Glucoside ubergefuhrt. Dank des lenkenden Einflusses des 2-O-Pivaloyl-Substituenten wird eine Orthoesterbildung bei den Koenigs-Knorr-Reaktionen stark unterdruckt. Mit dem o-Toluoylrest als Hydroxyschutzgruppe wird diese Lenkung nur in geringem Mas erreicht. Stereoselective Glycosylation of Steroid Alcohols Using 2,3,4,6-Tetra-O-pivaloyl-α-D-glucopyranosyl Bromide (Pivalobromoglucose) and 2,3,4,6-Tetra-O…

Evaluation of a novel monoclonal antibody against tumor-associated MUC1 for diagnosis and prognosis of breast cancer

There is still a great unmet medical need concerning diagnosis and treatment of breast cancer which could be addressed by utilizing specific molecular targets. Tumor-associated MUC1 is expressed on over 90 % of all breast cancer entities and differs strongly from its physiological form on epithelial cells, therefore presenting a unique target for breast cancer diagnosis and antibody-mediated immune therapy. Utilizing an anti-tumor vaccine based on a synthetically prepared glycopeptide, we generated a monoclonal antibody (mAb) GGSK-1/30, selectively recognizing human tumor-associated MUC1. This antibody targets exclusively tumor-associated MUC1 in the absence of any binding to MUC1 on health…

β-Alkyl- und β-Alkyl-α-hydroxycarbonsäure-Derivate über radikalische oder ionische 1,4-Addition von Dialkylaluminiumchloriden an α,β-ungesättigteN-Acylurethane

Multiple Sialyl Lewisx N-Glycopeptides: Effective Ligands for E-Selectin

Saccharide-induced peptide conformation in glycopeptides of the recognition region of LI-cadherin.

d-Glucose as a multivalent chiral scaffold for combinatorial chemistry

Due to their high density of functional groups and their availability in a variety of diastereomeric forms, monosaccharides are considered attractive scaffolds for combinatorial chemistry that allow the attachment and defined spatial alignment of up to five different pharmacophoric groups. For their application in combinatorial syntheses on solid phase, a set of selectively removable hydroxy protecting groups in combination with a cleavable anchor is required. Herein, we report on the construction and use of a versatile multivalent glucose building block for parallel synthesis on the solid phase.

Antibody Induction Directed against the Tumor-Associated MUC4 Glycoprotein

Mucin glycoproteins are important diagnostic and therapeutic targets for cancer treatment. Although several strategies have been developed to explore anti-tumor vaccines based on MUC1 glycopeptides, only few studies have focused on vaccines directed against the tumor-associated MUC4 glycoprotein. MUC4 is an important tumor marker overexpressed in lung cancer and uniquely expressed in pancreatic ductual adenocarcinoma. The aberrant glycosylation of MUC4 in tumor cells results in an exposure of its peptide backbone and the formation of tumor-associated glycopeptide antigens. Due to the low immunogenicity of these endogenous structures, their conjugation with immune stimulating peptide or prot…

ChemInform Abstract: Petasis Olefination in a Continuous-Flow Microwave Reactor: exo-Glycals from Sugar Lactones.

The titled conversion into exo-glycals can be steered by adjusting the resindence time an the concentration of the reaction mixture.

Combinatorial synthesis of amino acid- and peptide-carbohydrate conjugates on solid phase

Carbohydrates are useful polyfunctional scaffold molecules which allow the selective attachment of a number of different side chains. The combinatorial solid phase synthesis of diverse amino acid or peptide conjugates of a polyfunctional glucose scaffold based on a set of selectively removable and orthogonally stable protecting groups is described. The resulting carbohydrate-peptide hybrids constitute potential turn mimetics.

ChemInform Abstract: A Sialyl-Lewis A-Asparagine Building Block for Glycopeptide-Synthesis.

Chemoselective Removal of Protecting Groups from O-Glycosyl Amino Acid and Peptide (Methoxyethoxy)ethyl Esters Using Lipases and Papain

The selective C-terminal deprotection of O-glycopeptide (methoxyethoxy)ethyl esters is achieved under mild conditions (pH 6.6, 37 degrees C) by enzymatic hydrolysis using papain or lipase M from Mucor javanicus to give building blocks useful for chain-extending glycopeptide synthesis. On the other hand, the selective removal of acetyl protecting groups from the saccharide portion of glycopeptides is accomplished by alternative enzymatic hydrolysis with lipase WG from wheat germ to furnish model substrates for enzymatic glycosyl transfer reactions in order to extend the carbohydrate side chain of these conjugates.

ChemInform Abstract: Chemical and Enzymic Synthesis of Glycopeptides

Stereoselective Synthesis of Enantiomerically Pure Piperidine Derivatives by N-Galactosylation of Pyridones.

Stereoselective desymmetrization of 4-pyridone has been achieved through selective N-galactosylation, activation of the N-(galactosyl)pyridone by O-silylation and immediate addition of Grignard compounds. Chiral piperidine derivatives, e.g. (S)-(+)-coniine and (5S,9S)-(+)-indolozidine 167B, were synthesised in enantiomerically pure form using these highly regio- and stereoselective reactions. After N-galactosylation of 2-pyridone and O-silylation of the N-galactosyl-2-pyridone, addition of a Grignard compound proceeded with high 1,4-regioselectivity and complete diastereoselectivity, to furnish 4-substituted 5,6-dehydro-2-piperidones. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Ger…

Stereoselektive Festphasensynthese von chiralen Piperidinderivaten an einem immobilisierten Galactoseauxiliar

Fragment condensation on solid-phase in the synthesis of an amphiphilic glycopeptide from the homophilic recognition domain of epithelial cadherin 1

Abstract The lipo-glycopeptide 6 containing the homophilic recognition motif of mouse epithelial cadherin 1 was synthesised via a fragment condensation on a solid phase linked peptide using an allylic anchor and a pentafluorophenol-based coupling reagent.

Umwandlung von 2-Bromäthoxycarbonyl-Schutzgruppen in 2-Phosphonioäthoxycarbonyl-Schutzgruppen für Aminosäuren1)

Die Bromide 2 von 2-Phosphonioathoxycarbonylaminosauren (Peoc-Aminosauren) werden durch Umsetzung von 2-Bromathoxycarbonylaminosauren (Beoc-Aminosauren) mit tertiaren Phosphinen erhalten. Hierbei entstehen durch Reaktion mit Methyl(diphenyl)phosphin die mit der modifizierten Peoc-Gruppe geschutzten Verbindungen 2e - h in besonders guten Ausbeuten. Diese eignen sich zur Peptidsynthese nach dem Carbodiimid-Verfahren und sind besser in Wasser loslich als die entsprechenden Triphenylphosphonium-Derivate. Die Abspaltung der Me(Ph2)Peoc-Gruppe gelingt mit 0.01 N NaOH in Methanol/Wasser. Modification of 2-Brornoethoxycarbonyl Protective Groups to 2-Phosphonioethoxycarbonyl Protective Functions of …

An vier Positionen in beliebiger Reihenfolge selektiv deblockierbare Kohlenhydratgerüste für die kombinatorische Synthese

Fluorenylmethoxycarbonyl-N-methylamino Acids Synthesized in a Flow Tube-in-Tube Reactor with a Liquid-Liquid Semipermeable Membrane

Both steps of the N-methylation of 9-fluorenylmethoxycarbonyl (Fmoc) amino acids were carried out in a microstructured tube-in-tube reactor equipped with a semipermeable Teflon® AF 2400 membrane as the inner tubing. In the first step, gaseous formaldehyde was passed through the inner membrane to effect the acid-catalyzed conversion of the Fmoc amino acids into the corresponding N-Fmoc oxazolidinones. In the second step, liquid–liquid transfer of trifluoroacetic acid was used for the first time in such a reactor for the reductive opening of these oxazolidinones to give Fmoc N-methylamino acids in high yields.

Investigation of Diketopiperazines Containing a Guanidino-Functionalized Sidechain as Potential Catalysts of Enantioselective Strecker Reactions

Diketopiperazine 1 consisting of L-(γ-guanidino-α-amino)butyric acid and L-phenylalanine was synthesized as the hydroacetate and as the hydronitrate. Its structure was confirmed by X-ray analysis. In contrast to reports in the literature (Lipton et al.), compound 1 does not induce enantioselevtive catalysis of Strecker reactions. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Protein kinase CK2 governs the molecular decision between encephalitogenic T H 17 cell and T reg cell development

T helper 17 (TH17) cells represent a discrete TH cell subset instrumental in the immune response to extracellular bacteria and fungi. However, TH17 cells are considered to be detrimentally involved in autoimmune diseases like multiple sclerosis (MS). In contrast to TH17 cells, regulatory T (Treg) cells were shown to be pivotal in the maintenance of peripheral tolerance. Thus, the balance between Treg cells and TH17 cells determines the severity of a TH17 cell-driven disease and therefore is a promising target for treating autoimmune diseases. However, the molecular mechanisms controlling this balance are still unclear. Here, we report that pharmacological inhibition as well as genetic ablat…

Synthetic Tumor-Associated Glycopeptide Antigens from the Tandem Repeat Sequence of the Epithelial Mucin MUC4

In cancer research, the development of vaccines against tumor-associated antigens is of particular interest. Epithelial cells express mucin type glycoproteins, which are extensively O-glycosylated. In case of cancer, the expression of these mucins is increased, and their carbohydrate side chains show an aberrant glycosylation pattern. A set of single and double glycosylated hexadecapeptides representing the tandem repeat sequence of the epithelial mucin MUC4 carrying different tumor-associated carbohydrate antigens was prepared by sequential solid-phase glycopeptide synthesis. The crucial glycosyl amino acid building blocks containing the T N , T, sialyl-T N and (2,6)-sialyl-T antigens were…

Synthetic Glycopeptides of the Tandem Repeat Sequence of the Epithelial Mucin MUC4 with Tumour-associated Carbohydrate Antigens

Glycohexadecapeptides representing the tandem repeat sequence of the epithelial mucin MUC4 were prepared by applying a solid-phase methodology. The required glycosyl amino acid building blocks containing the tumour-associated saccharide antigens T N -, T,- sialyl-T N , (2,6)- and (2,3)-sialyl-T were synthesized according to a straightforward biomimetic strategy by stepwise extension of the saccharide side chain of a Fmoc-protected galactosamine threonine tert-butyl ester.

Synthese des Methylethers der Herzgift-Methylreduktinsäure ausD-Glucose

Der Methylether 5 der „Herzgift-Methylreduktinsaure” (2), eines Abbauproduktes der Calotropis-Cardenolide, wird in einer mehrstufigen Synthese aus D-Glucose als chiralem Ausgangsmaterial hergestellt. Damit wird die durch Abbaureaktionen getroffene Konfigurationszuordnung fur 2 durch Synthese von 5 bestatigt. Synthesis of the Methyl Ether of “Herzgift-Methylreduktinsaure” Starting from D-Glucose The methyl ether 5 of „Herzgift-Methylreduktinsaure” (2), a degradation product of the Calotropis cardenolides, has been synthesized starting from D-glucose as the chiral pool. The configuration of 2, previously based on the results of degradation, is confirmed by the synthesis of 5.

Tumor-Associated MUC1 Tandem-Repeat Glycopeptide Microarrays to Evaluate Serum- and Monoclonal-Antibody Specificity

A Fully Synthetic Four-Component Antitumor Vaccine Consisting of a Mucin Glycopeptide Antigen Combined with Three Different T-Helper-Cell Epitopes

In a new concept of fully synthetic vaccines, the role of T-helper cells is emphasized. Here, a synthetic antitumor vaccine consisting of a diglycosylated tumor-associated MUC1 glycopeptide as the B-cell epitope was covalently cross-linked with three different T-helper-cell epitopes via squaric acid ligation of two linear (glyco)peptides. In mice this four-component vaccine administered without external immune-stimulating promoters elicit titers of MUC1-specific antibodies that were about eight times higher than those induced by a vaccine containing only one T-helper-cell epitope. The promising results indicate that multiple activation of different T-helper cells is useful for applications …

Phosphororganische Verbindungen, 65. Die selektive Abspaltung von Allylgruppen aus Allylphosphonium‐, ‐arsonium‐ und ‐sulfoniumsalzen und aus Allylsulfonen durch „Cyanolys”︁

KCN spaltet Allylphosphonium-, -arsonium- und -sulfoniumsalze in Methacrylnitril und tertiare Phosphine, tertiare Arsine und Thioather auf. Durch alternierende Cyanolyse und Quartarisierung konnen Phosphonium- und Arsoniumsalze mit vier verschiedenen Liganden aufgebaut werden. Allylammoniumsalze, Allylphosphinoxide und -phosphonsaureester konnen nicht gespalten werden. Dagegen liefern Allylsulfone mit KCN in guten Ausbeuten Methacrylnitril und Sulfinsauren. Organic Phosphorus Compounds, 65. The Selective Elimination of Allyl Groups from Allylphosphonium, -arsonium and -sulfonium Salts and from Allyl sulfones by Cyanolysis KCN cleaves allylphosphonium, -arsonium, and -sulfonium salts to give…

Emil Fischer: unerreichter Klassiker, Meister der organisch-chemischen Forschung und genialer Wegbereiter der biologischen Chemie

Oligosaccharide recognition by selectins: Synthesis and biological activity of multivalent sialyl lewis-X ligands

Abstract Trivalent sialyl Lewis-X ligands 6–8 anchored onto flexible templates have been synthesized and evaluated as inhibitors of E-selectin and P-selectin mediated cell adhesion in cell culture assays and in vivo. Biological activities in vitro correlated with spacer length and lead to ligands with 3-fold (E-selectin) and 5-fold (P-selectin) improved receptor binding avidity per single tetrasaccharide moiety.

The (2-phenyl-2-trimethylsilyl)ethyl-(PTMSEL)-linker in the synthesis of glycopeptide partial structures of complex cell surface glycoproteins.

The (2-phenyl-2-trimethylsilyl)ethyl-(PTMSEL) linker represents a novel fluoride-sensitive anchor for the solid-phase synthesis of protected peptides and glycopeptides. Its cleavage is achieved under almost neutral conditions using tetrabutylammonium fluoride trihydrate in dichloromethane thus allowing the construction of complex molecules sensitive to basic and acidic media commonly required for the cleavage of standard linker systems. The advantages of the PTMSEL linker are demonstrated in the synthesis of glycopeptides from the liver intestine (LI)-cadherin and the mucin MUC1, bearing carbohydrate moieties such as N-linked chitobiose or O-linked sialyl-T(N)-residues. The synthesis of the…

Synthetic Inhibitors of Cell Adhesion: A Glycopeptide from E-Selectin Ligand 1 (ESL-1) with the Arabino Sialyl Lewisx Structure

Particularly selective methods are required for the synthesis of arabino sialyl Lewisx glycopeptides owing to the acid-labile β-arabinopyranoside bond. It is important for the inhibition of cell adhesion that the arabino sialyl Lewisx glycopeptide 1, which contains the Gly 672 -Asp 681 sequence of the E-selectin Ligand 1 (ESL-1), binds ten times more strongly than sialyl Lewisx to E-selectin, although it is monovalent and does not contain L-fucose, which is considered essential.

