Dipeptidyl Enoates As Potent Rhodesain Inhibitors That Display a Dual Mode of Action
Dipeptidyl enoates were prepared through a high-yielding two-step synthetic route. They have a dipeptidic structure with a 4-oxoenoate moiety as a warhead with multiple reactive sites. Dipeptidyl enoates were screened against rhodesain and human cathepsins B and L, and were found to be potent and selective inhibitors of rhodesain. Among them (S,E)-ethyl 5-((S)-2-{[(benzyloxy)carbonyl]amino}-3-phenylpropanamido)-7-methyl-4-oxooct-2-enoate (6) was the most potent, with an IC50 value of 16.4 nm and kinact/Ki=1.6×106 m−1 s−1 against rhodesain. These dipeptidyl enoates display a reversible mode of inhibition at very low concentrations and an irreversible mode at higher concentrations. Inhibition…
ChemInform Abstract: Diastereoselectivity in Organometallic Additions to the Carbonyl Group of Protected Erythrulose Derivatives.
We have investigated a number of nucleophillic additions to l-erythrulose derivatives (4−12) bearing protective O-silyl, O-benzyl, and O-trityl groups in various relative positions. The results are discussed in the frame of chelated vs nonchelated transition states with additional support of previously published theoretical calculations. Sound evidence appears to exist for the formation of α-chelates as the key intermediates in nucleophillic additions to these α,β-dioxygenated ketones. Since such evidence is still lacking in the case of β-chelates, proposals of their intermediacy have been relegated in favor of the more solid Felkin−Anh model, which predicts the same stereochemical result. …
ChemInform Abstract: Stereoselective Synthesis of syn-α-Methyl-β-hydroxy Esters.
Abstract Boron enolates of an ethyl ketone structurally related to erythrulose react with achiral aldehydes in a highly stereoselective fashion to yield 1,2- syn /1,3- syn stereoisomers. Oxidative cleavage of the aldol adducts yields enantiopure O -formylated syn -α-methyl-β-hydroxy esters, easily cleaved to the corresponding hydroxyl-free compounds. The aforementioned ketone behaves therefore as a chiral propionate enolate equivalent.
Antiprotozoal and cysteine proteases inhibitory activity of dipeptidyl enoates
A family of dipeptidyl enoates has been prepared and tested against the parasitic cysteine proteases rhodesain, cruzain and falcipain-2 related to sleeping sickness, Chagas disease and malaria, respectively. They have also been tested against human cathepsins B and L1 for selectivity. Dipeptidyl enoates resulted to be irreversible inhibitors of these enzymes. Some of the members of the family are very potent inhibitors of parasitic cysteine proteases displaying k2nd (M−1s−1) values of seven orders of magnitude. In vivo antiprotozoal testing was also performed. Inhibitors exhibited IC50 values in the micromolar range against Plasmodium falciparum, Trypanosoma brucei, Trypanosoma cruzi and ev…
A Synthetic Model for the [4+2] Cycloaddition in the Biosynthesis of the Brevianamides, Paraherquamides, and Related Compounds
Abstract The reactivity of model systems for the proposed [4+2] cycloaddition in the biosynthesis of the brevianamides, paraherquamides, and marcfortines is explored. The model for the intermolecular reaction reveals that the cycloaddition takes place under mild conditions only if activated, very reactive dienophiles are used. When relatively unreactive dienophiles such as cyclopentene and cyclohexene are used, harsh reaction conditions and/or a Lewis acid catalyst are necessary for the reaction. In contrast, the model for the intramolecular reaction demonstrates that the cycloaddition takes place within a few hours at room temperature, even in the absence of a Lewis acid catalyst. Conclusi…
Aldol Reactions with Erythrulose Derivatives: Stereoselective Synthesis of Differentially Protected syn -α,β-Dihydroxy Esters
Boron enolates of 1-O-silylated erythrulose 3,4-acetonides prepared with Brown's chloro-dicyclohexylborane/tertiary amine system have been shown to react with achiral aldehydes in a highly stereoselective way to yield a 1,2-syn/1,3-syn stereoisomer. Through oxidative cleavage of the aldol adducts with periodic acid hydrate, enantiopure syn-α,β-dihydroxy esters with either hydroxyl group differently protected have been prepared. These erythrulose derivatives therefore behave as a chiral hydroxy acetate (glycolate) enolate equivalent.
Design, Synthesis and Evaluation of Fluorescent Analogues of Abscisic Acid
A fluorescent analogue of abscisic acid has been prepared by combining (S)‐abscisic acid (ABA) with nitrobenzoxadiazole (NBD) fluorophore using ethanol amine as a linker. Isomerization of the double bond at the side chain of abscisic acid happened during the synthesis. The resulting fluorophore analogues derived from both isomeric compounds entered cells suggesting a wide applicability of the ABA‐NBD conjugates as fluorescent probes to study ABA mechanism of action. The functional properties of the isomeric ABA‐NBD conjugates were tested in vitro, by measuring TNFα expression and nitrite concentration in LPS‐stimulated macrophages and compared with their non‐fluorescent ABA isomers. Rationa…
Dipeptidyl Nitroalkenes as Potent Reversible Inhibitors of Cysteine Proteases Rhodesain and Cruzain.
