Acetylation of 5-Amino-1H-[1,2,4]triazole Revisited

The products of the acetylation reactions of the common herbicide 5-amino-1H-[1,2,4]triazole were investigated using HPLC, GC-MS, 1H NMR, and FTIR spectroscopy. The conventional annular monoacetylation procedures with acetyl chloride are not regioselective and furnish a mixture of isomers. Traditional diacetylation in neat acetic anhydride under reflux produces a mixture of di-, mono-, and triacetylated derivatives. By using equivalent amounts of acetic anhydride in a dimethylformamide solution, a rapid and selective annular monoacetylation of 5-amino-1H-[1,2,4]triazole was achieved. The monoacetylation proceeds via the formation of the intermediate, 1-acetyl-3-amino-1H-[1,2,4]triazole, whi…

Conformational studies into N-methylation of alanine diamide models: A quantitative approach

Abstract A systematic theoretical analysis was performed on N -acetyl- l -alanine N ′-methylamide (Ac- l -Ala-NHMe) and the analogues methylated on the N-terminus (Ac- l -(Me)Ala-NHMe), C-terminus (Ac- l -Ala-NMe 2 ), and both N/C-termini (Ac- l -(Me)Ala-NMe 2 ), to evaluate the influence of methylation of the amide group on the conformational properties of the affected residues. The ϕ , ψ potential energy surfaces were calculated at the B3LYP/6-31+G**//HF/3-21G level of theory with inclusion of the solvent (water) effect (SCRF method). The conformers localised were fully optimised at the B3LYP/6-31+G** in vacuo. The accessible areas of the potential energy surfaces; the number of conformer…

Conformational investigation of alpha,beta-dehydropeptides. VIII. N-acetyl-alpha,beta-dehydroamino acid N'-methylamides: conformation and electron density perturbation from infrared and theoretical studies.

The Fourier transform infrared spectra are analyzed in the regions of Vs(N-H), amide I, amide II and Vs(C alpha = C beta) bands for a series of Ac-delta Xaa-NHMe, where delta Xaa = delta Ala, (Z)-delta Abu, (Z)-delta Leu, (Z)-delta Phe and delta Val, to determine the predominant solution conformation of these alpha,beta-dehydropeptide-related molecules and the electron distribution perturbation in their amide bonds. The measurements were performed in dichloromethane (DCM). To confirm and rationalize the assignments, the spectra of the respective series of saturated Ac-Xaa-NHMe, recorded in DCM, and the spectra of these two series of unsaturated and saturated compounds, recorded in acetonitr…

Ethyl 1-acetyl-3-amino-1H-pyrazole-4-carboxyl­ate, a tetra­gonal structure with Z′ = 4

The title compound, C8H11N3O3, crystallizes with Z' = 4. One pyrazole N atom is substituted and excluded from inter­molecular contacts. The amine N, acetyl O and an ester O atom are involved in the formation of nearly planar mol­ecular layers. The layers are perpendicular to the c axis, with an inter­layer distance of 3.333 Å. The hydrogen-bonding patterns are similar for each mol­ecule, i.e. intra­molecular N-H...O, as well as inter­molecular N-H...O and C-H...N(pyrazole), bonds are present.

The conformational properties of dehydrobutyrine and dehydrovaline: theoretical and solid-state conformational studies

Dehydrobutyrine is the most naturally occurring dehydroamino acid. It is also the simplest dehydroamino acid having the geometrical isomers E/Z. To investigate its conformational properties, a theoretical analysis was performed on N-acetyl-α,β-dehydrobutyrine N′-methylamides, Ac-(E)-ΔAbu-NHMe and Ac-(Z)-ΔAbu-NHMe, as well as the dehydrovaline derivative Ac-ΔVal-NHMe. The ϕ, ψ potential energy surfaces and the localised conformers were calculated at the B3LYP/6-311 + + G(d,p) level of theory both in vacuo and with inclusion of the solvent (chloroform, water) effect (SCRF method). The X-ray crystal structures of Ac-(Z)-ΔAbu-NHMe and Ac-ΔVal-NHMe were determined at 85 and 100 K, respectively. …

Conformational investigation of α,β-dehydropeptides. IX. N-Acetyl-(E)-α,β-dehydrobutyrine N′-methylamide: stereoelectronic properties from infrared and theoretical studies*

The Fourier transform infrared spectra of Ac-(E)-deltaAbu-NHMe were analyzed to determine the predominant solution conformation(s) of this (E)-alpha,beta-dehydropeptide-related compound and the electron density perturbation in its amide groups. The measurements were performed in dichloromethane and acetonitrile in the region of mode vs (N-H), amide I, amide II and vs (C(alpha)=Cbeta). The equilibrium geometrical parameters, calculated by a method based on the density functional theory with the B3LYP functional and the 6-31G* basis set, were used to support spectroscopic interpretation and gain some deeper insight into the molecule. The experimental and theoretical data were compared with th…

Synthesis, crystal structure and molecular conformation of the tBuCO-D,L-Ala-Δz-Phe-NhiPr α,β-unsaturated dipeptide

The crystal structure of the tBuCO-D,L-Ala-delta Z-Phe-NHiPr dipeptide has been solved by X-ray diffraction. The peptide crystallizes in monoclinic space group P2(1)/c with a = 13.445 (3) A, b = 35.088 (4) A, c = 14.755 (3) A, beta = 116.73 (1) degree, Z = 12 and dc = 1.151 g.cm-3. The three independent molecules per asymmetric unit accommodate a beta II-folded conformation, but only one of them contains the typical i + 3----i interaction characterizing a beta-turn. In the other two molecules, the N...O distance exceeds 3.2 A, a value generally considered the upper limit for hydrogen bonds in peptides. In solution, the beta II-turn conformation is largely predominant.