Synthetic MUC1 Antitumor Vaccine Candidates with Varied Glycosylation Pattern Bearing R/S-configured Pam3 CysSerLys4.

The Toll-like receptor 2 ligand Pam3 CysSer is of particular interest for the construction synthetic vaccines because of its ability to stimulate of the innate immune system. Such vaccines usually comprise Pam3 CysSer with the natural R-configuration at the glycerol 2-position. Pam3 CysSer peptide vaccines with natural configuration have been shown to be more efficient than the corresponding R/S diastereomers. In order to clarify whether the effect of the configuration of Pam3 Cys on the immune response also applies to glycopeptide vaccines, MUC1 glycopeptide-lipopeptide vaccines bearing either R- or R/S-configured Pam3 CysSerLys4 were compared for their immunological effects. In order to f…

Stereoselective Synthesis of 2-Substituted Pyrrolidines

Using O-pivaloyl protected D-galactopyranosylamine and D-arabinopyranosylamine, (S) or (R) configured α-substituted homoallylamines are synthesized with high diastereoselectivity by reaction of the corresponding aldimines with allyltributylstannane. Electrophile-induced endo-trig-cyclization of these N-glycosylhomoallylamines gave the 2-substituted pyrrolidines of high diastereomeric purity.

Polymeric Selectin Ligands Mimicking Complex Carbohydrates: From Selectin Binders to Modifiers of Macrophage Migration

Novel polymeric cell adhesion inhibitors were developed in which the selectin tetrasaccharide sialyl-LewisX (SLeX ) is multivalently presented on a biocompatible poly(2-hydroxypropyl)methacrylamide (PHPMA) backbone either alone (P1) or in combination with O-sulfated tyramine side chains (P2). For comparison, corresponding polymeric glycomimetics were prepared in which the crucial "single carbohydrate" substructures fucose, galactose, and sialic acid side chains were randomly linked to the PHPMA backbone (P3 or P4 (O-sulfated tyramine)). All polymers have an identical degree of polymerization, as they are derived from the same precursor polymer. Binding assays to selectins, to activated endo…

ChemInform Abstract: Stereoselective Synthesis of Quinolizidine Alkaloids: (-)-Lasubin II.

Initially, lasubin II was synthesized diastereoselectively in racemic form [3]. Asymmetric syntheses of lasubin II were achieved based on stereoselective transformations of enantiomerically pure substrates [4] or, for example, via a diastereoselective aza-Diels-Alder reaction using a resolved chiral arylaldehyde tricarbonylchromium complex [5]. Recently, an enantioselectively catalyzed aza-Diels-Alder reaction [6] and a [2+2+2] cycloaddition reaction [7] were successfully used for the synthesis of enantiomerically pure lasubin II.

Variation of the glycosylation pattern in MUC1 glycopeptide BSA vaccines and its influence on the immune response.

Sulfated and Non-Sulfated Glycopeptide Recognition Domains of P-Selectin Glycoprotein Ligand 1 and their Binding to P- and E-Selectin

Total synthesis through block glycosylation and selective chemical O-sulfation of tyrosine residues yielded the glycopeptide recognition domain A (X=SO(3) (-)) of the P-selectin glycoprotein ligand 1, in which the terminal sialic acid of the complex hexasaccharide side chain was replaced by (S)-cyclohexyl lactic acid. In binding assays the O-sulfated structure A showed high affinity towards P-selectin, the non-sulfated towards E-selectin.

Synthetic Antitumor Vaccines Through Coupling of Mucin Glycopeptide Antigens to Proteins

The requirements for coupling reactions of carbohydrate molecules very much depend upon the biological recognition processes that should be investigated and upon the target structures of the desired carbohydrate ligand. If the carbohydrate conjugate itself is the recognized ligand, as for example, the binding site of a P-selectin ligand comprising sialyl-LewisX and a specific peptide sequence, the natural glycoside bond must be installed. A stereoselective and regioselective block glycosylation between a sialyl-LewisX trichloroacetimidate and a partially deprotected Thomsen–Friedenreich antigen derivative was developed to achieve this aim. In contrast, the coupling reactions by which glycop…

Eine neue synthese for 3-desoxy-3-iod-zucker über alkoxyphosphoniumsalze

Abstract The alkoxy phosphonium iodides of the 1,2:5,6-di-O-isopropylidene-gluco- and allofuranose are converted to the corresponding 3-iodo sugars without elimination or rearrangement.

Stereoselective Synthesis of Enantiomerically Pure Piperidine Derivatives byN-Galactosylation of Pyridones

Stereoselective desymmetrization of 4-pyridone has been achieved through selective N-galactosylation, activation of the N-(galactosyl)pyridone by O-silylation and immediate addition of Grignard compounds. Chiral piperidine derivatives, e.g. (S)-(+)-coniine and (5S,9S)-(+)-indolozidine 167B, were synthesised in enantiomerically pure form using these highly regio- and stereoselective reactions. After N-galactosylation of 2-pyridone and O-silylation of the N-galactosyl-2-pyridone, addition of a Grignard compound proceeded with high 1,4-regioselectivity and complete diastereoselectivity, to furnish 4-substituted 5,6-dehydro-2-piperidones. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Ger…

Synthetic Glycopeptides for the Development of Antitumor Vaccines.

ChemInform Abstract: Mucin Glycopeptide-Protein Conjugates - Promising Antitumor Vaccine Candidates

Recent efforts towards the development of synthetic glycopeptide vaccines, which aim at the active immunization of patients against their own tumor tissues, are outlined. To achieve sufficient tumor selectivity, glycopeptides of the tandem repeat region of tumor-associated mucin, MUC1, have been synthesized. Since the endogenous structures usually exert low immunogenicity, these glycopeptide antigens, as B-cell epitopes, were conjugated with immunostimulating components. In the present short review, work is outlined in which the MUC1 B-cell epitope peptides are conjugated with bovine serum albumin (BSA), keyhole limpet hemocyanin (KLH), or tetanus toxoid (TTox). In particular, the synthetic…

Vom Kohlenhydrat induzierte Peptidkonformation in Glycopeptiden aus der Erkennungsregion von LI-Cadherin

Stereoselective Combinatorial Ugi-Multicomponent Synthesis on Solid Phase

Sugars as Chiral Auxiliaries

Synthesis and Structural Model of an α(2,6)-Sialyl-T Glycosylated MUC1 Eicosapeptide under Physiological Conditions

To study the effect of O-glycosylation on the conformational propensities of a peptide backbone, a 20-residue peptide (GSTAPPAHGVTSAPDTRPAP) representing the full length tandem repeat sequence of the human mucin MUC1 and its analogue glycosylated with the (2,6)-sialyl-T antigen on Thr11, were prepared and investigated by NMR and molecular modeling. The peptides contain both the GVTSAP sequence, which is an effective substrate for GalNAc transferases, and the PDTRP fragment, a known epitope recognized by several anti-MUC1 monoclonal antibodies. It has been shown that glycosylation of threonine in the GVTSAP sequence is a prerequisite for subsequent glycosylation of the serine at GVTSAP. Furt…

Lewis Acid-Catalyzed Stereoselection on Carbohydrate Templates

The chirality and the complexing abilities of carbohydrates are utilized for chemical stereoselection in different reactions. In this sense, the carbohydrates are investigated as the chiral auxiliaries in alkylation reactions and in Michael additions of ester enolates. Furthermore, carbohydrates are demonstrated to be efficient chiral matrices in Lewis acid-catalyzed Diels-Alder reactions. They also effect stereoselection in a new synthesis of β-branched carboxylic acid derivatives. O-Acylated glycosylamines are shown to be potent chiral templates in the Strecker synthesis and in the Ugi four-component condensation to give α-amino acid derivatives in high yield and diastereoselectivity. In …

A novel synthesis of chain-extended amino sugar derivatives through aza-Cope rearrangement of N-galactosyl-N-homoallylamines

Abstract Chain-extended amino sugars are synthesized via stereocontrolled Lewis acid-catalyzed aza-Cope rearrangement of N-glycosyl homoallylamines in high yield and stereoselectivity.

P0493 : Selectin-targeting nanoparticles for immunomodulatory therapy of liver diseases

Glycosidsynthese mit 2,3,4,6-Tetra-O-pivaloyl-α-D-glucopyrancsylbromid

Die Glycosylierung von Benzylalkohol und Cholesterin gelingt mit 2,3,4,6-Tetra-O-pivaloyl-α-D-glucopyranosylbromid (2) in Gegenwart von Silbersalzen in hoher Ausbeute. Die bei Koenigs-Knorr-Synthesen mit 2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosylbromid (5) storende Orthoesterbildung wird beim Einsatz von 2 weitgehend unterdruckt. Die Lenkung der Reaktion zugunsten der Glycosidbildung wird dadurch erklart, das der tert-Butyl-Substituent im zwischenzeitlich gebildeten Acyloxoniumion A den nucleophilen Angriff am Acyloxoniumkohlenstoff sterisch behindert. Glycoside Synthesis Using 2,3,4,6-Tetra-O-pivaloyl-α-D-glucopyranosyl Bromide In the presence of silver salts the glycosylation of benzyl alc…

Enzymatic glycosylation of o-glycopeptides

Abstract O-Glycosylation of serine derivatives carried out with N-urethane protected glucosamine yields O-glycopeptides which are regio- and stereoselectively galactosylated with the aid of β-1,4-galactosyltransferase (EC 2.4.1.22).

Regioselective Glycosylation of Glucosamine and Galactosamine Derivates Using O-Pivaloyl Galactosyl Donors

Penta-O-pivaloyl-galactopyranose and tetra-O-pivaloyl-galactopyranosyl bromide after electrophilic activation reacted with 6-O-protected 2-azido-galactosides to give the precursor structures of the Thomsen-Friedenreich antigen disaccharide with high regioselectivity, but low yield.With 4,6-Obenzylidene protected 2-azidogalactosides and 2-O-pivaloyl phenylthio galactosides, T-antigen disaccharides of this type were obtained in good yields. Glycosylation reactions of 4,6-O-benzylidene protected glucosamine derivatives with O-pivaloyl protected galactosyl bromide efficiently gave lactolactosamine disaccharides. Even a thioglycoside was efficiently galactosylated by this method resulting in the…

ChemInform Abstract: Conjugate Addition of Dialkylaluminum Chlorides to Alkylidenemalonic Acid Derivatives.

A Synthetic Glycopeptide Vaccine for the Induction of a Monoclonal Antibody that Differentiates between Normal and Tumor Mammary Cells and Enables the Diagnosis of Human Pancreatic Cancer.

In studies within the realm of cancer immunotherapy, the synthesis of exactly specified tumor-associated glycopeptide antigens is shown to be a key strategy for obtaining a highly selective biological reagent, that is, a monoclonal antibody that completely differentiates between tumor and normal epithelial cells and specifically marks the tumor cells in pancreas tumors. Mucin MUC1, which is overexpressed in many prevalent cancers, was identified as a promising target for this strategy. Tumor-associated MUC1 differs significantly from that expressed by normal cells, in particular by altered glycosylation. Structurally defined tumor-associated MUC1 cannot be isolated from tumor cells. We synt…

The Allyl Ester as Carboxy-Protecting Group in the Stereoselective Construction of Neuraminic-Acid Glycosides

The application of the allyl-ester moiety as protecting principle for the carboxy group of N-acetylneuraminic acid is described. Peracetylated allyl neuraminate 2 is synthesized by reacting the caesium salt of the acid 1 with allyl bromide. Treatment of 2 with HCl in AcCl or with HF/pyridine gives the corresponding 2-chloro or 2-fluoro derivatives 3 and 4, respectively (Scheme 1). In the presence of Ag2CO3, the 2-chloro carbohydrate 3 reacts with di-O-isopropylidene-protected galactose 5 to give the 2–6 linked disaccharide with the α-D-anomer 6a predominating (α-D/β-D = 6:1; Scheme 2). Upon activation of the 2-fluoro derivative 4 with BF3 · Et2O, the β-D-anomer 6b is formed preferentially (…

A Carbohydrate-Based Julia–Kocienski Reagent for Syntheses of Chain-Extended and C-Linked Saccharides

The carbohydrate-derived Julia–Kocienski reagent 2-{[(3aS,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylsulfonyl}-1,3-benzothiazole (6) was prepared from d -ribose and investigated in the eponymous olefination. The base-promoted generation of the Julia anion induced a rearrangement­ to the corresponding l -lyxose epimer 2-{[(3aS,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylsulfonyl}-1,3-benzothiazole (12), which reacted readily with aldehydes and with a gluconolactone. The latter reaction furnished an exo-glycal-linked C-diglycoside.

Das System 2‐Halogenethylester/Cholinester als Zweistufen‐Schutzgruppe für die Carboxylfunktion von Aminosäuren und Peptiden

Das System 2-Chlorethyl- und 2-Bromethylester/Cholinester wird als Carbonsaure-Schutzfunktion beschrieben. Die 2-Chlorethyl-(OEt(Cl))- und die 2-Bromethylester (OEt(Br)) der Aminosauren (4) lassen sich einfach herstellen und mit Z- und Boc-Aminosauren zu Z- und Boc-Dipeptidestern 5 und 6 verknupfen. Die Esterfunktionen sind gegen nicht zu stark saure und basische Einflusse bestandig. Sie konnen mit Natriumiodid in DMF in 2-Iodethylester 8 ubergefuhrt werden, welche mit Zink in einer Eintopfreaktion spaltbar sind. Durch Umsetzung mit Trimethylamin gehen die hydrophoben 2-Halogenethylester in die hydrophilen Cholinester 10 und 11 uber. Diese sind sehr stabil gegen Sauren. Sie konnen in wasrig…

Inside Cover: Antibody Induction Directed against the Tumor-Associated MUC4 Glycoprotein (ChemBioChem 6/2015)

N-Glycosylamide – Abspaltung der anomeren Schutzgruppe und Einsatz als Glycosyldonoren in der Glycosidsynthese

The electronic substituent influence on the thermally allowed electrocyclic interconversion cyclobutene/butadiene. A MNDO study

The effects of donor/acceptor substitution on the conrotatory cyclobutene/butadiene interconversion have not yet been experimentally studied. MNDO Synchronous Transit/MINIMAX calculations for all possible combinations of NH2/NH3 + 3 groups at the fissile single bond reveal very large substituent effects on the opening reactions and reverse cyclisations. Diamino(1b/2b), diammonio-(1c/2c) and amino-ammonio-substitutions (1d/2d) change the activation energy of the reference ring opening reaction (1a →2a) from 49.9 kcal/mol to 34.7, 29.8 and 26.0 kcal/mol, respectively. This rate enhancement parallels the monotone shift of the transition state pathcoordinate towards the cyclobutenes. Relative t…

Stereoselective Synthesis of α-Arylalkylamines by Glycosylation-induced Asymmetric Addition of Organometallic Compounds to Imines

Arylalkylamines are of interest as building blocks for the synthesis of biologically active compounds and as chiral ligands or chiral auxiliaries in stereoselective syntheses [1]. Their stereoselective synthesis has been achieved by enantioselective reduction of ketimines using chiral reagents [2], as for example Corey’s oxaborolidines [3], or proline-derived triacyloxyborohydrides [4]. Particularly efficient asymmetric syntheses of chiral arylalkylamines have been accomplished by Noyori et al. [5] through enantioselective catalysis of hydrogen transfer reactions using a chiral 1,2-diphenyl-ethylenediamine ruthenium catalyst. Enantioselective transferhydrogenationshave also been achieved us…

Towards the Development of Antitumor Vaccines: A Synthetic Conjugate of a Tumor-Associated MUC1 Glycopeptide Antigen and a Tetanus Toxin Epitope.

