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ASYMMETRIC TRANSFORMATION OF AMINO ACIDS IN N-SALICYLIDENE AMINO ACYL-L-ISOLEUCINATOCOPPER(II)

A new asymmetric transformation of amino acids was described.Thus, when N-salicylidene-D-alanyl-, D-phenylalanyl-, or D-phenyl-glycyl-L-isoleucinatocopper(II) was incubated at pH 8.5 and 80 deg C, the resulting mixture at equilibrium contained a complex of L-L-dipeptide in the contents of 63-76percent.The epimerization of dipeptides is based on the enhanced activity of N-terminal amino acids through complex formation.

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Convergent synthesis of (-)-mirabazole B using a chloroimidazolidium coupling reagent, CIP

(-)-Mirabazole B (1), an alkaloid consisting of four successive thiazoline/thiazole rings, has been synthesized in a convergent route. The key intermediate, a linear tripeptide amide 13 composing of three S-benzyl-2-methylcysteine residues, was prepared using 2-chloro-1,3-dimelhyl-imidazolidium hexafluorophosphate (CIP) in the presence of 1-hydroxy-7-azabenzotriazole (HOAt) as a coupling agent. The successive thiazoline/thiazole rings were constructed by TiCl4-mediated cyclization followed by Hantzsch reaction without difficulty.

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Replacement of glycine with dicarbonyl and related moieties in analogues of the C-terminal pentapeptide of cholecystokinin: CCK2 agonists displaying a novel binding mode

Recent advances in the field of cholecystokinin have indicated the possible occurrence of multiple affinity states of the CCK2 receptor. Besides, numerous pharmacological experiments performed ‘in vitro’ and ‘in vivo’ support the eventuality of different pharmacological profiles associated to CCK2 ligands. Indeed, some agonists are essentially anxiogenic and uneffective in memory tests, whereas others are not anxiogenic and appear as able to reinforce memory. The reference compound for the latter profile is the CCK-8 analogue BC 264 (Boc-Tyr(SO3H)-gNle-mGly-Trp-(NMe)Nle-Asp-Phe-NH2). However, although tetrapeptide ligands based on CCK-4 (Trp-Met-Asp-Phe-NH2) are known to possess sufficient structural features for CCK2 recognition, none shares the properties of BC 264. Hence we have developed new short peptidic or pseud-opeptidic derivatives containing the C-terminal tetrapeptide of BC 264. Our results indicate that some compounds characterized by the presence of two carbonyl groups at the N-terminus, as in 2b (HO2C-CH2-CONH-Trp-(NMe)Nle-Asp-Phe-NH2), are likely to show a BC 264-like profile, bind to the CCK2 receptor in a specific way, and display remarkable affinities (2b: 0.28 nM on guinea-pig cortex membrane preparations). This original binding mode is discussed and further enlightened by NMR and molecular modeling studies.

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Stereoselective micellar catalysis. Reactions of amino-acid ester derivatives with N-acyl-L-histidine in micelles

Mixed micelles of the N-acyl-L-histidines (I) and cetyltrimethylammonium bromide (CTABr) are effective stereoselective catalysts for cleavage of the enantiomeric amino-acid ester derivatives (II). The rate enhancements and stereoselective effects depend on the hydrophobicity of (I) in micelles, and an increase in the chain length of the acyl part of (I) increases both the reaction rates and the enantiomer rate ratio. Mixed micelles with anionic and nonionic surfactants are relatively less effective stereoselective catalysts. Kinetic analysis indicates that the stereoselectivity in mixed micelles is mainly determined by catalytic acyl transfer to the optically active imidazole group of (I).