A ONE-POT SYNTHESIS OFNαBENZYLOXYCARBONYLNω-t-BUTOXYCARBONYL-L-ORNITHINE AND L-LYSINE

Convenient High Yielding Gram Scale Solution Synthesis of Methionine-Enkephalin.

A simple, large-scale synthesis of a cytokine, methionine-enkephalin, Tyr-Gly-Gly-Phe-Met, has been elaborated. Classical solution peptide chemistry methods without protection of amino acid side-chain functions and 1+(2+2) segment condensation were used. A nine-step synthesis from commercial amino acid derivatives was developed with yields ranging from 86% to 99%, averaging 92%. The purity of all intermediates was found to be 99.0-100% by HPLC. The process has been used to prepare greater than 150 g quantities of the pentapeptide as a monohydrate of 100% purity. Hydantoin formation was observed during saponification of Boc-Tyr-Gly-Gly-Phe-Met-OMe and minimised.

Large Scale Synthesis of Mono- and Di-urethane Derivatives of Lysine.

Orthogonally protected diurethane derivatives of lysine are valuable materials for peptide syntheses. An example is ZLys(Boc), which is exploited in the industrial production of certain well-established peptide drugs. 3,4) Another derivative is Fmoc-Lys(Boc), which is in common use in the laboratory synthesis of peptides. 5) The simplest route to these lysine derivatives seems to be using the copper complex for simultaneous protection of the a-amino and a-carboxyl function, N e -tert-butoxycarbonylation and then copper detachment. The obtained Lys(Boc) might be then subjected to N a -benzyloxycarbonylation.

Synthesis of peptides with α,β-dehydroamino acids, VI. Synthesis ofN-benzyloxycarbonyl andN-trifluoroacetyl dipeptides of α,β-dehydro-butyrine, -valine, -leucine, and -isoleucine

Condensation of Z- and TFA-amino acid amides with 2-oxo-acids, namely butanoic, 3-methylbutanoic, 4-methylpentanoic, and (3RS)-3-methylpentanoic acid, yields (in the presence of p-toluenesulfonic acid as a catalyst) Z- and TFA-dipeptides with C-terminal ΔAbu2) (1–4), ΔVal (5–8), ΔLeu (9–11), and ΔIle (12–15) (Table 1).

Increased LH and FSH release from the anterior pituitary of ovariectomized rat, in vivo, by copper-, nickel-, and zinc-LHRH complexes.

Abstract The effect of Cu 2+ , Ni 2+ , Zn 2+ and their complexes with LHRH on the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) was estimated in in vivo experiments with the use of the method proposed by Ramirez and McCann. Ovariectomized, estradiol, and progesterone pretreated rats were injected intraveneously either with LHRH alone, a metal ion alone, a mixture of metal and hormone, or a metal-LHRH complex. A metal alone or a mixture of it with LHRH did not affect gonadotropin release at all or no more than LHRH alone. However, the complex of Cu 2+ with LHRH brought about a high release of LH and even higher release of FSH. This indicates that copper complex i…

AN IMPROVED SYNTHESIS OFNα-BENZYLOXYCARBONYL-L-LYSINE

Conformational investigation of α,β-dehydropeptides. XVI. β-turn tendency in Ac-Pro-ΔXaa-NHMe: crystallographic and theoretical studies

The crystal structures of two diastereomeric alpha,beta-dehydrobutyrine peptides Ac-Pro-(Z)-DeltaAbu-NHMe (I) and Ac-Pro-(E)-DeltaAbu-NHMe (II) have been determined. Both dehydropeptides adopt betaI-turn conformation characterized by the pairs of (phi(i+1), psi(i+1)) and (phi(i+2), psi(i+2)) angles as -66, -19, -97, 11 degrees for I and -59, -27, -119, 29 degrees for II. In each peptide, the betaI turn is stabilized by (i + 3) --> i intramolecular hydrogen bonds with N...O distance of 3.12 A for I and 2.93 A for II. These structures have been compared to the crystal structures of homologous peptides Ac-Pro-DeltaVal-NHMe and Ac-Pro-DeltaAla-NHMe. Theoretical analyses by DFT/B3LYP/6-31 + G** …

Improved scalable syntheses of mono- and bis-urethane derivatives of ornithine.

In the search for a practical route to ornithine bisurethane derivatives useful for peptide synthesis, we elaborated the simple and efficient (86% yield) synthesis of N(epsilon)-tert-butoxycarbonyl-L-ornithine copper(II) complex (1). This served as substrate for obtaining N(epsilon)-tert-butoxycarbonyl-L-ornithine (2), N(alpha)-benzyloxycarbonyl-N(epsilon)-tert-butoxycarbonyl-L-ornithine (3) and N(alpha)-(9-fluorenyl)methoxycarbonyl-N(epsilon)-tert-butoxycarbonyl-L-ornithine (4). These were synthesized in 94-95% yields and with a purity above 99%.

ChemInform Abstract: A Simple Preparation of Mono-tert-butyl Benzyloxycarbonyl-L-glutamates.

(1995). A SIMPLE PREPARATION OF MONO-tert-BUTYL BENZYLOXYCARBONYL-L-GLUTAMATES. Organic Preparations and Procedures International: Vol. 27, No. 3, pp. 378-380.