Proliferation of cytotoxic T-cells, a prerequisite for the development of antitumor vaccines, was induced by 1, but not by its partial structures A and B. The conjugate 1 containing a tumor-associated Sialyl-TN -MUC-1 glycopeptide antigen A and a T-cell epitope B of tetanus toxin was synthesized by fragment condensation on a solid phase.

Glycopeptide-functionalized gold nanoparticles for antibody induction against the tumor associated mucin-1 glycoprotein

We report the preparation of gold nanoparticle (AuNP)-based vaccine candidates against the tumor-associated form of the mucin-1 (MUC1) glycoprotein. Chimeric peptides, consisting of a glycopeptide sequence derived from MUC1 and the T-cell epitope P30 sequence were immobilized on PEGylated AuNPs and the ability to induce selective antibodies in vivo was investigated. After immunization, mice showed significant MHC-II mediated immune responses and their antisera recognized human MCF-7 breast cancer cells. Nanoparticles designed according to this report may become key players in the development of anticancer vaccines.

ChemInform Abstract: Carbohydrate Auxiliaries in Stereoselective Syntheses of Decahydroquinoline Alkaloids.

Using tetra-O-pivaloyl-β-D-galactopyranosylamine as the chiral auxiliary, both trans- and cis-annelated decahydroquinoline alkaloids can be synthesized stereoselectively. This methodology of asymmetric synthesis is based on the effect that both enantiomers of 2,6-disubstituted piperidin-4-ones are selectively and alternatively accessible using the auxiliary as the identical stereodifferentiating tool. In addition, the carbohydrate auxiliary controls the stereoselective protonation of enolates formed by conjugate addition of cuprates to N-galactosyl octahydroquinolin-4-ones. The syntheses of trans-4a-epi-pumiliotoxin C and cis-4a-epi-perhydro-219A illustrate this concept of asymmetric synthe…

A Novel Allylic Anchor for Solid-Phase Synthesis—Synthesis of Protected and Unprotected O-Glycosylated Mucin-Type Glycopeptides

ChemInform Abstract: Synthesis of Glycopeptides with Lewisa Antigen Side Chain and HIV Peptide T Sequence Using the Trichloroethoxycarbonyl/Allyl Ester Protecting Group Combination.

Synthetic Glycopeptides for the Development of Antitumour Vaccines

Glycoproteins of tumour cells often are aberrantly glycosylated. In its tumour-associated form, the epithelial mucin MUC1 carries short saccharide structures such as TN, T, sialyl-TN, and sialyl-T antigens. Due to the incomplete saccharide components, peptide epitopes of the backbone become accessible to the immune system. For the construction of synthetic antitumour vaccines, glycopeptides have been synthesized which contain tumour-associated saccharide antigens and peptide sequences from the tandem repeat portion of MUC1. In the synthesis of these glycopeptides, preformed glycosyl–amino acid building blocks are applied in solution- or solid-phase strategies. Examples are given for the use…

ChemInform Abstract: Carbohydrates as Chiral Auxiliaries

Synthesis of ?-fucosyl glycosides and disaccharides using 4-methoxybenzyl (Mpm) protected fucosyl donors

The 4-methoxybenzyl (Mpm) group removable by selective oxidation was applied as a nonneighbouring-group-active protection of fucose hydroxy functions in the stereoselective synthesis of α-fucosides of acceptors containing double bonds sensitive to hydrogenation. With this aim, the synthesis of the α-fucosyl chloride (4) carrying the acidsensitive Mpm protection was elaborated.

Stereoselektive c-glycosidsynthese durch titan-(iv)-katalysierte addition von silylenolethern an 2-acyloxy-3-keto-glycale

Abstract C-Glycosides are stereoselectively formed by the titan-(IV)-catalysed addition of silyl enolethers 2 to 2,4,6-tri-O-acyl-1-deoxy-D-erythro-hex-1-enopyran-3-uloses 1 followed by elimination of the 4-acyloxy substituent. Cyclohexenyl silylether 2a reacts with 2-acetoxy-3-keto-glycal derivative la forming only one product 3a . Thus, the reaction seems to be diastereospecific with respect to both new chiral centers of the product.

Leopold Horner (1911-2005): Nestor der präparativen organischen Chemie

Der 1,3‐Dithian‐2‐ylmethoxycarbonyl‐(Dmoc)‐Rest als Zweistufen‐Schutzgruppe für die Aminofunktion von Aminosäuren und Peptiden

Der 1,3-Dithian-2-ylmethoxycarbonyl-(Dmoc)-Rest (4) als Schutzgruppe fur die Aminofunktion ist gegen Basen und gegen Trifluoressigsaure stabil. Peptidsynthesen mit Dmoc-Aminosauren werden nach dem Mischanhydrid- und nach dem modifizierten Carbodiimid-Verfahren durchgefuhrt. Zur Abspaltung der Dmoc-Schutzgruppe wird diese mit Peressigsaure am Schwefel oxidiert (z. B. zu 13, 14). Die dabei gebildete CH-acide Form kann unter milden basischen Bedingungen von der blockierten Aminofunktion abgelost werden. The 1,3-Dithian-2-ylmethoxycarbonyl (Dmoc) Group as Two-Step Amino Protective Function in Peptide Chemistry The 1,3-dithian-2-ylmethoxycarbonyl (Dmoc) group (4) as amino protective function is …

Stereoselective Synthesis of Chiral Piperidine Derivatives Employing Arabinopyranosylamine as the Carbohydrate Auxiliary.

Stereoselective synthesis of 2-substituted dehydropiperidinones and their further transformation to variously disubstituted piperidine derivatives was achieved employing D-arabinopyranosylamine as the stereodifferentiating carbohydrate auxiliary. A domino Mannich–Michael reaction of 1-methoxy-3-(trimethylsiloxy)butadiene (Danishefsky's diene) with O-pivaloylated arbinosylaldimines furnished N-arabinosyl dehydropiperidinones in high diastereoselectivity. Subsequent conjugate cuprate addition gave 2,6-cis-substituted piperidinones, while enolate alkylation furnished 2,3-trans-substituted dehydropiperidinones. Electrophilic substitution at the enamine structure afforded 5-nitro- and 5-halogen…

Allylester als selektiv abspaltbare Carboxyschutzgruppen in der Peptid- undN-Glycopeptidsynthese

Allylester eignen sich als Schutz der Carboxyfunktion bei Peptid- und N-Glycopeptidsynthesen und konnen von Aminosauren einfach hergestellt werden. Unter den Bedingungen der Boc- und Z-Gruppenabspaltung im Sauren sind die Allylester bestandig. Durch Behandlung mit katalytischen Mengen von Tris(triphenylphosphan)rhodium(I)-chlorid in Ethanol/wasser (9:1) werden sie im neutralen bis schwach basischen Milieu schonend gespalten. Der N-terminale Schutz und die N-glycosidische Bindung bleiben dabei unverandert erhalten. Die dadurch mogliche selektive Deblockierung der α-Carboxyfunktion geschutzter N-glycosylierter Asparagin-Derivate 15 wird zur gezielten C-terminalen Kettenverlangerung zu N-Glyco…

ChemInform Abstract: Synthesis of Biologically Interesting Glycopeptides

A Synthetic MUC1 Anticancer Vaccine Containing Mannose Ligands for Targeting Macrophages and Dendritic Cells

A MUC1 anticancer vaccine equipped with covalently linked divalent mannose ligands was found to improve the antigen uptake and presentation by targeting mannose-receptor-positive macrophages and dendritic cells. It induced much stronger specific IgG immune responses in mice than the non-mannosylated reference vaccine. Mannose coupling also led to increased numbers of macrophages, dendritic cells, and CD4+ T cells in the local lymph organs. Comparison of di- and tetravalent mannose ligands revealed an increased binding of the tetravalent version, suggesting that higher valency improves binding to the mannose receptor. The mannose-coupled vaccine and the non-mannosylated reference vaccine ind…

Synthesis of a polymer-bound galactosylamine and its application as an immobilized chiral auxiliary in stereoselective syntheses of piperidine and amino acid derivatives.

A 2,3,4-tri-O-pivaloylated beta-D-galactopyranosyl azide bearing a hydroxy-functionalized spacer unit at the C-6 position of the galactose was synthesized and immobilized on the solid phase by using a polymer-bound chlorosilane. The azide was reduced to the corresponding galactopyranosylamine, which served as a versatile chiral auxiliary in highly diastereoselective Ugi four-component condensation reactions at ambient temperature. Fluoride-induced cleavage from the polymeric support furnished N-glycosylated N-acylated alpha-amino acid amides. The reaction of the immobilized galactosylamine with aldehydes gave rise to the corresponding aldimines, which underwent a domino Mannich-Michael cond…

ChemInform Abstract: Glycosylation-induced Asymmetric Synthesis: -Amino Acid Esters via Mannich Reactions.

D-Glucose as a Pentavalent Chiral Scaffold

A novel carbohydrate-based scaffold for combinatorial chemistry has been developed. This scaffold allows the selective attachment of five different side chains, giving rise to products of enormous structural diversity. As a demonstration of its usefulness, a series of model compounds has been prepared in high purity and yield by multistep parallel synthesis on a solid phase. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Synthetische Vakzine aus tumorassoziierten MUC1-Glycopeptid-Antigenen und Rinderserumalbumin

Leopold Horner (1911-2005): Nestor of Preparative Organic Chemistry

ChemInform Abstract: Ceric Ammonium Nitrate - A Versatile Oxidizing Reagent

Inside Back Cover: Microarray Analysis of Antibodies Induced with Synthetic Antitumor Vaccines: Specificity against Diverse Mucin Core Structures (Chem. Eur. J. 16/2017)

Chemoenzymatisch-chemische Synthese eines (2-3)-Sialyl-T-Threonin-Bausteins und dessen Einsatz in der Synthese der N-terminalen Sequenz von Leukämie-assoziiertem Leukosialin (CD43)

Synthetische Vakzine aus tumorassoziierten MUC1-Glycopeptidantigenen und einem T-Zellepitop für die Induzierung einer hochspezifischen humoralen Immunantwort

A fully synthetic vaccine consisting of a tumor-associated glycopeptide antigen and a T-cell epitope for the induction of a highly specific humoral immune response.

Synthesis of tumor-associated glycopeptide antigens for the development of tumor-selective vaccines

In contrast to normal cells, the glycoprotein profile on epithelial tumor cells is distinctly altered. Due to an incomplete formation of the glycan side-chains resulting from a premature sialylation, additional peptide epitopes become accessible to the immune system in mucin-type glycoproteins on tumor cells. These tumor-associated structure alterations constitute the basis for a selective immunological attack on cancer cells. For the construction of immunostimulating antigens, glycopeptide partial structures from the mucins MUC1 and MUC4 carrying the tumor-associated sialyl-T(N), alpha2,6-sialyl-T and alpha2,3-sialyl-T antigens have been synthesized. Employing different linkers such as the…

Synthesis of the Glycopeptide Partial Sequence A80-A84 of Human Fibroblast Interferon

The glycopentapeptide H-(GlcNAcβ1-)Asn-Glu-Thr-Ile-Val-OH (10) representing the partial sequence A80–A84 of human fibroblast interferon was synthesized using the newly developed allyl-ester protection of carboxy functions. The allyl esters, which are stable to acids and to bases, can be cleaved under very mild, neutral conditions using tris(triphenylphosphine)rhodium(I) chloride or tetrakis(triphenylphosphine)palladium(0) as a catalyst. This synthetic method opens up a preparative route to glycopeptide model structures of glycoproteins of high biological interest.

Advances in N ‐ and O ‐Glycopeptide Synthesis – A Tool to Study Glycosylation and Develop New Therapeutics

Die Reaktion von 2-Halogenethoxycarbonyl-Verbindungen mit tertiären Phosphanen

(2-Bromethoxycarbonyl)aminosauren 1, einschlieslich der Sarkosin-Derivate 13 und 15, reagieren mit Methyldiphenylphosphan zu den 2-Phosphonioethoxycarbonyl-Verbindungen, welche unter milden basischen Bedingungen zu den freien Aminoverbindungen gespalten werden. Die gleiche Schutzgruppenumwandlung gelingt an 2-Bromethoxycarbonyl-geschutzten Alkoholen 3. Phenolen 4 und den sekundaren Aminen 11 und 12 sowie an Aminosaure- und Peptid-(2-bromethylestern) nicht. In diesen Fallen bildet sich das Ethylen-1,2-bisphosphoniumsalz 6. Reaction of 2-Haloethoxycarbonyl Compounds with Tertiary Phosphanes (2-Bromoethoxycarbonyl)amino acids 1 including the sarcosine derivatives 13 and 15 react with methyldip…

Palladium-Catalyzed C—C Coupling Reactions in the Enantioselective Synthesis of 2,4-Disubstituted 4,5-Dehydropiperidines Using Galactosylamine as a Stereodifferentiating Auxiliary.

