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Titolo:
Protease inhibitors. Part 8: Synthesis of potent Clostridium histolyticum collagenase inhibitors incorporating sulfonylated L-alanine hydroxamate moieties
Autore:
Scozzafava, A; Supuran, CT;
Indirizzi:
Univ Florence, Lab Chim Inorgan & Bioinorgan, I-50121 Florence, Italy UnivFlorence Florence Italy I-50121 Bioinorgan, I-50121 Florence, Italy
Titolo Testata:
BIOORGANIC & MEDICINAL CHEMISTRY
fascicolo: 3, volume: 8, anno: 2000,
pagine: 637 - 645
SICI:
0968-0896(200003)8:3<637:PIP8SO>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN NEUTROPHIL COLLAGENASE; CARBONIC-ANHYDRASE INHIBITORS; MATRIX METALLOPROTEINASES; INDIVIDUAL COLLAGENASES; CONVERTING ENZYME; THIOL INHIBITORS; DRUG DESIGN; ISOZYME-I; DERIVATIVES; ACIDS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
54
Recensione:
Indirizzi per estratti:
Indirizzo: Supuran, CT Univ Florence, Lab Chim Inorgan & Bioinorgan, Via Gino Capponi7, I-50121 Florence, Italy Univ Florence Via Gino Capponi 7 Florence Italy I-50121 Italy
Citazione:
A. Scozzafava e C.T. Supuran, "Protease inhibitors. Part 8: Synthesis of potent Clostridium histolyticum collagenase inhibitors incorporating sulfonylated L-alanine hydroxamate moieties", BIO MED CH, 8(3), 2000, pp. 637-645

Abstract

A series of hydroxamates was prepared by reaction of alkyl/arylsulfonyl halides with N-2-chlorobenzyl-L-alanine, followed by conversion of the COOH moiety to the CONHOH group, with hydroxylamine in the presence of carbodiimides. Other structurally related compounds were obtained by reaction of N-2-chlorobenzyl-L-alanine with aryl isocyanates, arylsulfonyl isocyanates or benzoyl isothiocyanate, followed by the similar conversion of the COOH into the CONHOH moiety. The new compounds were assayed as inhibitors of the Clostridium histolyticum collagenase, ChC (EC 3.4.24.3), a bacterial zinc metallo-peptidase which degrades triple helical collagen as well as a large number of synthetic peptides. The prepared hydroxamate derivatives proved to be100-500 times more active collagenase inhibitors than the corresponding carboxylates. Substitution patterns leading to best ChC inhibitors (both for carboxylates as well as for the hydroxamates) were those involving perfluoroalkylsulfonyl- and substituted-arylsulfonyl moieties, such as pentafluorophenylsulfonyl; 3- and 4-protected-aminophenylsulfonyl-; 3- and 4-carboxyphenylsulfonyl-; 3-trifluoromethyl-phenylsulfonyl; as well as 1- and 2-naphthyl-, quinoline-8-yl- or substituted-arylsulfonylamidocarboxyl moieties amongothers. Similarly to the matrix metalloproteinase (MMP) hydroxamate inhibitors, ChC inhibitors of the type reported here must incorporate hydrophobicmoieties at the P-2' and P-3' Sites, in order to achieve tight binding to the enzyme. This study also proves that the 2-chlorobenzyl moiety, investigated here for the first time, is an efficient P-2, anchoring moiety for obtaining potent ChC inhibitors. (C) 2000 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 30/11/20 alle ore 16:29:38