Conformational properties of N-acetyl-L-alanine N',N'-dimethylamide

Ab initio/DFT analysis of the conformational properties of free Ac-Ala-NMe(2) (N-acetyl-L-alanine-N',N'-dimethylamide) in terms of the N-H.O, N-H.N, C-H.O hydrogen bonds and C(delta+) = O(delta-) dipole attractions was performed. The Ala residue combined with the C-terminal tertiary amide prefers an extended conformation and that characteristic of the (i + 1)th position of the betaVIb turn. These can be easily remodelled into a structure compatible with the (i + 1)th position of the betaII/betaVIa turn. The residue has also the potential to adopt the conformation accommodated at both central positions of the betaIII/betaIII' turn or the (i + 1)th position of the betaI/beta'I turn.

Synthesis, structure and properties of N-acetylated derivatives of methyl 5-amino-1H-[1,2,4]triazole-3-carboxylate.

Methyl 5-amino-1H-[1,2,4]triazole-3-carboxylate hydrochloride (1). and free ester (2). were obtained and 2 was reacted with Ac(2)O to give the acetylated products 3-6. Compounds 1-6 were studied using HPLC, GC-MS, FTIR and multinuclear NMR spectroscopy, including the cross-polarisation magic angle spinning (CPMAS) technique. The results of the acetylation of 2 were compared to those of the acetylation of 5-amino-1H-[1,2,4]triazole, and for 2 a significant decrease in the susceptibility to acetylation was found. The reaction of 2 with Ac(2)O at 20 degrees C, regardless of the amount and the concentration of the latter, including neat Ac(2)O, proceeds fully regioselectively and leads to one p…

LOWER ALIPHATIC 2-OXOACIDS AND THEIR ETEYL ESTERS FROM ETHYL ESTERS OF 2-HYDROXY ACIDS

(1989). LOWER ALIPHATIC 2-OXOACIDS AND THEIR ETEYL ESTERS FROM ETHYL ESTERS OF 2-HYDROXY ACIDS. Organic Preparations and Procedures International: Vol. 21, No. 1, pp. 75-82.

Coordination of copper(II) ions by α,β-dehydro-dipeptides. Potentiometric and spectroscopic study

Abstract Potentiometric and spectroscopic data have shown that the double bond within dehydro-peptides considerably affects their behaviour as ligands relative to their saturated parents, with proton and copper(II) ions.

ARGININE, HISTIDINE AND TRYPTOPHAN IN PEPTIDE SYNTHESIS. THE INDOLE FUNCTION OF TRYPTOPHAN

A SIMPLE PREPARATION OF MONO-tert-BUTYL BENZYLOXYCARBONYL-L-GLUTAMATES

(1995). A SIMPLE PREPARATION OF MONO-tert-BUTYL BENZYLOXYCARBONYL-L-GLUTAMATES. Organic Preparations and Procedures International: Vol. 27, No. 3, pp. 378-380.

The effect of β-methylation on the conformation of α, β-dehydrophenylalanine: a DFT study

Dehydroamino acids are non-coded amino acids that offer unique conformational properties. Dehydrophenylalanine (ΔPhe) is most commonly used to modify bioactive peptides to constrain the topography of the phenyl ring in the side chain, which commonly serves as a pharmacophore. The Ramachandran maps (in the gas phase and in CHCl3 mimicking environments) of ΔPhe analogues with methyl groups at the β position of the side chain as well as at the C-terminal amide were calculated using the B3LYP/6-31 + G** method. Unexpectedly, β-methylation alone results in an increase of conformational freedom of the affected ΔPhe residue. However, further modification by introducing an additional methyl group a…

Molecular and crystal structure of Nα-(9-fluorenyl)-methoxycarbonyl-L-ornithine hydrochloride diethyl ether solvate

The solid-state conformation of the first N-protected ornithine derivative has been established by X-ray analysis. The hydrochloride of Nα-(9-fluorenyl)methoxycarbonyl-l-ornithine crystallises as diethyl ether solvate. The backbone (ω0 ϕ, ψ χ1) torsion angles are (174.9°,–84.0°, 145.9°,–171.0°). The conformation of the urethane amide bonds istrans. The ornithine aliphatic side chain adopts preferred fully extended conformation which is stabilised by the hydrogen bonding of the-NH3+ group to the diethyl ether molecule, carboxyl group and Cl− anions.

The synthesis, structure and properties of N-acetylated derivatives of ethyl 3-amino-1H-pyrazole-4-carboxylate.

Ethyl 3-amino-1H-pyrazole-4-carboxylate (1) was yielded through total synthesis and reacted with acetic anhydride to give the acetylated products 2-6. Compounds 1-6 were studied with HPLC, X-ray, FT-IR, (1)H-NMR, (13)C-NMR and MS. Acetylation was carried out in solvents of various polarity, namely; chloroform; dioxane; DMF; acetic anhydride, at room temperature and at boiling points; and in the presence and absence of DMAP. The acetylated products are mainly nitrogen atoms in the ring. The position of the ring proton in the solution was based on NOESY; multinuclear HMBC, HSQC spectra and calculations. For equivalent amounts (1-1.5 mol) of acetic anhydride at room temperature two products of…

The conformation cis of N-acetyl-N-methyl-α,β-dehydroalanine N′-methylamide and saturated analogues