Abstract Stereoselective synthesis of enantiomerically pure 2,4-disubstituted piperidine derivatives, which are considered interesting pharmacophoric structures, was achieved starting with a tandem Mannich–Michael reaction sequence on O -pivaloylated N -galactosyl aldimines. Subsequent conversion of the thus formed 2-substituted dehydropiperidinones into the corresponding enol triflates was carried out by conjugate hydride addition and trapping the enolate with N , N -bis(trifluoromethanesulfonyl)aniline. Their Suzuki–Miyaura coupling with aryl and heteroaryl boronic acids was performed under conditions compatible with the carbohydrate structure, in particular, with the sensitive N -glycosi…

Preparation of Biomolecule Microstructures and Microarrays by Thiol-ene Photoimmobilization

A mild, fast and flexible method for photoimmobilization of biomolecules based on the light-initiated thiol-ene reaction has been developed. After investigation and optimization of various surface materials, surface chemistries and reaction parameters, microstructures and microarrays of biotin, oligonucleotides, peptides, and MUC1 tandem repeat glycopeptides were prepared with this photoimmobilization method. Furthermore, MUC1 tandem repeat glycopeptide microarrays were successfully used to probe antibodies in mouse serum obtained from vaccinated mice. Dimensions of biomolecule microstructures were shown to be freely controllable through photolithographic techniques, and features down to 5 …

Glycosyl azides as building blocks in convergent syntheses of oligomeric lactosamine and Lewisx saccharides

Abstract Oligosaccharides containing type 2 lactosamine repeating units, e.g. neo-lacto-octaose and trimeric Lewis x derivatives, are constructed using neo-lactosamine azide building blocks. The azido group provides a favorable protection of the anomeric position which is stable to versatile protecting group manipulations and glycosylation reactions. On the other hand, glycosyl azides can be converted into glycosyl fluorides via a 1,3-dipolar cycloaddition with di- tert -butyl-acetylenedicar☐ylate and subsequent treatment of the resulting N -glycosyl triazoles with hydrogen fluoride-pyridine complex. Activation of the lactosamine fluorides with Lewis acids affords the possibility to extend …

Synthese von geschützten Asparagin-Glycopeptiden durch N-terminale Peptidketten- Verlängerung. _ Teilsequenzen der Rinder-Desoxyribonuclease A und des luteinisierenden Hormons

N-[2-(Triphenylphosphonio)ethoxycarbonyl] -[Peoc-]asparaginsaure-benzylester (8h) und -tert-butylester (8i) werden mit 2-Acetamido-3,4,6-tri-O-acetyl-2-desoxy-β -D-glucopyranosylamin (2) zu den N4-Glycosylasparagin-Derivaten 19 verknupft. Aus diesen kann die Peoc-Gruppe selektiv mit Diethylamin/tert-Butylalkohol oder Morpholin/Methylendichlorid abgespalten werden, wobei in den entstandenen N4-Glycosylasparaginestern 22 alle anderen Schutzgruppen und die glycosidische Bindung erhalten bleiben. Durch Kondensation von 22 mit Peoc-Aminosauren 8 entstehen die voll geschutzten N4-Glycosylasparagin-Dipetide 24 und 30. Bei Kondensation der N2 deblockierten N4-Glycosylasparaginester 22 mit den Peoc-…

Synthetic MUC1 Antitumor Vaccine with Incorporated 2,3-Sialyl-T Carbohydrate Antigen Inducing Strong Immune Responses with Isotype Specificity

The endothelial glycoprotein MUC1 is known to underlie alterations in cancer by means of aberrant glycosylation accompanied by changes in morphology. The heavily shortened glycans induce a collapse of the peptide backbone and enable accessibility of the latter to immune cells, rendering it a tumor-associated antigen. Synthetic vaccines based on MUC1 tandem repeat motifs, comprising tumor-associated 2,3-sialyl-T antigen, conjugated to the immunostimulating tetanus toxoid, are reported herein. Immunization with these vaccines in a simple water/oil emulsion produced a strong immune response in mice to which stimulation with complete Freund's adjuvant (CFA) was not superior. In both cases, high…

Titelbild: Tumor-Associated MUC1 Tandem-Repeat Glycopeptide Microarrays to Evaluate Serum- and Monoclonal-Antibody Specificity (Angew. Chem. 44/2009)

Glycoside synthesis via electrophile-induced activation of N-allyl carbamates

Abstract O-Benzyl-, O-acyl-, N-acyl- and isopropylidene-protected glycosyl N-allylcarbamates, obtained from anomerically unprotected monosaccharides and allyl isocyanate, are activated by an electrophile-induced cyclisation and react with hydroxyl compounds to form the corresponding glycosides.

Carbohydrates as chiral templates: asymmetric ugi-synthesis of alpha-amino acids using galactosylamines as the chiral matrices

Abstract In the presence of Lewis acid catalysts O-acetyl- (1) and O-pivaloyl- (2) protected β-D-galactopyranosylamines react with aldehydes, isocyanides and carboxylic acids in Ugi-four-component-condensations to give the corresponding N-galactosyl-amino acid amide derivatives 3,5 in almost quantitative yields. Zinc chloride is the most effective Lewis acid catalyst. At 0°C or even at room temperature the (2R,β-D)-diastereomers of the amino acid derivatives 3,5 are formed with high diastereoselectivity. If the sterically more demanding O-pivaloyl galactosylamine 2 is used at -78°C to -25°C the stereoselectivity often exeeds 20:1 favouring the (2R,β-D) diastereomers 5. After one recrystalli…

Stereoselective Total Synthesis of the Diastereomeric Tricyclic Alkaloids Tetraponerine-7 and Tetraponerine-8 Using O-Pivalo­ylated d-Arabinopyranosylamine as the Common Auxiliary

Based on a diastereoselective domino Mannich–Michael reaction cascade of 2- N -[( S )-3-{(benzyloxycarbonyl)[4-( tert -butyldiphenylsiloxy)butyl]amino}octylidene]-2,3,4-tri- O -pivaloyl-α- d -arabinopyranosylamine with the Danishefsky diene, the major component of the neurotoxic venom of the New Guinean ant Tetraponera punctulata , tetraponerine-8, and its diastereomer tetraponerine-7 were synthesized in pure form. While the Mannich reaction of the arabinosyl imine of the required ( S )-configured β-aminoaldehyde gave the 2-substituted piperidinone precursor of tetraponerine-8 with excellent diastereoselectivity, the analogous Mannich reaction of the ( R )-configured β-aminoaldehyde afforde…

Der 2‐(Triphenylphosphonio)äthoxycarbonyl‐Rest als Schutzgruppe für die Aminofunktion in Aminosäuren und Peptiden

Die-2(Triphenylphosphonio)athoxycarbonyl-(Peoc)-Gruppe wird als neue Amino-Schutzgruppe fur Aminosauren und Peptide beschrieben. Sie ist unter milden, basischen Bedingungen abspaltbar und zeichnet sich andererseits durch besondere Bestandigkeit gegenuber starken Sauren aus. Mit der Peoc-Gruppe geschutzte Aminosauren, Peptide oder deren Derivate besitzen eine erhohte, teilweise sehr gute Loslichkeit in Wasser. Durch Variation des Phosphoniumzentrums kann die Basenempfindlichkeit der Peoc-Gruppe in weiten Bereichen verandert werden. The 2-(Triphenylphosphonio)ethoxycarbonyl Group as an Amino Protective Function in Peptide Chemistry A new amino protective function in amino acids and peptides, …

Synthesis of β-d-mannosides from β-d-glucosides via an intramolecular Sn2 reaction at C-2

Abstract The selective synthesis of β- d -mannosides was achieved by first synthesizing β- d -glucosides that carry a N -phenylcarbamoyl protecting group at O-3. These derivatives were transformed into the corresponding β- d -mannosides by intramolecular nucleophilic substitution with inversion of configuration at C-2, the O -triflyl group being the leaving group. Subsequent intramolecular attack of the neighboring carbamoyl group resulted in the formation of the 2,3-carbonate of the desired β d -mannoside.

Chemical and chemoenzymatic synthesis of glycopeptide selectin ligands containing sialyl Lewis X structures.

Stereoselective syntheses of piperidinones and their modification by organometallic coupling reactions

Dehydropiperidinones stereoselectively obtained from N-arabinosyl imines were iodinated at the enaminone structure. Knochel iodine-magnesium exchange afforded Grignard compounds of these piperidinone derivatives which reacted, either directly or after transmetalation to zinc or copper intermediates, with alkyl-, aryl- or acylhalides to give correspondingly substituted piperidinones. Stereoselective conjugate allyl cuprate addition to a thus obtained 5-allyl dehydropiperidinone and ring-closing metathesis of the product gave a hydroquinolinone containing three stereogenic centers.

ChemInform Abstract: The Allyl Ester as Carboxy-Protecting Group in the Stereoselective Construction of Neuraminic Acid Glycosides.

The application of the allyl-ester moiety as protecting principle for the carboxy group of N-acetylneuraminic acid is described. Peracetylated allyl neuraminate 2 is synthesized by reacting the caesium salt of the acid 1 with allyl bromide. Treatment of 2 with HCl in AcCl or with HF/pyridine gives the corresponding 2-chloro or 2-fluoro derivatives 3 and 4, respectively (Scheme 1). In the presence of Ag2CO3, the 2-chloro carbohydrate 3 reacts with di-O-isopropylidene-protected galactose 5 to give the 2–6 linked disaccharide with the α-D-anomer 6a predominating (α-D/β-D = 6:1; Scheme 2). Upon activation of the 2-fluoro derivative 4 with BF3 · Et2O, the β-D-anomer 6b is formed preferentially (…

[1] Neoglycoproteins from synthetic glycopeptides

Publisher Summary Saccharide side chains of glycoproteins influence the physicochemical properties of the biomacromolecules and their stability against proteolytic degradation. Saccharide side chains of glycoproteins also play important roles as ligands in biological recognition and in the organized distribution of these compounds within multicellular organisms. Carbohydrate-lectin interactions are important, for example, in viral infections and for the recruitment and invasion of leukocytes into injured tissues. Although in a number of processes carbohydrates were revealed to be decisive recognition labels, in other biological selections peptide sequences proved to be the recognized areas.…

Synthetic O-glycopeptides as model substrates for glycosyltransferases

Abstract A new approach to O-glycopeptides of the glucosamine type is described. N-Urethane protected, peracetylated glucosamine is converted into its 1-thio (1-bromo) derivative and used for glycosylation of a variety of protected serine or threonine derivatives as acceptors. The urethane group is easily exchanged for the natural N-acetyl moiety and O-deacetylation is achieved with hydrazine/methanol. The resulting O-GlcNAc derivatives are subjected to an enzymatic galactosylation procedure using β-1,4-galactosyltransferase (EC 2.4.1.22) to furnish O-glycopeptides of the neolactosamine type.

Reversal of asymmetric induction in stereoselective strecker synthesis on galactosyl amine as the chiral matrix

Abstract The reversal of the direction of asymmetric induction in Lewis acid catalyzed Strecker synthesis using the 2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosyl amine 1 is described. In isopropanol or tetrahydrofuran 1 had given ( R )-diastereomers of the corresponding α-amino nitriles preferably. However, in chloroform in the presence of heterogeneous zinc chloride the same auxiliary alternatively leads to an excess of the ( S )-diastereomers.

Carbohydrates as Polyfunctional Scaffolds in Combinatorial Synthesis

Carbohydrates are inexpensive, polyfunctional molecules which contain a high density of stereogenic centers. Taking advantage of these particular properties monosaccharides like glucose or mannose have been used for the construction of peptidomimetics which simulate recognition sites of somatostatin or RGD ligands of integrins. Due to their poly functionality, carbohydrates are considered promising scaffolds for combinatorial syntheses either in solution or on solid phase. The application of carbohydrate scaffolds, however, requires sets of orthogonally stable, selectively removable protecting groups, and the challenge in this combinatorial strategy increases with increasing number of hydro…

Eine vollsynthetische Vier-Komponenten-Antitumor-Vakzine mit einem MUC1-Glycopeptid und drei verschiedenen T-Helferzell- Epitopen

In einem neuen Konzept fur vollsynthetische Vakzine wird die Rolle von T-Helferzellen hervorgehoben. In einer solchen synthetischen Antitumor-Vakzine wurde ein zweifach glycosyliertes tumorassoziiertes MUC1-Glycopeptid als B-Zellepitop mit drei verschiedenen T-Helferzell-Epitopen durch Quadratsaurekonjugation zweier linearer (Glyco)Peptide kovalent verknupft. In Mausen loste die Impfung mit dieser Vier-Komponenten-Vakzine ohne zusatzliche Immunstimulantien etwa achtmal hohere MUC1-spezifische Antikorpertiter aus als eine Vakzine, die nur ein T-Helferzell-Epitop enthielt. Diese ermutigenden Ergebnisse zeigen, dass die gleichzeitige Aktivierung von T-Helferzellen verschiedener Spezifitat nutz…

Stereoselektive synthese von D-α-hydroxycarbonsäuren bzw. D-α-hydroxycarbonsäuren enthaltenden depsipeptiden aus L-aminosäuren

Abstract Depsipeptides containing D-α-hydroxy carboxylic acids are efficiently synthesized by the reactions of L-α-halo-carboxylic acid esters (obtained from L-amino acids) with caesium salts of N-protected amino acids.

Archaea Analogue Thiolipids for Tethered Bilayer Lipid Membranes on Ultrasmooth Gold Surfaces

The (2-Phenyl-2-trimethylsilyl)ethyl(PTMSEL) Linker—A Novel Linker for the Solid-Phase Synthesis of Protected Peptides and Glycopeptides Cleavable with Fluoride This work was supported by the Volkswagen-Stiftung and by the Fonds der Chemischen Industrie. M.W. is grateful for a fellowship of the Boehringer-Ingelheim-Stiftung.

3.13 Carbohydrate Derived Auxiliaries: Amino Sugar and Glycosylamine Auxiliaries

The stereodifferentiating potential of carbohydrate auxiliaries is illustrated by examples of oxazolidinones derived from amino sugars and aldimines of glycosylamines. Taking advantage of the bicyclic structure of amino sugar-derived oxazolidinones, reactions of their unsaturated or deprotonated N -acyl derivatives show an efficient exo - versus endo -differentiation. High diastereoselectivity is achieved in the syntheses of β -branched or α -substituted carboxylic acid derivatives. Imines of glycosylamines, in particular of 2,3,4,6-tetra- O -pivaloyl- β - d -galactopyranosylamine, are characterized by a conformation stabilized through the exo -anomeric effect and by their ability to coordi…

ChemInform Abstract: Glycosylation-Induced Asymmetric Synthesis of 1-Substituted Tetrahydroisoquinolines.

The Development of Vaccines from Synthetic Tumor‐Associated Mucin Glycopeptides and their Glycosylation‐Dependent Immune Response

Tumor-associated carbohydrate antigens are overexpressed as altered-self in most common epithelial cancers. Their glycosylation patterns differ from those of healthy cells, functioning as an ID for cancer cells. Scientists have been developing anti-cancer vaccines based on mucin glycopeptides, yet the interplay of delivery system, adjuvant and tumor associated MUC epitopes in the induced immune response is not well understood. The current state of the art suggests that the identity, abundancy and location of the glycans on the MUC backbone are all key parameters in the cellular and humoral response. This review shares lessons learned by us in over two decades of research in glycopeptide vac…

ChemInform Abstract: Synthesis of Glycopeptide Partial Structures of Virus Coat Glycoproteins

N-Glycosyl Amides: Removal of the Anomeric Protecting Group and Conversion into Glycosyl Donors.