Dipeptidyl nitroalkenes are potent reversible inhibitors of cysteine proteases. Inhibitor 11 resulted to be the most potent one with Ki values of 0.49 and 0.44 nM against rhodesain and cruzain, respectively. According to enzymatic dilution and dialysis experiments, as well as computational and NMR studies, dipeptidyl nitroalkenes are tightly binding covalent reversible inhibitors. We thank Fundacion Española para la Ciencia y la Tecnología (Fecyt) and Generalitat Valenciana (AICO/2016/32) for financial support. T S. and B.E. thank the DFG (Deutsche Forschungsgemeinschaft) in the framework of the SFB630 for financial support. We thank Universitat Jaume I for technical suppport and funding. U…
Diastereoselective synthesis of enantiomeric tertiary alcohols via nucleophilic additions to protected D- and L-erythrulose derivatives
Abstract The diastereoselectivity of the addition of several organometallic reagents to the carbonyl group of protected D - and L -erythrulose derivatives has been investigated. Tertiary alcohols are stereoselectively formed, the diastereomeric ratio being markedly dependent on the reagent type, solvent and temperature.
Boron aldol additions with erythrulose derivatives: dependence of stereoselectivity on the type of protecting group
Abstract Boron aldol additions of 1- O -silylated 3,4-di- O -benzyl- and 3,4-di- O -benzoyl- l -erythrulose and achiral aldehydes using dicyclohexylboron chloride have been investigated. The dibenzyl derivative gave syn/syn stereoisomers with high stereoselectivity, whereas the dibenzoyl derivative gave syn/anti stereoisomers. It is believed that, while the dibenzoyl erythrulose gives rise to the E enolate in the presence of dicyclohexylboron chloride, as usually observed with this reagent, only the Z enolate is formed in the case of the dibenzyl derivative.
ChemInform Abstract: Aldol Reactions with Erythrulose Derivatives: Stereoselective Synthesis of Differentially Protected syn-α,β-Dihydroxy Esters.
Boron enolates of 1-O-silylated erythrulose 3,4-acetonides prepared with Brown's chloro-dicyclohexylborane/tertiary amine system have been shown to react with achiral aldehydes in a highly stereoselective way to yield a 1,2-syn/1,3-syn stereoisomer. Through oxidative cleavage of the aldol adducts with periodic acid hydrate, enantiopure syn-α,β-dihydroxy esters with either hydroxyl group differently protected have been prepared. These erythrulose derivatives therefore behave as a chiral hydroxy acetate (glycolate) enolate equivalent.
Stereoselective synthesis of syn-α-methyl-β-hydroxy esters
Abstract Boron enolates of an ethyl ketone structurally related to erythrulose react with achiral aldehydes in a highly stereoselective fashion to yield 1,2- syn /1,3- syn stereoisomers. Oxidative cleavage of the aldol adducts yields enantiopure O -formylated syn -α-methyl-β-hydroxy esters, easily cleaved to the corresponding hydroxyl-free compounds. The aforementioned ketone behaves therefore as a chiral propionate enolate equivalent.
ChemInform Abstract: Boron Aldol Additions with Erythrulose Derivatives: Dependence of Stereoselectivity on the Type of Protecting Group.
Abstract Boron aldol additions of 1- O -silylated 3,4-di- O -benzyl- and 3,4-di- O -benzoyl- l -erythrulose and achiral aldehydes using dicyclohexylboron chloride have been investigated. The dibenzyl derivative gave syn/syn stereoisomers with high stereoselectivity, whereas the dibenzoyl derivative gave syn/anti stereoisomers. It is believed that, while the dibenzoyl erythrulose gives rise to the E enolate in the presence of dicyclohexylboron chloride, as usually observed with this reagent, only the Z enolate is formed in the case of the dibenzyl derivative.
Highly diastereoselective additions of organometallic reagents to 1-O-silylated 3,4-Di-O-benzyl-L-erythrulose derivatives
Abstract The diastereoselectivity of the addition of several organometallic reagents to the carbonyl group of the title compounds has been investigated. Some organomagnesium reagents display high diastereoselectivities (90–99%) and the major products are those predicted by the α-chelation model.
Synthesis of Protected Enantiopure Erythrulose Derivatives
D- and l-Erythrulose derivatives 2–6 bearing protective O-silyl and O-benzyl groups in various positions were synthesized in enantiopure form from l-ascorbic acid, D-isoascorbic acid, and D-glucose.
Diastereoselectivity in Organometallic Additions to the Carbonyl Group of Protected Erythrulose Derivatives
We have investigated a number of nucleophillic additions to L-erythrulose derivatives (4-12) bearing protective O-silyl, O-benzyl, and O-trityl groups in various relative positions. The results are discussed in the frame of chelated vs nonchelated transition states with additional support of previously published theoretical calculations. Sound evidence appears to exist for the formation of alpha-chelates as the key intermediates in nucleophillic additions to these alpha,beta-dioxygenated ketones. Since such evidence is still lacking in the case of beta-chelates, proposals of their intermediacy have been relegated in favor of the more solid Felkin-Anh model, which predicts the same stereoche…
Rat mammary-gland transferrin: nucleotide sequence, phylogenetic analysis and glycan structure
The complete cDNA for rat mammary-gland transferrin (Tf) has been sequenced and also the native protein isolated from milk in order to analyse the structure of the main glycan variants present. A lactating-rat mammary-gland cDNA library in lambda gt10 was screened with a partial cDNA copy of rat liver Tf and subsequently rescreened with 5′ fragments of the longest clones. This produced a 2275 bp insert coding for an open reading frame of 695 amino acid residues. This includes a 19-amino acid signal sequence and the mature protein containing 676 amino acids and one N-glycosylation site in the C-terminal domain at residue 490. Phylogenetic analysis was carried out using 14 translated Tf nucle…