A series of three homologous amino acids derivatives: N-acetyl-N-methyl-α,β–dehydroalanine N′-methylamide (1), N-acetyl-N-methyl-L-alanine N′-methylamide (2), and N-acetyl-N-methyl-DL-alanine N′-methylamide have been synthesised. The racemic species undergoes spontaneous separation into L and D-enantiomers. From these two chiral forms, the structure of L-enantiomer (3) was analysed. The molecules of 1 – 3 adopt the cis arrangement of the N-terminal amide bond. The molecular conformations are similar for 1 (φ, ψ = 94.6(1)°, −1.7(1)°) and 3 (φ, ψ = 111.5(1)°, −23.8(1)°), and also 2 (φ, ψ = −114.8(2)°, 29.5(2)°), if inversion through the chiral C2 carbon is considered. They are stabilised by i…

Conformational investigation of α, β-dehydropeptides

The crystal structure of Ac-Pro-delta Val-NHCH3 was examined to determine the influence of the alpha,beta-dehydrovaline residue on the nature of peptide conformation. The peptide crystallizes from methanol-diethyl ether solution at 4 degrees in needle-shaped form in orthorhombic space group P2(1)2(1)2(1) with a = 11.384(2) A, b = 13.277(2) A, c = 9.942(1) A, V = 1502.7(4) A3, Z = 4, Dm = 1.17 g.cm-3 and Dc = 1.18 g.cm-3. The structure was solved by direct methods using SHELXS-86 and refined to an R value of 0.057 for 1922 observed reflections. The peptide is found to adopt a beta-bend between the type I and the type III conformation with phi 1 = -68.3(4) degrees, psi 1 = -20.1(4) degrees, p…

ChemInform Abstract: Arginine, Histidine, and Tryptophan in Peptide Synthesis. The Indole Function of Tryptophan

Co-ordination of copper(II) ions by prolyl-α,β-dehydroamino acids: comparative studies and general considerations

Potentiometric and spectroscopic measurements and theoretical calculations have revealed that α,β-dehydroamino acid residues have a considerable effect on the co-ordination ability of an adjacent amide nitrogen towards Cu2+ ions. Also the side chain of such residues affects the stability constants and, in some cases, the binding mode of short peptides containing α,β-dehydroamino acid residues. The theoretical calculations showed that all dehydroamino acids except α,β-dehydroalanine tend to bend a peptide chain towards a turn conformation. This has a very strong impact on the co-ordination ability of a dehydropeptide ligand.

Synthesis of peptides with α,β‐dehydroamino acids, I. synthesis of N‐benzyloxycarbonyl and N‐trifluoroacetyl dipeptides of dehydroalanine and dehydrophenylalanine

Condensation of amides of N-(benzyloxycarbonyl)- and N-(trifluoroacetyl)amino acid with pyruvic and phenylpyruvic acid yields, in the presence of p-toluenesulfonic acid as a catalyst, N-(benzyloxycarbonyl)- and N-(trifluoroacetyl)dehydro dipeptides with C-terminal Δ Ala and ΔPhe, respectively (Table 2 and 3). Synthese von Peptiden mit α,β-Dehydroaminosauren, I. - Synthese von N-(Benzyloxycarbonyl)-und N-(Trifluoracetyl) dipeptiden von Dehydroalanin und Dehydrophenylalanin Die Kondensation von Nα-(Benzyloxycarbonyl)- und Nα-(Trifluoracetyl)aminosaureamiden mit Brenztrauben- und Phenylbrenztraubensaure in Gegenwart von p-Toluolsulfonsaure als Katalysator fuhrt zu N-(Benzyloxycarbonyl)- und N-…

Molecular and crystal structure of Ac-(Z)-ΔAbu-NMe2 and Ac-DL-Abu-NMe2 as compared to those of related molecules

Abstract The molecular and crystal structures of two homologous amino acid derivatives: N-acetyl-α,β-dehydro-butyrine N´,N´-dimethylamide (1) and N-acetyl-DL-butyrine N´,N´-dimethylamide (2), have been determined by X-ray crystallography. Similar solid-state association of both compounds is observed; despite different molecular conformation, they form centrosymmetric dimers linked by the intermolecular N–H…O hydrogen bonds. The conformation of two crystallographically independent molecules of 1 [with torsion angles ϕ, ψ, χ 1 ≈ (–47°, 130°, 3°), respectively] is also characteristic of other related diamides – ΔAla, ΔPhe and ΔLeu – previously studied in the solid state. To analyse whether thi…

Conformational investigation of α,β‐dehydropeptides. XV: N‐acetyl‐α,β‐dehydroamino acid N ′N ′‐dimethylamides: conformational properties from infrared and theoretical studies

The FTIR spectra were analysed in the region of the nu(s)(N-H), AI(C=O) and nu(s)(Calpha=Cbeta) bands for a series of Ac-DeltaXaa-NMe2, where DeltaXaa = DeltaAla, (Z)-DeltaAbu, (Z)-DeltaLeu, (Z)-DeltaPhe and DeltaVal, to determine a predominant solution conformation of these alpha,beta-dehydropeptide-related molecules. Measurements were taken in CCl4, DCM and MeCN solutions. In the same way, spectra of saturated analogues Ac-Xaa-NMe2, where Xaa = Ala, Abu, Leu, Phe and Val, were investigated. To help interpret the spectroscopic results, conformational maps were calculated by the B3LYP/6-31+G** method. Also, the relative energies of all conformers of the dehydro compounds in vacuo as well as…