Synthetische Vakzine aus tumorassoziierten Glycopeptidantigenen durch immunkompatible Verankerung über Thioether an Rinderserumalbumin

Amino Sugars and Glycosylamines as Tools in Stereoselective Synthesis

Synthesis of Glycopeptides Containing Carbohydrate and Peptide Recognition Motifs

ChemInform Abstract: O- and N-Glycopeptides: Synthesis of Selectively Deprotected Building Blocks

Stereoselective Synthesis of Quinolizidine Alkaloids: (–)-Lasubin II

Initially, lasubin II was synthesized diastereoselectively in racemic form [3]. Asymmetric syntheses of lasubin II were achieved based on stereoselective transformations of enantiomerically pure substrates [4] or, for example, via a diastereoselective aza-Diels-Alder reaction using a resolved chiral arylaldehyde tricarbonylchromium complex [5]. Recently, an enantioselectively catalyzed aza-Diels-Alder reaction [6] and a [2+2+2] cycloaddition reaction [7] were successfully used for the synthesis of enantiomerically pure lasubin II.

C-Glycosyl amino acids through hydroboration-cross-coupling of exo-glycals and their application in automated solid-phase synthesis.

O-Glycosylation is one of the most important post-translational modifications of proteins. The attachment of carbohydrates to the peptide backbone influences the conformation as well as the solubility of the conjugates and can even be essential for binding to specific ligands in cell-cell interactions or for active transport over membranes. This makes glycopeptides an interesting class of compounds for medical applications. To enhance the long-term availability of these molecules in vivo, the stabilization of the glycosidic bond between the amino acid residue and the carbohydrate is of interest. The described modular approach affords β-linked C-glycosyl amino acids by a sequence of Petasis …

ChemInform Abstract: Enantioselective Syntheses of 2-Alkyl-, 2,6-Dialkylpiperidines and Indolizidine Alkaloids Through Diastereoselective Mannich-Michael Reactions.

(p-Sulfomethyl)phenylalanine as a mimic of O-sulfatyl-tyrosine in synthetic partial sequences of P-Selectin glycoprotein ligand 1 (PSGL-1)

Abstract Fmoc- l -( p -sulfomethyl)phenylalanine, a bioisosteric mimic of acid-sensitive O -sulfatyl tyrosine, was synthesized from l -tyrosine according to a novel route. Partial sequences of the recognition site of P-Selectin glycoprotein ligand 1 (PSGL-1), which contain (sulfomethyl)phenylalanine were synthesized on solid-phase. By fragment condensation, a sialyl Lewis x peptide conjugate containing a (sulfomethyl)phenylalanine mimic of O -sulfatyl tyrosine was prepared without destruction of the acid-sensitive fucoside bond within the saccharide side chain. Compounds of this type are of interest as sufficiently acid-stable potential inhibitors of P-Selectin in inflammatory processes.

A new method of anomeric protection and activation based on the conversion of glycosyl azides into glycosyl fluorides

Glycosyl azides provide reliable anomeric protection stable to conditions for hydrolytic removal of ester groups, for reductive opening or release of acetalic diol protection, for the introduction of ether-type protection, and for glycosylation processes. The utility of this anomeric protection is further enhanced as glycosyl azides may be converted into glycosyl fluorides, which can be activated for glycosylation reactions. To this end, glycosyl azides have been subjected to 1,3-dipolar cycloaddition with di-tert-butyl acetylenedicarboxylate. On treatment with hydrogen fluoride-pyridine complex the N-glycosyl triazole derivatives directly give glycosyl fluorides.

Sulfatierte und nicht sulfatierte Glycopeptid-Erkennungsdomänen des P-Selektin-Glycoprotein-Liganden 1 und ihre Bindung an P- und E-Selektin

Totalsynthese via Blockglycosylierung und selektive chemische O-Sulfatierung von Tyrosinresten ergaben die Glycopeptid-Erkennungsregion A (X=SO3−) des P-Selektin-Glycoprotein-Liganden 1, in dem die terminale Sialinsaure der komplexen Hexasaccharid-Seitenkette durch (S)-Cyclohexylmilchsaure als Mimetikum ersetzt ist. In Bindungsassays zeigt die O-sulfatierte Form A hohe Affinitat zu P-Selektin, die nicht sulfatierte Form zu E-Selektin.

ChemInform Abstract: Stereoselective Synthesis of Bromopiperidinones and Their Conversion to Annulated Heterocycles.

N-Galactopyranosyland N-glucopyranosyl imines of aliphatic, aromatic and heteroaromatic aldehydes react with 1-methoxy-3-trimethylsilyloxy-1,3-butadiene in a domino Mannich-Michael reaction cascade to give 2-substituted 5,6-dehydro-piperidin-4-ones with high diastereoselectivity. Treatment of these cyclic enaminones with N-bromo-succinimide yields the corresponding 2-substituted 5-bromo-5,6-dehydropiperidinones which react with L-Selectride R © or methylcuprate to afford the saturated bromo-piperidinones with high diastereoselectivity. Condensation reactions of these products with thioamides afford thiazolopiperidines.

Emil Fischer—Unequalled Classicist, Master of Organic Chemistry Research, and Inspired Trailblazer of Biological Chemistry

MUC1-Glycopeptidkonjugate mit T-Zellepitopen von Tetanus-Toxoid als vollsynthetische Antitumor-Vakzine mit Eigenverstärkungseffekt

ChemInform Abstract: Chemical and Chemoenzymatic Synthesis of Glycopeptide Selectin Ligands Containing Sialyl Lewis X Structures

Stereoselektive Synthese enantiomerenreiner Nupharamin-Alkaloide aus dem Castoreum (Bibergeil)

Tierische Parfumalkaloide: Eine stereoselektive Mannich-Michael-Reaktion an N-Galactosylfurylaldimin zu 1 (Piv = Pivaloyl), anschliesende konjugierte Cuprataddition und stereoselektive Protonierung des gebildeten Enolats, alle kontrolliert vom Kohlenhydrat, ermoglichen erstmals die Totalsynthese des all-cis-Nupharamins 2 aus dem Castoreum. Enolatprotonierung nach Abspaltung des Kohlenhydrats fuhrt alternativ zum Epimer 3.

ChemInform Abstract: β-Branched α-Halo Carboxylic Acid Derivatives via Stereoselective 1,4-Addition of Dialkylaluminum Chlorides to α,. beta.-Unsaturated N-Acyloxazolidinones.

Synthetic (glyco-)peptides of the homophilic recognition domain of E-cadherin lead to increased E-cadherin mRNA synthesis and are inductors of cell differentiation in primary lung cancer cell lines

E-cadherin is one of the critical molecules involved in the metastatic process in many types of cancer. Once combined, E-cadherin exceeds the amount of membranous E-cadherin on the cellular surface by activation of intracellular signaling cascades. Studies on transformed keratinocytes of the HaCat cell line showed induction of differentiation by synthetical partial structures of the homophilic binding region of E-cadherin. The knowledge of effects in lung cancer cells is sparse. Therefore, the effects in primary lung cancer cell lines were investigated. Four primary lung cancer cell lines were incubated for 3, 6, 12, 15, 18, and 24h with synthetic partial structures (peptide and glycopeptid…

ChemInform Abstract: Carbohydrates as Chiral Templates: Asymmetric Ugi-Synthesis of α-Amino Acids Using Galactosylamines as the Chiral Matrices.

Synthesis of sialyl-Tn antigen. Regioselective sialylation of a galactosamine threonine conjugate unblocked in the carbohydrate portion

Abstract Regioselective and stereocontrolled formation of the sialyl-Tn antigen conjugate 6 was achieved by reacting the NeuNAc-2-xanthate 2 with the GalNAc threonine acceptor 5 bearing three hydroxy groups. Complete deprotection afforded the sialyl-Tn antigen structure 11 .

ChemInform Abstract: Synthesis of TN and T Antigen Glycopeptide Sequences of Tumor- Associated MUC-1 Using S-Pent-4-enyl Thioglycosides.

The synthesis of glycopeptides 34 and 38 with tumor associated TN and T antigen structure containing a partial sequence of the tandem repeat unit of the polymorphic epithelial mucin MUC-1 were achieved via fragment condensations. Electrophilic activation of S-pent-4-enyl thioglycosides was appiled for the construction of O-glycosyl amino and saccharide building blocks.

Selektive enzymatische Schutzgruppenabspaltungen: Der n-Heptylester als Carboxylschutzgruppe in der Peptidsynthese

Selective Enzymatic Removal of Protecting Groups: n-Heptyl Esters as Carboxy Protecting Functions in Peptide Synthesis Amino acid heptyl (Hep) esters are accessible as generally crystalline hydro tosylates 3 from the amino acids by azeotropic esterification with 1-heptanol in high yields. They can be condensed with Z-, Boc-, and Aloc-protected amino acids to give the dipeptides 7–9 in the presence of 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). From the fully protected dipeptides the N-terminal protecting groups are cleaved by chemical methods without affecting the Hep esters. On the other hand, the heptyl esters can be hydrolyzed under mild conditions (pH = 7.0, 37°C) and with hi…

Fully synthetic self-adjuvanting thioether-conjugated glycopeptide-lipopeptide antitumor vaccines for the induction of complement-dependent cytotoxicity against tumor cells.

Glycopeptides of tumor-associated mucin MUC1 are promising target structures for the development of antitumor vaccines. Because these endogenous structures were weakly immunogenic, they were coupled to immune-response-stimulating T-cell epitopes and the Pam(3)Cys lipopeptide to induce strong immune responses in mice. A new thioether-ligation method for the synthesis of two- and three-component vaccines that contain MUC1 glycopeptides as the B-cell epitopes, a T-cell epitope peptide, and the Pam(3)CSK(4) lipopeptide is described. The resulting fully synthetic vaccines were used for the vaccination of mice, either in a liposome with Freund's adjuvant or in aqueous PBS buffer. The three-compon…

Fully synthetic vaccines consisting of tumor-associated MUC1 glycopeptides and a lipopeptide ligand of the Toll-like receptor 2.

ChemInform Abstract: Desymmetrization Reactions on 4-Pyridone Using Carbohydrate Templates.

ChemInform Abstract: Auxiliary-Controlled Stereoselective Enolate Protonation: Enantioselective Synthesis of cis and trans Annulated Decahydroquinoline Alkaloids.

Abstract The diastereoselective synthesis of the octahydroquinoline enone precursor of pumiliotoxin C is achieved via tandem Mannich-Michael reaction on N-galactosyl imines. Conjugate cuprate addition to the bicyclic enone stereoselectively forms the trans annulated 4a- epi -pumiliotoxin C skeleton in the presence of the carbohydrate auxiliary, and the cis annulated pumiliotoxin C skeleton in its absence.

Spacer-separated sialyl LewisX cyclopeptide conjugates as potential E-selectin ligands.

Completely protected sialyl LewisX azide was synthesized from a neolactosamine azide precursor carrying a 3-O-allyloxycarbonyl group as the temporary protecting group. After its Pd(0)-catalyzed deprotection and stereoselective alpha-fucosylation, the obtained LewisX azide was subjected to O-deacetylation in the galactose unit and subsequent regio- and stereoselective sialylation. Reduction of the anomeric azido group afforded the sialyl LewisX amine building block. Two molecules of this tetrasaccharide ligand were conjugated to a preformed cyclooctapeptide containing two equidistant l-asparagine units equipped with carboxy-terminated tetraethyleneglycol side chains to give, after deprotecti…

Stereoselective synthesis of benzomorphan derivatives with perpivaloylated galactose as the chiral auxiliary.

ChemInform Abstract: Recent Advances in the Synthesis of Glycopeptides

ChemInform Abstract: Reversal of Asymmetric Induction in Stereoselective Strecker Synthesis on Galactosyl Amine as the Chiral Matrix.

Abstract The reversal of the direction of asymmetric induction in Lewis acid catalyzed Strecker synthesis using the 2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosyl amine 1 is described. In isopropanol or tetrahydrofuran 1 had given ( R )-diastereomers of the corresponding α-amino nitriles preferably. However, in chloroform in the presence of heterogeneous zinc chloride the same auxiliary alternatively leads to an excess of the ( S )-diastereomers.

The development of synthetic antitumour vaccines from mucin glycopeptide antigens.

Based on important cell-biological and biochemical results concerning the structural difference between membrane glycoproteins of normal epithelial cells and epithelial tumour cells, tumour-associated glycopeptide antigens have been chemically synthesised and structurally confirmed. Glycopeptide structures of the tandem repeat sequence of mucin MUC1 of epithelial tumour cells constitute the most promising tumour-associated antigens. In order to generate a sufficient immunogenicity of these endogenous structures, usually tolerated by the immune system, these synthetic glycopeptide antigens were conjugated to immune stimulating components: in fully synthetic two-component vaccines either with…

ChemInform Abstract: Comparative Lipase-Catalyzed Hydrolysis of Ethylene Glycol Derived Esters. The 2-Methoxyethyl Ester as a Protective Group in Peptide and Glycopeptide Synthesis.

Stereoselective Conjugate Addition of Mixed Organoaluminum Reagents to ?,?-Unsaturated N-Acyloxazolidinones Derived from Carbohydrates.

The stereoselective synthesis of β-branched carboxylic acid derivatives was accomplished by conjugate addition of mixed organoaluminum reagents to chiral α,β-unsaturated N-acyloxazolidinones. Mixed organoaluminum reagentswere generated in situ by transmetalation of Grignard or organolithium compounds with methylaluminum dichloride. Efficient stereocontrol was achieved using different bicyclic glycosamine-derived oxazolidinones, yielding alternatively (R)- or (S)-configured β-branched carboxylic acid derivatives.

Totalsynthese der Glycopeptid-Erkennungsregion des P-Selektin- Glycoprotein-Liganden 1

ChemInform Abstract: Carbohydrates as Chiral Templates: Diastereoselective Ugi Synthesis of (S)-Amino Acids Using O-Acylated D-Arabinopyranosylamine as the Auxiliary.

Abstract Enantiomerically pure (S)-amino acids are synthesized via a highly diastereoselective Ugi reaction using 2,3,4-tri-O-pivaloyl-α-D-arabinopyranosylamine as the chiral template.