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Rational design and binding of modified cell-wall peptides to vancomycin-group antibiotics: Factorising free energy contributions to binding

Modified cell-wall peptides have been rationally designed and studied in a semi-quantitative approach to factorising free energy contributions in binding to vancomycin-group antibiotics in aqueous solution. Binding energies for succinyl and fumaryl-D-Ala dipeptides. and N-oxalyl-gamma-aminobutyric acid analogues, are compared with binding energies for the natural substrate N-Ac-D-Ala-D-Ala, and the truncated mono-peptide N-Ac-D-Ala. We estimate the binding energy of the N-terminal carboxyl group, by four independent analyses, to he -(14 to 17)¡À7 kJ mol-1 when differences in ligand binding energies are corrected for differences in contributions from the “cost” of restricting rotations and “benefits” of hydrophobic interactions. The carboxylate interaction comprises both a charged – COO-…HN hydrogen bond plus face to face pi-stacking between the carboxylate group and an aromatic ring in the antibiotic binding pocket.

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Substituted hippurates and hippurate analogs as substrates and inhibitors of peptidylglycine alpha-hydroxylating monooxygenase (PHM)

Peptidyl alpha-hydroxylating monooxygenase (PHM) functions in vivo towards the biosynthesis of alpha-amidated peptide hormones in mammals and insects. PHM is a potential target for the development of inhibitors as drugs for the treatment of human disease and as insecticides for the management of insect pests. We show here that relatively simple ground state analogs of the PHM substrate hippuric acid (C6H5-CO-NH-CH2-COOH) inhibit the enzyme with Ki values as low as 0.5 muM. Substitution of sulfur atom(s) into the hippuric acid analog increases the affinity of PHM for the inhibitor. Replacement of the acetylglycine moiety, -CO-NH-CH2-COOH with an S-(thioacetyl)thioglycolic acid moiety, -CS-S-CH2-COOH, yields compounds with the highest PHM affinity. Both S-(2-phenylthioacetyl)thioglycolate and S-(4-ethylthiobenzoyl)thioglycolic acid inhibit the proliferation of cultured human prostate cancer cells at concentrations >100-fold excess of their respective Ki values. Comparison of Ki values between mammalian PHM and insect PHM shows differences in potency suggesting that a PHM-based insecticide with limited human toxicity can be developed.

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Carboxylic acid bioisosteres of gamma-linked dipeptide analogues of the folate-based thymidylate synthase (TS) inhibitor, 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583)

Tetrazole carboxylic acid bioisosteres of gamma-linked dipeptide derivatives of 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid (ICI 198583), a folate-based inhibitor of thymidylate synthase (TS), were synthesised by multistep routes starting from the appropriate pteroic acid analogue and Z-D-Ala or D-Glu. They exhibited excellent TS inhibitory activities which, however, were not accompanied by a parallel improvement in the L1210 cell growth inhibition.

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Effect of Linker Stereochemistry on the Activity of Indolinobenzodiazepine Containing Antibody-Drug Conjugates (ADCs)

Antibody-drug conjugates (ADCs) that incorporate potent indolinobenzodiazepine DNA alkylators as the payload component are currently undergoing clinical evaluation. In one ADC design, the payload molecules are linked to the antibody through a peptidase-labile l-Ala-l-Ala linker. In order to determine the role of amino acid stereochemistry on antitumor activity and tolerability, we incorporated l- and d-alanyl groups in the dipeptide, synthesized all four diastereomers, and prepared and tested the corresponding ADCs. Results of our preclinical evaluation showed that the l-Ala-l-Ala configuration provided the ADC with the highest therapeutic index (antitumor activity vs toxicity).

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Synthesis of steroidal triply-bridged cyclophanes

Steroidal triply-bridged cyclophanes are synthesised using cholic acid derivatives as bridge units; cyclophane 3 moderately binds to organic guest molecules and enantio-selectively binds to N-Z-phenylalanine.

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Reagent-controlled diastereoselective synthesis of (2S,3R)- and (2R,3R)-2,3-diaminobutanoic acid derivatives using proline-catalyzed alpha-hydrazination reaction

(2S,3R)- and (2R,3R)-2,3-Diaminobutanoic acid (Dab) derivatives were efficiently synthesized from Cbz-(R)-alanine using the proline-catalyzed diastereoselective alpha-hydrazination reaction and the SmI2-promoted reductive cleavage of the N-N bond as the key steps.

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