N-Methyldehydroamino acids promote a configuration cis of N-methylamide bond

Abstract Dehydroamino acids with a methylated N-terminal tertiary amide bond occur in natural small cyclic peptide toxins. To investigate their conformational preferences a systematic theoretical analysis was performed on N ′-methylamides of N -acetyl- N -methyldehydroamino acids (Ac-Δ(Me)Xaa-NHMe, where Xaa = ( Z )-Abu, ( E )-Abu, Val, ( Z )-Phe, and ( E )-Phe) considering the configuration trans and cis of the tertiary amide bond. The ϕ , ψ potential energy surfaces were calculated at the B3LYP/6-31+G ∗∗ //HF/3-21G level with inclusion of the solvent (water) effect (SCRF method). The conformers localised were fully optimised at the B3LYP/6-31+G ∗∗ in vacuo. The accessible areas of the pot…

The Molecular and Crystal Structure of tert-Butyl N.ALPHA.-tert-Butoxycarbonyl-L-(S-trityl)cysteinate and the Conformation-Stabilizing Function of Weak Intermolecular Bonding.

The title compound, C31H37NO4S [systematic name: (R)-tert-butyl-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propanoate] is an L-cysteine derivative with three functions: NH2, COOH and SH, blocked by protecting groups tert-butoxycarbonyl, tert-butyl and trityl, respectively. The main chain of the molecule adopts the extended, nearly all-trans C5 conformation with the intramolecular N-H...O=C hydrogen bond. The urethane group is not involved in any intermolecular hydrogen bonding. Only weak intermolecular hydrogen bonds and hydrophobic contacts are observed in the crystal structure. These are C-H...O hydrogen bonds and CH/pi interactions with donor...acceptor distances, C...O ca. 3.5 A a…

Conformational investigation of alpha,beta-dehydropeptides. XIII. Conformational properties of N-acetyl-alpha,beta-dehydrovaline N',N'-dimethylamide.

The crystal structure of Ac-DeltaVal-NMe(2) (DeltaVal = alpha,beta-dehydrovaline) was determined by X-ray crystallography. The found angles phi = -60 degrees and psi = 125 degrees correspond exactly to the respective values of the (i + 1)th residue in idealised beta-turn II/VIa. Ab initio/DFT studies revealed that the molecule adopts the angle psi restricted only to about |130 degrees | and very readily attains the angle phi = about -50 degrees. This is in line with its solid-state conformation. Taken together, these data suggest that the DeltaVal residue combined with a C-terminal tertiary amide is a good candidate at the (i + 1)th position in a type II/VIa beta-turn.

New adsorbents for thymidylate synthase affinity chromatography

New affinity adsorbents, intended for chromatography of thymidylate synthase (EC 2.1.1.45) from different sources, consisting of p-[N-[(2-amino-4-hydroxy-6-quinazolinyl)-methyl]-N-2-propynylamino]benzoyl-γ-[α-(3-carboxypropylamino)]glutamyl-glutamyl immobilized either on macroporous copolymer of acrylonitrile and n-butyl acrylate or on macroporous polymer of acrylonitrile itself, both crosslinked with divinylbenzene and having aminoethyl groups, were obtained. Both adsorbents were found to be effective in dUMP-dependent binding of thymidylate synthase from regenerating rat liver.

Sulfamide antifolates inhibiting thymidylate synthase: synthesis, enzyme inhibition and cytotoxicity

Synthesis and biological evaluation are described of seven new analogues (3-9) of two potent thymidylate synthase inhibitors, 10-propargyl-5,8-dideazafolate (1) and its 2-methyl-2-deamino congener ICI 198583 (2). While the new compunds 3 and 4 were analogues of 1 and 2, respectively, containing a p-aminobenzenesulfonyl residue in place of the p-aminobenzoic acid residue, the remaining 5 new compounds were analogues of 4 with the L-glutamic acid residue replaced by glycine (5), L-valine (6), L-alanine (7), L-phenylglycine (8) or L-norvaline (9). The new analogues were tested as inhibitors of thymidylate synthases isolated from tumour (Ehrlich carcinoma), parasite (Hymenolepis diminuta) and n…

Unusual binding ability of α,β-dehydrodipeptides towards metal ions

Abstract Ni II , Zn II and Co II complexes of α,β-dehydro-dipeptides (containing Gly, Leu, Ala, Val or Phe residues) were studied by potentiometric and spectroscopic methods. Deprotonation and coordination of amide nitrogens occurred in all cases around the physiological pH range. The dipeptides with composition of Xaa-Δ-Ala formed octahedral species, while Gly-Δ-Xaa (Xaa = Leu or Phe) formed square planar bis complexes with Ni II .

Geometrical and conformational preferences of the 9‐fluorenylmethoxycarbonyl‐amino moiety

Structural parameters, originating from x-ray crystallographic data, have been compiled for 13 derivatives of amino acids, peptides and related compounds, which contain a total of 14 Fmoc-NH- moieties. For these moieties, molecular geometries and conformations--described by the omegao, theta1, theta2 and theta3' torsion angles--were analysed and compared with the corresponding parameters for the Z-NH- and Boc-NH-moieties (290 and 553, respectively). To gain a deeper insight into the conformational features of the Fmoc-NH- moiety, ab initio free molecule calculations were performed for fully relaxed minima. Also the potential energy surface as a function of the torsion angles (theta3', theta…

Conformational investigation of α, β‐dehydropeptides. XI. Molecular and crystal structure of Ac‐(Z )‐ΔPhe‐NMe2 as compared to those of related molecules