Carbohydrate Scaffolds for Combinatorial Syntheses That Allow Selective Deprotection of All Four Positions Independent of the Sequence

Synthetische Antitumorvakzine aus Tetanus-Toxoid-Konjugaten von MUC1-Glycopeptiden mit Thomsen-Friedenreich-Antigen und dessen fluorsubstituiertem Analogon

Protective Groups in Organic Synthesis. 2. Auflage. Herausgegeben vonT. W. Greene undP. G. M. Wuts. Wiley, Chichester. 1991. XVI, 473 S., geb. £47.50. — ISBN 0-471-62301-6

Synthetic Glycopeptides from the Mucin Family as Potential Tools in Cancer Immunotherapy

Compared to glycoproteins of healthy cells, glycoproteins of tumor cells are often aberrantly glycosylated. Thus, glycopeptide fragments of surface glycoproteins of tumor cells are of interest as tumor-associated antigens for the distinction between normal and tumor cells. Cancer immunotherapy directed at selectively targeting these tumor-associated glycoprotein structure alterations--deficient glycosylation and, thus, exposure of peptide epitopes which are masked in normal cells--is considered a promising approach for the treatment of cancer. For this purpose, glycoproteins from the mucin family are of particular interest. Mucins belong to a class of heavily O-glycosylated, high-molecular …

Antitumor Vaccines Based on Synthetic Mucin Glycopeptides

The interest in tumor-associated glycoconjugate antigens was particularly initiated by Springer, who published in 1984 that glycoproteins on the outer cell-membrane of epithelial tumor cells have an altered glycosylation consisting of the Thomsen-Friedenreich (T-) antigen and its precursor the TN-antigen structure (Springer 1984). He and his coworkers also had found that monoclonal antibodies induced with glycoproteins from tumor cell membranes showed cross-reactivity to desialylated glycophorin A. It was concluded from these observations that the T-and TN-glycoproteins on the epithelial tumor cells must be structurally related to asialoglycophorin A (Springer et al. 1983) (Fig. 11.1a). Gly…

ChemInform Abstract: Tumor-Associated Glycopeptide Antigens and Their Modification in Anticancer Vaccines

Immunization with a Synthetic Human MUC1 Glycopeptide Vaccine against Tumor-Associated MUC1 Breaks Tolerance in Human MUC1 Transgenic Mice.

Breaking tolerance is crucial for effective tumor immunotherapy. We showed that vaccines containing tumor-associated human MUC1 glycopeptides induce strong humoral antitumor responses in mice. The question remained whether such vaccines work in humans, in systems where huMUC1 is a self-antigen. To clarify the question, mice transgenic in expressing huMUC1, mimicking the self-tolerant environment, and wild-type mice were vaccinated with a synthetic vaccine. This vaccine comprised STn and Tn antigens bound to a MUC1 tandem repeat peptide coupled to tetanus toxoid. The vaccine induced strong immune responses in wild-type and huMUC1-transgenic mice without auto-aggressive side effects. All anti…

Stereoselective Synthesis of Enantiomerically Pure Nupharamine Alkaloids from Castoreum

An animalic note: The first total synthesis of the all-cis nupharamine 2, an alkaloid from beaver castoreum, is based on the stereoselective domino Mannich-Michael reaction of N-galactosylfurylaldimine to give 1 (Piv = pivaloyl), subsequent conjugate cuprate addition, and stereoselective protonation of the enolate. These reactions are all controlled by the carbohydrate. Protonation of the enolate after cleavage of the auxiliary leads to epimer 3.

Synthesis and Biological Evaluation of a Multiantigenic Tn/TF-Containing Glycopeptide Mimic of the Tumor-Related MUC1 Glycoprotein

Synthetic multivalent glycopeptide-lipopeptide antitumor vaccines: impact of the cluster effect on the killing of tumor cells.

Multivalent synthetic vaccines were obtained by solid-phase synthesis of tumor-associated MUC1 glycopeptide antigens and their coupling to a Pam3 Cys lipopeptide through click reactions. These vaccines elicited immune responses in mice without the use of any external adjuvant. The vaccine containing four copies of a MUC1 sialyl-TN antigen showed a significant cluster effect. It induced in mice prevailing IgG2a antibodies, which bind to MCF-7 breast tumor cells and initiate the killing of these tumor cells by activation of the complement-dependent cytotoxicity complex.

Biomimetic synthesis of the tumor-associated (2,3)-sialyl-T antigen and its incorporation into glycopeptide antigens from the mucins MUC1 and MUC4.

Glycoproteins on epithelial tumor cells often exhibit aberrant glycosylation profiles. The incomplete formation of the glycan side chains resulting from a down-regulated glucosamine transfer and a premature sialylation results in additional peptide epitopes, which become accessible to the immune system in mucin-type glycoproteins. These cancer-specific structure alterations are considered to be a promising basis for selective immunological attack on tumor cells. Among the tumor-associated saccharide antigens, the (2,3)-sialyl-T antigen has been identified as the most abundant glycan, found in several different carcinoma cell lines. According to a linear biomimetic strategy, the (2,3)-sialyl…

Synthesis of Biologically Interesting Glycopeptides.

哺乳動物に見い出される大部分のタンパクは糖タンパクである。それらの糖鎖は生物学的選択性、特に膜上での認識過程に重要な働きをしている。全ての糖タンパクは糖鎖とペプチドとの間にグリコシド結合を有している。それゆえに糖ペプチドの化学合成は、立体特異的なグリコシド結合の生成と、グリコシド結合に影響を与えない選択的な保護が要求される。ベンジルグループとそれらの水素添加による脱離法は、これらの要求を満たす。しかしながら、これらの保護法を用いる方法は糖質の水酸基のブロックを必要とするので、ペプチド部分の官能基は撰択的に脱離可能でそしてベンジル基に対して orthogonal に安定なグループで保護されなければならない。この意味においてフルオレニルメトキシカルボニル (Fmoc) 基と、弱塩基、モルフォリンによる脱離と、パラジウム (0) 触媒によるアリル基転移によって脱離可能なアリルオキシカルボニル (Aloc) 基は、糖ペプチド化学においてアミノ基の保護基として有用である事が明らかにされた。同様なパラジウム (0) の化学を用いるアリルエステルと、酸により除去可能なtert-ブチルエステルはカルボキシル基の保護に有用である事が分かった。ベンジル基とアリルエステル (HYCRAM™) を用いる糖ペプチドの固相合成におけるアンカーシステムとして有効に利用される事が示された。

ChemInform Abstract: Glycopeptides as Signal Molecules. A Synthetic Challenge on Its Way Towards Interdisciplinary Application

Emil Fischer — Unequalled Classicist, Master of Organic Chemistry Research, and Inspired Trailblazer of Biological Chemistry

Induction of Cell Differentiation in Transformed Keratinocytes by Synthetic (Glyco)peptides from the Homophilic Recognition Domain of E-Cadherin

Reduced Breast Tumor Growth after Immunization with a Tumor-Restricted MUC1 Glycopeptide Conjugated to Tetanus Toxoid.

Abstract Preventive vaccination against tumor-associated endogenous antigens is considered to be an attractive strategy for the induction of a curative immune response concomitant with a long-lasting immunologic memory. The mucin MUC1 is a promising tumor antigen, as its tumor-associated form differs from the glycoprotein form expressed on healthy cells. Due to aberrant glycosylation in tumor cells, the specific peptide epitopes in its backbone are accessible and can be bound by antibodies induced by vaccination. Breast cancer patients develop per se only low levels of T cells and antibodies recognizing tumor-associated MUC1, and clinical trials with tumor-associated MUC1 yielded unsatisfac…

Synthese vonN-Glycopeptid-Partialstrukturen der Verknüpfungsregion sowohl der Transmembran-Neuraminidase eines Influenza-Virus als auch des Faktors B des menschlichen Komplementsystems

Mit Hilfe der Schutzgruppenkombination Boc-Gruppe/Allylester und Acetylschutz im Kohlenhydratteil wurden die geschutzten N-Chitobiosyl-asparagin-peptide 12a und 14 synthetisiert, die der Verknupfungsregion des Faktors B des menschlichen Komplementsystems und einer Influenza-Virus-Neuraminidase entsprechen. Aus dem vollgeschutzten Glycopeptid 12a liesen sich der Allylester und die Acetylschutzgruppen simultan mit methanolischem Ammoniak und die Boc-Schutzgruppe mit wasserfreier Trifluoressigsaure ohne storende Nebenreaktionen entfernen. Versuche, die Boc-Gruppe aus an den Kohlenhydrat-Hydroxyfunktionen deblockierten Glycopeptiden abzulosen, fuhrten uberwiegend zur Spaltung der O-glycosidisch…

Synthesis of glycopeptides and neoglycoproteins containing the fucosylated linkage region of N-glycoproteins.

Abstract N-Glycoproteins fucosylated in the core region occur in tumor membranes and virus envelopes. Partial structures of such N-glycoproteins containing fucosylated chitobiosyl asparagine conjugates were synthesized using the allyloxycarbonyl (Aloc) and the tert-butyl ester protecting groups in the peptide portion. As the α-fucosidic bond of the conjugates revealed to be very sensitive to acids when carrying ether-type protecting groups, a method for exchanging the protecting groups of the fucose portion of saccharides was developed. Conjugates containing O-acetyl protected fucose proved to be stable against acids used in glycopeptide syntheses. These methods were applied in the synthesi…

Der 2‐(Methylthio)äthoxycarbonyl‐Rest als Zweistufen‐Schutzgruppe für die Aminofunktion in Aminosäuren und Peptiden

Die 2-(Methylthio)athoxycarbonyl(Mtc)-Gruppe wird als neue Amino-Schutzgruppe fur Aminosauren und Peptide beschrieben. Zu ihrer Einfuhrung eignen sich sowohl das Mtc-p-Nitrophenolat als auch das Mtc-Phenolat. Die Mtc-Schutzgruppe ist in Masig alkalischem oder saurem Medium bestandig. Durch zwei unterschiedliche und einfache Reaktionen kann die unempfindliche Mtc-Gruppe in gegenuber Basen sehr empfindliche Schutzgruppen umgewandelt werden und wird deshalb als Zweistufen-Schutzgruppe bezeichnet. Die Methylierung zur 2-(Dimethylsulfonio)-athoxycarbonyl-Schutzgruppe verlauft nicht immer befriedigend, erbringt jedoch oft N-geschutzte Verbindungen, die sehr gut in Wasser loslich sind. Nahezu quan…

Enzymatische hydrolyse hydrophiler ester durch lipasen - eine milde carboxydeblockierung von peptiden und glycopeptiden

Abstract The markedly hydrophilic 2-(N-morpholino)ethyl (MoEt) esters of protected peptides and glycopeptides are selectively and efficiently cleaved by lipases in water/acetone (10:1) at pH 7.

Water-Soluble Polymers Coupled with Glycopeptide Antigens and T-Cell Epitopes as Potential Antitumor Vaccines

Highly decorated: Tumor-associated MUC1 glycopeptide and tetanus toxoid T-cell epitope P2 can be attached to water-soluble poly(N-(2-hydroxypropyl)methacrylamide) carriers by orthogonal ligation techniques. Fully synthetic vaccine A with additional nanostructure-promoting domains induced antibodies that exhibit high affinity to tumor cells.

ChemInform Abstract: Glycopeptide Synthesis Using O-Pentafluorophenyluronium Salts as Novel Condensing Reagents.

Pentafluorophenyluronium salts and related coupling reagents for the solid-phase synthesis of peptides and glycopeptides have been developed and employed in the synthesis of a glycopeptide sequence from the cell adhesion molecule E-CAD 1.

Stereospecific CC-bond formation with rabbit muscle aldolase - A chemoenzymatic synthesis of (+)-exo-brevicomin

Abstract (+)-(1S,5R,7S)-Exo-brevicomin 9, a sex pheromone of the western pine bark beetle, is synthesized using an aldol reaction catalyzed by fructose-1,6-diphosphate aldolase (EC 4.1.2.13) from rabbit muscle as the key step by which the absolute configuration of the target is established.

ChemInform Abstract: The Development of Synthetic Antitumor Vaccines from Mucin Glycopeptide Antigens

Ein durch eine synthetische Glycopeptid-Vakzine induzierter monoklonaler Antiköper unterscheidet normale von malignen Brustzellen und ermöglicht die Diagnose von humanen Pankreaskarzinomen

Highly regioselective synthesis of a 3-O-sulfonated arabino Lewisa asparagine building block suitable for glycopeptide synthesis

Using the stannylene method, the trisaccharide 2-acetamido-3-O-[6-O-benzyl-beta-D-galactopyranosyl]-4-O-[2,3,4-tri-O-benzyl-beta-D-arabinopyranosyl]-6-O-benzyl-2-deoxy-beta-D-glucopyranosyl azide was regioselectively sulfonated and, after reduction of the anomeric azide, coupled to Fmoc alpha-allyl aspartate. After Pd(0)-catalyzed deallylation, the sulfatyl Lewis(a) asparagine building block was obtained, suitable for solid-phase glycopeptide synthesis applying the fluoride labile PTMSEL linker system.

HYCRON, an Allylic Anchor for High-Efficiency Solid Phase Synthesis of Protected Peptides and Glycopeptides

The recently developed allylic HYCRON anchor1 exhibits excellent properties for the solid phase synthesis of protected peptides and glycopeptides. Model reactions with analogous low molecular weight compounds assessed the acid- and base-stability of the polar and flexible HYCRON linkage. The new anchor is available in a two-step synthesis and allows the use of both the Boc- and the Fmoc-strategy, which can even be combined within one synthesis. Protected glycopeptides are released under almost neutral conditions, taking advantage of the Pd(0)-catalyzed allyl transfer to a weakly basic nucleophile such as N-methylaniline. The highly efficient synthesis of O-αGalNAc(TN)-peptides of the MUC-1 …

ChemInform Abstract: Fluorenylmethoxycarbonyl-N-methylamino Acids Synthesized in a Flow Tube-in-Tube Reactor with a Liquid-Liquid Semipermeable Membrane.

Synthetische Inhibitoren der Zelladhäsion: ein Glycopeptid aus dem E-Selektin-Liganden 1 (ESL-1) mit Arabino-Sialyl-Lewisx-Struktur

Synthetic vaccines consisting of tumor-associated MUC1 glycopeptide antigens and a T-cell epitope for the induction of a highly specific humoral immune response.

PHOSPHORORGANISCHE VERBINDUNGEN 871SYNTHESE UND REAKTIONEN CYCLISCHER PHOSPHONIUMSALZE MIT ZWEI PHOSPHORATOMEN IN SIEBEN-, ACHT-, NEUN-, ZEHN- UND ELFRINGEN SOWIE MIT VIER PHOSPHORATOMEN IN SECHZEHN-, ACHTZEHN- UND ZWANZIGRINGEN

Abstract Die im Titel gennanten cyclischen Phosphoniumsalze mit zwei und vier Phosphoratomen als Ringglieder konnen nach zwei Verfahren erhalten werden: 1. Umsetzung eines α,ω-Alkanbisphosphins A mit einen α,ω-Dihalogenalkan B, und 2. Verknupfung eines α,ω-dihalogenierten Bisphosphoniumsalzes der Struktur E mit einem Bisphosphin A. Die Anwendung des Verdunnungsprinzips fuhrt zu keiner Verbesserung der Ausbeuten an Cyclophosphoniumsalzen. Durch Einwirkung von LiAlH4 auf die Cyclophosphoniumsalze mit Benzyl-Liganden erhalt man in guten Ausbeuten die diesen entsprechenden Cyclophosphine. Mit Alkalihydroxyd entstehen aus den Cyclophosphoniumsalzen unter Abspaltung von Toluol die erwarteten Cycl…

ChemInform Abstract: Synthesis of Tumor-Associated Glycopeptide Antigens

Carbohydrates and peptides linked together in glycoproteins constitute important components of the molecular communication between cells in multicellular organisms. Cell morphogenesis and tumorigenesis are accompanied by changes in the glycoprotein profiles of the outer cell membranes. Glycopeptide fragments of glycoproteins that have altered structures in tumor cells are of interest as tumor-associated antigens for the distinction between normal cells and tumor cells. In contrast to glycoproteins isolated from biological sources, synthetic glycopeptides are obtained in pure form and exactly specified structures. The methods developed for the synthesis of glycopeptides with tumor-associated…

Synthetische (Glyco)peptide aus der homophilen Erkennungsregion von E-Cadherin zur Induktion von Zelldifferenzierung in transformierten Keratinocyten

Synthesis of tumor-associated glycopeptide antigens.