A series of three homologous dimethyldiamides Ac-(Z)-ΔPhe-NMe2, Ac-L-Phe-NMe2 and Ac-DL-Phe-NMe2 have been synthesized and their structures determined from single-crystal X-ray diffraction data. To learn more about the conformational preferences of the compounds studied, the fully relaxed ϕ, ψ conformational energy maps on the free molecules of Ac-ΔAla-NMe2 and Ac-(Z)-ΔPhe-NMe2 were obtained with the HF/3-21G method and the calculated minima re-optimized with the DFT/B3LYP/6-31G** method. The crystal state results have been compared with the literature data. The studied dimethyldiamide Ac-ΔXaa-NMe2 combines the double bond in positions α, β and the C-terminal tertiary amide within one molec…

Susceptibility of Methyl 3-Amino-1H-pyrazole-5-carboxylate to Acylation

Abstract In the search for a new method of synthesis of hybrid peptides with aminopyrazole carboxylic acid, we tried to force selective acylation at the aromatic amino group instead of at the ring nitrogen atom with fairly gentle acylating agents. The acylating agents used were acid anhydrides: acetic anhydride, tert-butyl pyrocarbonate, and 2-(2-methoxyethoxy)ethoxyacetic acid/dicyclohexylcarbodiimide. We succceded in acylation at this amino group with almost none at the ring nitrogen atom. Sometimes, however, acylation in small quantities at the ring nitrogen atom was observed as a by-product. To remove this by-product, imidazole was used. Thus, we were able to obtain the hybrid peptides …

Conformational investigation of ?,?-dehydropeptides.N-acetyl-(E)-dehydrophenylalanineN?-methylamide: conformational properties from infrared and theoretical studies, part XIV

N-Acetyl-(E)-dehydrophenylalanine N'-methylamide [Ac-(E)-DeltaPhe-NHMe], one of a few representative (E)-alpha,beta-dehydroamino acids, was studied by FTIR in dichloromethane and acetonitrile. To support spectroscopic interpretations and to gain some deeper insight into the Ac-(E)-DeltaPhe-NHMe molecule, the Ramachandran potential energy surface was calculated by the B3LYP/6-31G*//HF/3-21G method and the conformers localized were fully optimized at the B3LYP/6-31 + G** level. The spectra and calculations were compared with those of the related molecules Ac-DeltaAla-NHMe and Ac-(Z)-DeltaPhe-NHMe. The title compound assumes two conformational states in equilibrium in dichloromethane solution …

Stereoelectronic properties ofN-acetyl-α,β-dehydroamino acidN′-methylamides

α,β-Dehydroamino acids are useful peptide modifiers. However, their stereoelectronic properties still remain insufficiently recognized. Based on FTIR experiments in the range ofvs(N-H), AI, AII andvs(Cα=Cβ) and ab initio calculations with B3LYP/6–31G*, we studied the solution conformational preferences and the amide electron density perturbation of Ac-ΔXaa-NHMe, where ΔXaa=ΔAla, (E)-ΔAbu, (Z)-ΔAbu, (Z)-ΔLeu, (Z)-ΔPhe and ΔVal. Each of these dehydroamides adopts a C5 structure, which in Ac-ΔAla-NHMe is fully extended and accompanied by the strong C5 hydrogen bond. Interaction with bond Cα=Cβ lessens the amidic resonance within the flanking amide groups. TheN-terminal C=O bond is noticeably s…

Association of model peptides and dehydropeptides: N-acetyl-L-butyrine and (Z)-dehydrobutyrine N',N'-dimethylamides.

These comparative studies on the aggregation behaviour of Ac-(Z)-DeltaAbu-NMe(2) and Ac-L-Abu-NMe(2) in carbon tetrachloride were performed by the analysis of their FTIR spectra and by theoretical calculations. The percentage of the monomeric form (alpha) decreased as concentration increased and this occurred to a higher degree for the (Z)-DeltaAbu derivative than for its saturated analogue. The dimerization constant K(D), calculated on the basis of the intensity of the monomer and associate bands in the nu(s)(N-H) vibration region, is by three orders of magnitude larger for Ac-(Z)-DeltaAbu-NMe(2) than for Ac-L-Abu-NMe(2). The obtained dimer geometries of the dehydro- compound were calculat…

Conformational investigation of α,β-dehydropeptides VII*. Conformation of Ac-Pro-ΔAla-NHCH3 and Ac-Pro-(E)-ΔAbu-NHCH3: comparison with (Z)-substituted α,β-dehydropeptides†

The crystal structure and solution conformation of Ac-Pro-deltaAla-NHCH3 and the solution conformation of Ac-Pro-(E)-deltaAbu-NHCH3 were investigated by X-ray diffraction method and NMR, FTIR and CD spectroscopies. Ac-Pro-deltaAla-NHCH3 adopts an extended-coil conformation in the crystalline state, with all-trans peptide bonds and the deltaAla residue being in a C5 form, phi(1)=-71.4(4), psi(1)=-16.8(4), phi(2)= -178.4(3) and psi(2)= 172.4(3) degrees. In inert solvents the peptide also assumes the C5 conformation, but a gamma-turn on the Pro residue cannot be ruled out. In these solvents Ac-Pro-(E)-deltaAbu-NHCH3 accommodates a beta(II)-turn, but a minor conformer with a nearly planar dispo…

Large-Scale Synthesis of Mammalian Gonadoliberin without protection of side-chain functions

A simple, Large-scale preparation of mammalian gonadoliberin was elaborated using classical solution methods without protecting side-chain functions. At the final stage, a hexapeptide segment was condensed with the corresponding tetrapeptide and the obtained decapeptide was purified by a single chromatographic procedure on silica gel. The total efficiency of the whole synthesis and the purity of the product amounted to 34% and 98.3%, respectively.