Carbohydrates and peptides linked together in glycoproteins constitute important components of the molecular communication between cells in multicellular organisms. Cell morphogenesis and tumorigenesis are accompanied by changes in the glycoprotein profiles of the outer cell membranes. Glycopeptide fragments of glycoproteins that have altered structures in tumor cells are of interest as tumor-associated antigens for the distinction between normal cells and tumor cells. In contrast to glycoproteins isolated from biological sources, synthetic glycopeptides are obtained in pure form and exactly specified structures. The methods developed for the synthesis of glycopeptides with tumor-associated…

ChemInform Abstract: Synthetic Inhibitors of Cell Adhesion: A Glycopeptide from E-Selectin Ligand 1 (ESL-1) with the Arabino Sialyl Lewisx Structure.

Buchbesprechung: Glycoscience Chemistry and Chemical Biology. Band I–III. Herausgegeben von Betram Fraser-Reid, Kuniaki Tatsuta und Joachim Thiem

Enhanced immunogenicity of multivalent MUC1 glycopeptide antitumour vaccines based on hyperbranched polymers.

Enhancing the immunogenicity of an antitumour vaccine still poses a major challenge. It depends upon the selected antigen and the mode of its presentation. We here describe a fully synthetic antitumour vaccine, which addresses both aspects. For the antigen, a tumour-associated MUC1 glycopeptide as B-cell epitope was synthesised and linked to the immunostimulating T-cell epitope P2 derived from tetanus toxoid. The MUC1-P2 conjugate is presented multivalently on a hyperbranched polyglycerol to the immune system. In comparison to a related vaccine of lower multivalency, this vaccine exposing more antigen structures on the hyperbranched polymer induced significantly stronger immune responses in…

Enantioselective Strecker Reaction Catalyzed by an Organocatalyst Lacking a Hydrogen-Bond-Donor Function

ChemInform Abstract: Stereoselective Synthesis of 3-Substituted and 3,4-Disubstituted Piperidine and Piperidin-2-one Derivatives.

The reaction of various electrophiles with N-galactosylpyridinone derivatives proceeds with moderate to high diastereoselectivity to afford the target compounds.

Book Review: Glycoscience Chemistry and Chemical Biology. Vols. I–III. Edited by Bertram Fraser-Reid, Kuniaki Tatsuta and Joachim Thiem

Multiple Sialyl-Lewisx-N-Glycopeptide: Effektive Liganden für E-Selectin

Cover Picture: Synthesis and Biological Evaluation of a Multiantigenic Tn/TF-Containing Glycopeptide Mimic of the Tumor-Related MUC1 Glycoprotein (ChemMedChem 9/2006)

Chemoenzymatische „Chiral-Pool”-Synthese von (+)-exo-Brevicomin aus Kohlenhydraten mit Fructose-1,6-diphosphat-Aldolase

Chemoenzymatic “Chiral-Pool” Synthesis of (+)-exo-Brevicomin from Carbohydrates Using Fructose 1,6-Diphosphate Aldolase Fructose-1,6-diphosphate aldolase (EC 4.1.2.13) catalyzes the stereospecific aldol reaction between 1,3-dihydroxyacetone phosphate (4) and 5-oxohexanal (3) or its 5-dithiane-protected analog 8. The products of the aldol reactions are dephosphorylated with acid phosphatase (EC 3.1.3.2). Whereas the aldol adduct of 3 cyclizes spontaneously to give the bicyclic brevicomin precursor 3, the adduct of 8 first has to be deprotected with sulfuryl chloride and wet silica gel. The resulting bicyclic α-hydroxy ketone 3 is reduced with LiAlH4 to form the 1,2-diol 14 which is then deox…

ChemInform Abstract: Synthesis of α-Fucosyl Glycosides and Disaccharides Using 4- Methoxybenzyl (Mpm) Protected Fucosyl Donors.

The 4-methoxybenzyl (Mpm) group removable by selective oxidation was applied as a nonneighbouring-group-active protection of fucose hydroxy functions in the stereoselective synthesis of α-fucosides of acceptors containing double bonds sensitive to hydrogenation. With this aim, the synthesis of the α-fucosyl chloride (4) carrying the acidsensitive Mpm protection was elaborated.

Synthese von geschützten Serin-Glycopeptiden durch N-terminale Peptidketten-Verlängerung

O-(2-Acetamido-3,4,6-tri-O-acetyl-2- desoxy-β-D-glucopyranosyl)serin-methylester (4) wird mit den 2-Phosphonioethoxycarbonyl-(Peoc-)Aminosauren 5 zu den voll geschutzten O-Glycodipeptiden 6 umgesetzt. Aus den Verbindungen 6 wird die Peoc-Gruppe mit Morpholin/Methylendichlorid vollstandig und selektiv zu 7 abgespalten, wobei weder β-Eliminierung des Kohlenhydratteils noch Esteraminolyse zu beobachten ist. Die N-deblockierten Glycodipeptide 7 reagieren mit den Peoc-Aminosauren 5 zu den geschutzten O-Glycotripeptiden 8. Mit Z-Asparagin (9) kann der Leucyl-(O-glycosyl)serinester 7a zum geschutzten Glycotripeptid 10 verknupft werden, das die fur N-Glycoproteine typische Sequenz -Asn-X-Ser- entha…

Zur Entwicklung von Antitumor-Impfstoffen: ein synthetisches Konjugat aus tumorassoziiertem MUC1-Glycopeptidantigen und dem Tetanustoxin-Epitop

Chemoenzymatic-Chemical Synthesis of a (2-3)-Sialyl T Threonine Building Block and Its Application to the Synthesis of the N-Terminal Sequence of Leukemia-Associated Leukosialin (CD 43).

Protection of all functional groups of the carbohydrate portion of the chemoenzymatically synthesized sialyl T threonine ester 1 (R=R1 =H, R2 =tBu, Fmoc=9-fluorenylmethoxycarbonyl) and subsequent acidolysis of the tert-butyl ester afforded the building block 2 (R=Ac, R1 =Me, R2 =H). The latter is a useful tool in the solid-phase synthesis of the N-terminal sequence 3 of the leukemia-associated leukosialin.

Synthetic vaccines consisting of tumor-associated MUC1 glycopeptide antigens and bovine serum albumin.

Microarray analysis of antibodies induced with synthetic antitumor vaccines : specificity against diverse mucin core structures

Glycoprotein research is pivotal for vaccine development and biomarker discovery. Many successful methodologies for reliably increasing the antigenicity toward tumor-associated glycopeptide structures have been reported. Deeper insights into the quality and specificity of the raised polyclonal, humoral reactions are often not addressed, despite the fact that an immunological memory, which produces antibodies with cross-reactivity to epitopes exposed on healthy cells, may cause autoimmune diseases. In the current work, three MUC1 antitumor vaccine candidates conjugated with different immune stimulants are evaluated immunologically. For assessment of the influence of the immune stimulant on a…

Synthesis of Deoxy Sialyl Lewisx Analogues, Potential Selectin Antagonists

Variation des Glycosylierungsmusters von Vakzinen aus MUC1- Glycopeptiden und Rinderserumalbumin und der Einfluss auf die Immunreaktion

Chemical and enzymatic synthesis of glycopeptides

Progress recently made in the synthesis of biologically relevant N- and O-glycopeptides is illustrated by examples. In this context, developments in the preparation of complex saccharide side chains and in the subsequent coupling to peptide portions is described. Special emphasis is given to the synthesis of Lewis antigen-type structures. Furthermore, modern methods in solid phase peptide syntheses utilizing glycosylated building blocks are presented. Recent advances in glycopeptide syntheses employing enzymatic methods in deprotection steps as well as in peptide/saccharide chain elongation are reported.

ChemInform Abstract: Mixed Dialkylaluminum Chlorides and Mixed Trimethylorganoaluminates in Chemoselective 1,4-Addition Reactions to Alkylidene Malonic Acid Diethyl Ester.

Mixed alkyl-methyl- and aryl-methylorganoaluminum chlorides 6 were formed by reaction of methylaluminum dichloride with organolithium or Grignard compounds and used for chemoselective 1,4 addition of higher alkyl, aryl, alkenyl and alkinyl groups to alkylidine malonic esters 1 and 2. As an alternative, mixed trimethylorganoaluminates 7 can also be applied for these Michael addition reactions. For conjugate addition of alkenyl groups to alkylidene malonates 1 and 2, alkenyl diisopropylalanes 10 obtained from alkynes and diisopropylaluminum hydride proved the most efficient reagents. Using these novel mixed organoaluminum compounds, β-branched malonic (carboxylic) acid derivatives 3c, 8, 9 an…

ChemInform Abstract: Regio- and Stereoselective Addition of Grignard Reagents to N-Galactosyl-2-pyridone: Synthesis of 4-Substituted 5,6-Didehydro-2-piperidinones.

ChemInform Abstract: Selectively Deprotectable Carbohydrates Based on Regioselective Enzymatic Reactions.

Oxacyclododecindione, a Novel Inhibitor of IL-4 Signaling from Exserohilum rostratum

In a screening program for new metabolites from fungi inhibiting the IL-4 mediated signal transduction, a novel chlorinated macrocyclic lactone, designated as oxacyclododecindione, was isolated from fermentations of the imperfect fungus Exserohilum rostratum. The structure was determined by a combination of spectroscopic techniques. Oxacyclododecindione inhibits the IL-4 induced expression of the reporter gene secreted alkaline phosphatase (SEAP) in transiently transfected HepG2 cells with IC50 values of 20-25 ng/ml (54-67.5 nM). Studies on the mode of action of the compound revealed that the inhibition of the IL-4 dependent signaling pathway is caused by blocking the binding of the activat…

Polymere Selectinliganden als komplexe Glykomimetika: von Selectinbindung bis zur Modifizierung der Makrophagenmigration

Bei neuartigen polymeren Inhibitoren der Zelladhasion wird das Selectin-bindende Tetrasaccharid Sialyl-LewisX (SLeX) multivalent auf einem biokompatiblen Poly(2-hydroxypropyl)methacrylamid (PHPMA) entweder alleine (P1) oder in Kombination mit O-sulfatierten Tyramin-Seitenketten (P2) prasentiert. Zum Vergleich wurden entsprechende polymere Glykomimetika hergestellt, in denen die entscheidenden Fucose-, Galactose und Sialinsaure-Seitenketten statistisch verteilt im PHPMA-Ruckgrat (P3 oder P4 (O-sulfatiertes Tyramin) vorliegen. Alle Polymere haben den gleichen Polymerisationsgrad, da sie vom selben Ausgangspolymer abstammen. Assays fur die Bindung an Selectine, aktivierte Endothelzellen und Ma…

Synthese sterisch gehinderter Peptide und Depsipeptide nach einem Säurechlorid-Verfahren mit 2-Phosphonioethoxycarbonyl-(Peoc-)Aminosäuren und -Hydroxysäuren

2-(Triphenylphosphonio)ethoxycarbonyl-(Peoc-)aminosauren 1 und -hydroxysauren 5 werden mit Oxalylchlorid in bei Raumtemp. stabile Saurechloride 2 bzw. 6 ubergefuhrt. Mit diesen aktivierten Verbindungen werden sterisch gehinderte Amidbindungen — z. B. in den geschutzten Valin-Peptiden 3a—g und in Hydroxyacyl-Dipeptiden 7 — hergestellt. Nach Schutzgruppenabspaltung aus der voll geschutzten Form 7a entsteht so die Sporidesmolsaure B (9a), die in ihren Eigenschaften mit dem Abbauprodukt aus dem Sporidesmolid I ubereinstimmt. Trotz zweimaliger Anwendung der Saurechlorid-Kondensation ist keine Racemisierung eingetreten. Syntheses of Sterically Hindered Peptides and Depsipeptides by Means of an Ac…

Inhibitors of inducible NO synthase expression: total synthesis of (S)-curvularin and its ring homologues.

(S)-Curvularin and its 13-, 14-, and 16-membered lactone homologues were synthesized through a uniform strategy in which a Kochi oxidative decarboxylation and ring-closing metathesis reactions constitute the key processes. In the evaluation of the anti-inflammatory effects of the synthesized compounds in assays using cells stably transfected with a human iNOS promoter-luciferase reporter gene construct, the 14- and 16-membered homologues showed a slightly higher inhibitory effect towards iNOS promoter activity than curvularin itself. However, the larger ring homologues also exhibited higher cytotoxicity, manifest in downregulated eNOS promoter activity. In contrast, the di-O-acetyl and 4-ch…

Vollsynthetische Vakzinen aus tumorassoziierten MUC1-Glycopeptiden und einem Lipopeptid-Liganden des Toll-like Rezeptors 2

CpG-Loaded Multifunctional Cationic Nanohydrogel Particles as Self-Adjuvanting Glycopeptide Antitumor Vaccines

Self-adjuvanting antitumor vaccines by multifunctional cationic nanohydrogels loaded with CpG. A conjugate consisting of tumor-associated MUC1-glycopeptide B-cell epitope and tetanus toxin T-cell epitope P2 is linked to cationic nanogels. Oligonucleotide CpG complexation enhances toll-like receptor (TLR) stimulated T-cell proliferation and rapid immune activation. This co-delivery promotes induction of specific MUC1-antibodies binding to human breast tumor cells without external adjuvant.

Fluorenylmethoxycarbonyl-ProtectedO-Glycosyl-N-methyl Amino Acids: Building Blocks for the Synthesis of Conformationally Tuned Glycopeptide Antigens

Peptide antibiotics often contain N-methylated amino acids. These N-methylamino components enhance the metabolic stability and strongly influence the conformational behavior of these peptide drugs. N-Methyl-O-glycosyl amino acids, in particular, threonine and serine derivatives, are unknown so far. Fmoc-protected N-methyl-O-glycosyl-threonine and -serine building blocks, including sialyl TN antigens, have been synthesized for the first time by converting the Fmoc-protected O-glycosyl amino acids or their tert-butyl esters into the corresponding oxazolidinones followed by reductive ring-opening. These new components are considered interesting for the construction of modified mucin glycopepti…

Mit Glycopeptid-Antigenen und T-Zell-Epitopen verknüpfte wasserlösliche Polymere als potenzielle Antitumor-Vakzine

β-Branched α-Halo Carboxylic Acid Derivatives via Stereoselective 1,4 Addition of Dialkylaluminum Chlorides to α,β-Unsaturated N-Acyloxazolidinones

The stereoselective synthesis of β-branched α-halo carboxylic acids containing two newly formed chiral centers is accomplished by a reaction cascade consisting of the 1,4 addition of dialkylaluminum chlorides to α,β-unsaturated N-acyloxazolidinones and subsequent reaction of the intermediate aluminum enolates with N-halosuccinimide. The most efficient stereocontrol in these tandem processes has been achieved with oxazolidinones derived from glucosamine. Not only aryl substituted but also purely aliphatic β-branched α-halo carboxylic acids can be stereoselectively synthesized by this method. However, the reactions of β-aryl α,β-unsaturated N-acyloxazolidinones show the highest diastereoselec…

Convenient Synthesis of Biologically Important Retinoids

The toxic and teratogenic effects caused by the highly biologically active (all-E)-retinoic acid and its derivatives prompted us to synthesize a number of retinoids. We developed synthetic approaches to (all-E)-retinyl β-D-glucuronide 3, methyl (retinoyl β-D-glucopyranoside)uronate 5, (all-E)-retinoic acid β-D-glucopyranosyl ester 8 and (all-E)-retinoyl β-D-glucuronide 6 in high purity and yield. Compound 3 was synthesized under Koenigs-Knorr conditions from (all-E)-retinol and an α-halogenose. Compounds 5 and 8 were prepared by esterification of a silver salt of (all-E)-retinoic acid with an α-glycosyl halide in pyridine. (all-E)-Retinoyl β-D-glucuronide 6 was prepared by reaction of (all-…

Stereoselective glycosylation of Alcohols and Silyl Ethers Using Glycosyl Fluorides and Boron Trifluoride Etherate

The stereoselective glycosylation of alcohols and their silyl ethers has been achieved using O-alkyl-, O-acyl-, and acetal-protected glycosyl fluorides of the pyranose and furanose series and boron trifluoride etherate in CH2Cl2.

ChemInform Abstract: The (2-Phenyl-2-trimethylsilyl)ethoxycarbonyl (Psoc) Group - A Novel Amino Protecting Group.

Carbohydrates as chiral templates: Diastereoselective Ugi synthesis of (S)-amino acids using O-acylated D-arabinopyranosylamine as the auxiliary

Abstract Enantiomerically pure (S)-amino acids are synthesized via a highly diastereoselective Ugi reaction using 2,3,4-tri-O-pivaloyl-α-D-arabinopyranosylamine as the chiral template.

Synthetic antitumor vaccines containing MUC1 glycopeptides with two immunodominant domains-induction of a strong immune response against breast tumor tissues.

A shot in the arm for cancer treatment: two MUC1 tetanus toxoid vaccines were synthesized and induced a strong immune response in mice. The antibodies elicited by the vaccines show a high selectivity for the tumor cells in mammary carcinoma tissues and also distinguish between tumor tissues at different stages.

ChemInform Abstract: Stereoselective Synthesis of α-Arylalkylamines by Glycosylation-Induced Asymmetric Addition of Organometallic Compounds to Imines.

Arylalkylamines are of interest as building blocks for the synthesis of biologically active compounds and as chiral ligands or chiral auxiliaries in stereoselective syntheses [1]. Their stereoselective synthesis has been achieved by enantioselective reduction of ketimines using chiral reagents [2], as for example Corey’s oxaborolidines [3], or proline-derived triacyloxyborohydrides [4]. Particularly efficient asymmetric syntheses of chiral arylalkylamines have been accomplished by Noyori et al. [5] through enantioselective catalysis of hydrogen transfer reactions using a chiral 1,2-diphenyl-ethylenediamine ruthenium catalyst. Enantioselective transferhydrogenationshave also been achieved us…

Synthesis of active principles from the leaves of Moringa oleifera using S-pent-4-enyl thioglycosides

Abstract α - l -Rhamnosides of 4-hydroxy-benzyl compounds with nitrile, carbamate, and thiocarbamate groups occurring in Moringa oleifera leaf extracts and the α - l -rhamnoside of anisaldehyde derivatives were synthesised. Electrophilic activation of S -pent-4-enyl thiorhamnosides was applied for the construction of glycosidic linkages.

Stereoselective Syntheses of Piperidine-Containing Heterocycles Using Carbohydrate Auxiliaries

Der (2-Phenyl-2-trimethylsilyl)ethyl-(PTMSE)-Ester – eine neutral spaltbare Carboxyschutzgruppe/The (2-Phenyl-2-trimethylsiylyl)ethyl (PTMSE) Ester – a Carboxy Protecting Group Cleavable under Neutral Conditions

(2-Phenyl-2-trimethylsilyl)ethyl (PTMSE) esters of aminoacids and peptides are stable under the conditions of hydrogenolytic cleavage of benzoxycarbonyl(Z) and benzyl ester groups, base-induced removal of Fmoc groups, palladium(0)-catalyzed removal of allyloxycarbonyl (Aloc) and even acidolytic cleavage of Boc groups. PTMSE esters are also stable under the conditions of peptide condensation reactions. The PTMSE ester is selectively cleaved by treatment with tetrabutylammonium fluoride (TBAF) trihydrate in dichloromethane, i. e. under almost neutral conditions, within a few minutes and, therefore, considered a valuable novel carboxy protecting group.

Correction to: Carbohydrates as Stereodifferentiating Auxiliaries

Enantioselective Organocatalysis of Strecker and Mannich Reactions Based on Carbohydrates.

Efficient organocatalysts for enantioselective Strecker and Mannich reactions were constructed from glucosamine as a readily accessible chiral scaffold. A variety of aromatic aldimines were subjected to hydrocyanation with good to excellent yield (72–98 %) and, in part, high enantioselectivity (69–95 % ee). Influence of the catalyst architecture on the enantioselectivity obviously arises from restrictions imposed on the conformational flexibility of the monosaccharidic backbone. In the asymmetric Mannich reaction moderate yields (up to 76 %) and enantioselectivities (up to 58 % ee) have been achieved with the described catalyst.

Arabinosylamine in Asymmetric Syntheses of Chiral Piperidine Alkaloids.

The stereodifferentiating potential of arabinosyl aldimines was utilized in stereoselective syntheses of 2-substituted dehydropiperidinones and their further transformation to 2,6-cis-substituted piperidinones. The absolute configuration was proven by X-ray analysis and by the synthesis of the enantiomerically pure alkaloid (+)-dihydropinidine. The presented method offers the possibility to synthesize piperidine derivatives enantiomeric to those obtained by the application of the corresponding galactosylamine auxiliary.

ChemInform Abstract: Chemoselective Removal of Protecting Groups from O-Glycosyl Amino Acid and Peptide (Methoxyethoxy)ethyl Esters Using Lipases and Papain.

The selective C-terminal deprotection of O-glycopeptide (methoxyethoxy)ethyl esters is achieved under mild conditions (pH 6.6, 37 degrees C) by enzymatic hydrolysis using papain or lipase M from Mucor javanicus to give building blocks useful for chain-extending glycopeptide synthesis. On the other hand, the selective removal of acetyl protecting groups from the saccharide portion of glycopeptides is accomplished by alternative enzymatic hydrolysis with lipase WG from wheat germ to furnish model substrates for enzymatic glycosyl transfer reactions in order to extend the carbohydrate side chain of these conjugates.

Synthetic vaccines of tumor-associated glycopeptide antigens by immune-compatible thioether linkage to bovine serum albumin.

Stereoselective Synthesis of 3-Substituted and 3,4-Disubstituted Piperidine und Piperidin-2-one Derivatives

The stereoselective synthesis of 3-substituted and 3,4-disubstituted piperidine and piperidin-2-one derivatives was achieved starting from 2-pyridone. After N-galactosylation and subsequent O-silylation, nucleophilic addition of organometallic reagents proceeded with high regio- and stereoselectivity at 4-position. Substituents at position 3 were stereoselectively introduced by reaction of electrophiles with amide enolates of the N-galactosyl-2-piperidones.

Mucin Glycopeptide-Protein Conjugates - Promising Antitumor Vaccine Candidates

Recent efforts towards the development of synthetic glycopeptide vaccines, which aim at the active immunization of patients against their own tumor tissues, are outlined. To achieve sufficient tumor selectivity, glycopeptides of the tandem repeat region of tumor-associated mucin, MUC1, have been synthesized. Since the endogenous structures usually exert low immunogenicity, these glycopeptide antigens, as B-cell epitopes, were conjugated with immunostimulating components. In the present short review, work is outlined in which the MUC1 B-cell epitope peptides are conjugated with bovine serum albumin (BSA), keyhole limpet hemocyanin (KLH), or tetanus toxoid (TTox). In particular, the synthetic…

ChemInform Abstract: Glycoconjugates as Tumor-Associated Antigens and Ligands in Regulatory Processes

Eine vollsynthetische Vakzine aus einem tumorassoziierten Glycopeptid-Antigen und einem T-Zell-Epitop zur Induktion einer hochspezifischen humoralen Immunantwort

Developments in the Synthesis of Glycopeptides Containing Glycosyl l-Asparagine, l-Serine, and l-Threonine

ChemInform Abstract: Stereoselective Synthesis of Glycosides and Anomeric Azides of Glucosamine.

The β-azide of O-acetyl protected N-acetyl glucosamine is efficiently accessible via a phasetransfer-catalyzed reaction of the corresponding glycosyl chloride with sodium azide. The azido group revealed to be a useful anomeric protection for modifications of the protecting group pattern of the glucosamine unit. Exchange of the O-acyl groups by 4-methoxybenzylidene and 4-methoxybenzyl (Mpm) protection delivered regioselectively blocked glucosaminyl azide derivatives. In contrast, the N-phthaloyl protected glucosaminyl azide was obtained quantitatively from the corresponding glycosyl fluoride via a boron trifluoride-promoted reaction with trimethylsilyl azide. N-Phthaloyl glucosaminyl fluorid…

Synthesis of Tn/T Antigen MUC1 Glycopeptide BSA Conjugates and Their Evaluation as Vaccines

The tumor-associated mucin MUC1 over-expressed in most epithelial tumor tissues is considered a promising target for immunotherapy. The extracellular part of MUC1 contains a domain of numerous tandem repeats of the amino acid sequence HGVTSAPDTRPAPGSTAPPA, including five potential O-glycosylation sites. In this study, T9 and S15 have been chosen as the positions of glycosylation. The glycopeptides N-terminally equipped with a triethylene glycol spacer were synthesized by microwave-assisted Fmoc solid-phase peptide synthesis. After detachment from the resin and deprotection, the MUC1 glycopeptides were conjugated to bovine serum albumin (BSA). To evaluate the immunological properties, balb/c…

Glycosylation-induced asymmetric synthesis: β-amino acid esters via Mannich reactions

Abstract Activation of Schiff bases by N-glycosylation induces asymmetric Mannich reactions with O-silyl ketene acetals to give β-amino acid esters in good yields.

Synthese und Reaktionen der 3-O-Phosphoniogluco-und -allofuranosen

Aus den bicyclischen Gluco- (3, 5, 7 und 9) und Allofuranosen 11 werden mit Triphenylphosphan (1), Azodicarbonsaure-diethylester (2) und Alkylierungs- oder Acylierungsmitteln isolierbare 3-O-Phosphoniokohlenhydrate (4, 6, 8, 10 und 12) hergestellt. Durch Erwarmen der allo-konfigurierten Salze 12 konnen an C-3 epimere gluco-konfigurierte Substitutionsprodukte in groser Vielfalt gewonnen werden. Die Reaktionen der gluco-konfigurierten Salze werden stark vom Charakter des einzufuhrenden Nucleophils und von Nachbargruppen im Kohlenhydratgerust beeinflust. Wahrend das Iodid 4a und das Azid 4g unter Substitution zum allo-Derivat 15 reagieren, tritt in den Fallen mit Bromid, Chlorid oder Sulfonat …

Cover Picture: Tumor-Associated MUC1 Tandem-Repeat Glycopeptide Microarrays to Evaluate Serum- and Monoclonal-Antibody Specificity (Angew. Chem. Int. Ed. 44/2009)

Ceric Ammonium Nitrate - a versatile oxidizing reagent

Synthesis and biological activity of novel sialyl-lewisX conjugates

Abstract Novel sialyl Lewis X conjugates have been synthesized and evaluated as inhibitors of E- and P-selectin mediated cell adhesion in cell culture assays. The most potent conjugate in the static inhibition assays exhibited a significant and dose-dependent pharmacological potency as inhibitor of the edotoxin-induced leukocyte adhesion to the endothelium of postcapillary venules in rats.

Chemoenzymatic synthesis of O-glycopeptides carrying the tumor associated TN-antigen structure

Abstract The application of the lipase-catalyzed C-terminal deprotection of heptyl esters for the construction of acid- and base-labile O -glycopeptides carrying the characteristic structural element of the tumor associated T N -antigen (GalNAc α→Ser/Thr) is described

ChemInform Abstract: Inhibitors of Inducible NO Synthase Expression: Total Synthesis of (S)-Curvularin (Ia) and Its Ring Homologues.

CCDC 945345: Experimental Crystal Structure Determination

Related Article: Sonja Schwolow, Horst Kunz, Joachim Rheinheimer, Till Opatz|2013|Eur.J.Org.Chem.|2013|6519|doi:10.1002/ejoc.201301088

CCDC 945347: Experimental Crystal Structure Determination

Related Article: Sonja Schwolow, Horst Kunz, Joachim Rheinheimer, Till Opatz|2013|Eur.J.Org.Chem.|2013|6519|doi:10.1002/ejoc.201301088

CCDC 920035: Experimental Crystal Structure Determination

Related Article: Stefan Koch, Dieter Schollmeyer, Holger Löwe, Horst Kunz|2013|Chem.-Eur.J.|19|7020|doi:10.1002/chem.201300150

CCDC 813647: Experimental Crystal Structure Determination

Related Article: Till Opatz, Christopher Kallus, Tobias Wunberg, Wolfgang Schmidt, Stefan Henke, Horst Kunz|2002|Carbohydr.Res.|337|2089|doi:10.1016/S0008-6215(02)00301-4

CCDC 945348: Experimental Crystal Structure Determination

Related Article: Sonja Schwolow, Horst Kunz, Joachim Rheinheimer, Till Opatz|2013|Eur.J.Org.Chem.|2013|6519|doi:10.1002/ejoc.201301088

CCDC 945346: Experimental Crystal Structure Determination

Related Article: Sonja Schwolow, Horst Kunz, Joachim Rheinheimer, Till Opatz|2013|Eur.J.Org.Chem.|2013|6519|doi:10.1002/ejoc.201301088