Binding of Cu2+, Zn2+, and Ni(2+)-GnRH complexes with the rat pituitary receptor.

Complex of copper with the gonadotropin-releasing hormone, GnRH, competed more efficiently for the GnRH receptor than native GVRH, while complexes of nickel with GnRH and zinc with GnRH had slightly lower affinity. Copper ion added to the incubation mixture inhibited the buserelin binding to the receptor.

Conformational analysis of α,β-dehydropeptide models at the HF and DFT levels

Abstract The Ramachandran potential energy surfaces of N-acetyl-α,β-dehydroamino acid N′-monomethylamides Ac-ΔXaa-NHMe (ΔXaa=ΔAla, (Z)-ΔPhe; 1, 2) and N-acetyl-α,β-dehydroamino acid N′,N′-dimethylamides Ac-ΔXaa-NMe2 (ΔXaa=ΔAla, (Z)-ΔPhe, (Z)-ΔAbu; 3–5) were calculated at the HF/6-31G*//HF/3-21G level. The conformers localised were fully optimised at the DFT/B3LYP/6-31+G** level and their relative stabilities were analysed in terms of both π-conjugation and internal hydrogen bonding. The Ac-ΔXaa-NMe2 molecules reveal the low-energy conformer H/F, φ=−41±4°, ψ=128±4°, which is not too easily accessible for common amino acid residues. This conformer is stabilised by the bifurcated N2–CH3 O1 int…

Synthesis of Mammalian Gonadoliberin Analogs with the N-terminal glutamine or glutamine or glutamic acid

Synthesis of two mammalian gonadoliberin analogs, [Gln1]GnRH and [Glu1]GnRH, in solution by the peptide segment coupling of the [(2 + 4) + 4] type has been described.

Thymidylate synthases from Hymenolepis diminuta and regenerating rat liver: purification, properties, and inhibition by substrate and cofactor analogues.

Comparative studies of thymidylate synthases, isolated from the tapeworm, Hymenolepis diminuta, and regenerating liver of its host, rat, aimed at a possibility of specific inhibition of the helminthic enzyme, are presented. While similar in structure (dimers with monomer molecular masses of 33.7 kDa and 34.9 kDa, respectively) and parameters describing interactions with substrates and products, the tapeworm and rat enzymes differed in the dependences of reaction velocity on temperature (Arrhenius plots biphasic and linear, respectively). The tapeworm, compared with the host, enzyme was less sensitive to the competitive slow-binding inhibition by 5-fluoro-dUMP and its 2-thio congener, but eq…

N-Acetyl-α, β-dehydroamino acid N’-methylamides and N’, N’-Dimethylamides

Association of model peptides and dehydropeptides: N-acetyl-l-alanine- and dehydroalanine N′,N′-dimethylamides

Abstract The comparative studies on the association of Ac-ΔAla-NMe 2 and Ac- l -Ala-NMe 2 in carbon tetrachloride were performed by the analysis of their average molecular weight, dipole moments and FTIR spectra. To aid spectroscopic interpretation and gain some deeper insight into the nature of associates, the geometries of the minimum energy of the dimers of Ac-ΔAla-NMe 2 and Ac- l -Ala-NMe 2 were calculated by the B3LYP/6-31+G** method. The average molecular weight in the studied concentration range, for the ΔAla and l -Ala peptide, as determined by the osmometric method, did not exceed 1.5 and 1.2 of the monomeric mass, respectively. Accordingly, the percentage of the monomeric form (α)…

Conformational properties of N-acetyl-N-methyl-alpha,beta-dehydroalanine N'-methylamide.

The conformational properties of Ac-Delta(Me)Ala-NHMe (N-acetyl-N-methyl-alpha,beta-dehydroalanine N'-methylamide), as the simplest model of N-methyl-alpha,beta-dehydroamino acids, was examined with theoretical methods and in comparison with Ac-DeltaAla-NHMe and Ac-DeltaAla-NMe(2). The N-terminal amide of the Delta(Me)Ala residue easily adopts the configuration cis and the torsion angles phi, psi are highly flexible. The Delta(Me)Ala residue is a conformational flexibilizer as compared to the parent DeltaAla, which is a conformational stiffener. This seems to be the reason why Delta(Me)Ala is found in small natural cyclic peptides, where it ensures the conformational flexibility necessary f…

ChemInform Abstract: Convenient High Yielding Gram Scale Solution Synthesis of Methionine-Enkephalin.

A simple, large-scale synthesis of a cytokine, methionine-enkephalin, Tyr-Gly-Gly-Phe-Met, has been elaborated. Classical solution peptide chemistry methods without protection of amino acid side-chain functions and 1+(2+2) segment condensation were used. A nine-step synthesis from commercial amino acid derivatives was developed with yields ranging from 86% to 99%, averaging 92%. The purity of all intermediates was found to be 99.0-100% by HPLC. The process has been used to prepare greater than 150 g quantities of the pentapeptide as a monohydrate of 100% purity. Hydantoin formation was observed during saponification of Boc-Tyr-Gly-Gly-Phe-Met-OMe and minimised.

Peptide synthesis with 5-amino-1-methyl-1H-[1,2,4]triazole-3-carboxylic acid

Abstract In the search for the peptide synthesis of new potential lexitropsins, starting with methyl 5‐amino‐1‐methyl‐1H‐[1,2,4]triazole‐3‐carboxylate 1a, we synthesized the chloroacetyl derivative of 2a, which was hydrolyzed to acid 2b and ammonolyzed to the peptide 2c. A more effective route was the use of (t‐butoxycarbonyl)glycyl‐benzotriazolide 3 to the acylation 1a, which leads the N/C protected peptide 4. This peptide was selectively N‐deprotected to be the useful segment 5 for further peptide syntheses to the N‐terminus. It was also C‐deprotected, that is hydrolyzed to give peptide 2c for further C‐extension. To the best of our knowledge, this is the first peptide that is a derivativ…

Synthesis of peptides with α,β‐dehydroamino acids, III. Debenzyloxycarbonylation and detrifluoroacetylation of dehydroalanine and dehydrophenylalanine peptides

The removal of amino protecting groups from a series of twelve model Z-3) or TFA-dipeptides of dehydroalanine and (Z)-dehydrophenylalanine was investigated. During this deprotection, peptides with Δ Ala are prone to side reactions to a higher extent than those with Δ Phe. Therefore it is interesting to note that from the Δ Ala peptides, the Z group can be split off in preparative manner with HCO2NH4 in the presence of Pd C (Table 4). Synthese von Peptiden mit α,β-Dehydroaminosauren, III.– Debenzyloxycarbonylierung und Detrifluoracetylierung von Dehydroalanin- und Dehydrophenylalanin-Peptiden An einer Serie von zwolf Z-3) oder TFA-Modellpeptiden mit Dehydroalanin und (Z)-Dehydrophenylalanin …

Conformational investigation of α,β‐dehydropeptides Part VI. Molecular and crystal structure of benzyloxycarbonylglycyl‐(Z )‐dehydrophenylalanine

The structure of a peptide containing C-terminal dehydrophenylalanine, Z-Gly-(Z)-delta Phe (C19H18N2O5, MW = 354) was determined from single-crystal X-ray diffraction data. Needle-shaped crystals were grown from a 1:1 mixture of methanol-acetone in the monoclinic space group P2(1) with a = 14.717(4), b = 4.941(2), c = 12.073(4) A, beta = 103.72(4) degrees; V = 852.86(8) A3, Z = 2 and Dc = 1.32 g cm-3. The structure was solved by direct methods using SHELXS-86 and refined to a final R-index of 0.032 for 1714 observed reflections. The peptide adopts a conformation folded at the glycine residue, and principal torsion angles are omega 0 = -167.6(2) degrees, phi 1 = -71.8(3) degrees, psi 1 = -31…

An Improved Synthesis of 1-Methyl-2-trichloroacetylimidazole.

(2005). AN IMPROVED SYNTHESIS OF 1-METHYL-2-TRICHLOROACETYLIMIDAZOLE. Organic Preparations and Procedures International: Vol. 37, No. 4, pp. 403-405.

Ovulation-inducing activity of luliberin (LHRH) complexed by copper(II), nickel(II), and zinc(II) ions.

We have shown that the complexation of luteinizing hormone releasing hormone, luliberin (LHRH), a hypothalamic neurohormone, by Cu(II), Ni(II), and Zn(II) may affect its basic, ovulation-inducing potency in the dose responsive manner. Some explanation of the obtained results are offered here.

Conformational investigation of αβ-dehydropeptides

Solution conformations of three series of model peptides, homochiral Ac-Pro-L-Xaa-NHCH3 and heterochiral Ac-Pro-D-Xaa-NHCH3 (Xaa = Val, Phe, Leu, Abu, Ala) as well as alpha,beta-unsaturated Ac-Pro-delta Xaa-NHCH3 [delta Xaa = delta Val, (Z)-delta Phe, (Z)-delta Leu, (Z)-delta Abu] were investigated in CDCl3 and CH2Cl2 by 1H-, 13C-NMR, and FTIR spectroscopy. NH stretching absorption spectra, solvent shifts delta delta for NH (Xaa) and NHCH3 on going from CDCl3 to (CD3)2SO, diagnostic interresidue proton NOEs, and trans-cis isomer ratios were examined. These studies performed showed the essential difference in conformational propensities between homochiral peptides (L-Xaa) on the one hand and…

ARGININE, HISTIDINE AND TRYPTOPHAN IN PEPTIDE SYNTHESIS. THE IMIDAZOLE FUNCTION OF HISTIDINE

Conformational investigation of α,β-dehydropeptides. X. Molecular and crystal structure of Ac-ΔAla-NMe2 compared with those of Ac-L-Ala-NMe2, Ac-DL-Ala-NMe2 and other dimethylamides

A series of three homologous dimethyldiamides Ac-DeltaAla-NMe2, Ac-L-Ala-NMe2 and Ac-DL-Ala-NMe2 has been synthesized and the structures of these amides determined from single-crystal X-ray diffraction data. To learn more about the conformational preferences of compounds studied, the fully relaxed (phi-psi) conformational energy maps in vacuo (AM1) of Ac-DeltaAla-NMe2 and Ac-L-Ala-NMe2 were obtained, and the calculated minima reoptimized with the DFT/B3LYP/6-31G** method. The crystal-state results have been compared with the literature data. Ac-DeltaAla-NMe2 and other alpha,beta-dehydroamino acid dimethyldiamides, Ac-DeltaXaa-NMe2 adopt the conservative conformation of the torsion angles ph…