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Titolo:
Protease inhibitors - Part 12. Synthesis of potent matrix metalloproteinase and bacterial collagenase inhibitors incorporating sulfonylated N-4-nitrobenzyl-beta-alanine hydroxamate moieties
Autore:
Scozzafava, A; Ilies, MA; Manole, G; Supuran, CT;
Indirizzi:
Univ Florence, Lab Chim Inorgan & Bioinorgan, I-50121 Florence, Italy UnivFlorence Florence Italy I-50121 Bioinorgan, I-50121 Florence, Italy Univ Agr Sci & Vet Med, Fac Biotechnol, Dept Chem, Bucharest 71331, Romania Univ Agr Sci & Vet Med Bucharest Romania 71331 Bucharest 71331, Romania Colentina Hosp, Dept Internal Med, Bucharest, Romania Colentina Hosp Bucharest Romania Dept Internal Med, Bucharest, Romania
Titolo Testata:
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
fascicolo: 1, volume: 11, anno: 2000,
pagine: 69 - 79
SICI:
0928-0987(200007)11:1<69:PI-P1S>2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
CARBONIC-ANHYDRASE INHIBITORS; HUMAN NEUTROPHIL COLLAGENASE; CLOSTRIDIUM-HISTOLYTICUM; INDIVIDUAL COLLAGENASES; SULFONAMIDE INHIBITORS; DRUG DESIGN; ACID; SELECTIVITY; DERIVATIVES; BINDING;
Keywords:
N-4-nitrobenzyl-beta-alanine; hydroxamate; sulfonyl halide; matrix metalloproteinase; bacterial collagenase; enzyme inhibitor;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
45
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 et al., "Protease inhibitors - Part 12. Synthesis of potent matrix metalloproteinase and bacterial collagenase inhibitors incorporating sulfonylated N-4-nitrobenzyl-beta-alanine hydroxamate moieties", EUR J PH SC, 11(1), 2000, pp. 69-79

Abstract

N-4-Nitrobenzyl-beta-alanine was reacted with alkyl/arylsulfonyl halides, followed by conversion of the COOH to the CONHOH group. Structurally related compounds were obtained by reaction of N-4-nitrobenzyl-beta-alanine with aryl isocyanates, arylsulfonyl isocyanates or benzoyl isothiocyanate, followed by similar conversion of the COOH into the CONHOH moiety. Another subseries of derivatives was prepared from sulfanilyl- or metanilyl-4-nitrobenzyl-beta-alanine by reaction with arylsulfonyl isocyanates, followed by the introduction of the hydroxamate moiety. The new compounds were assayed as inhibitors of four matrix metalloproteinases (MMPs), MMP-1, MMP-2, MMP-8 and MMP-9, and of the Clostridium histolyticum collagenase (ChC). Some of the prepared hydroxamate derivatives proved to be very effective collagenase/gelatinase inhibitors, depending on the substitution pattern at the sulfonamido moiety. Substitutions leading to the best inhibitors of MMP-1, a short-pocket enzyme, were those involving pentafluorophenylsulfonyl or 3-trifluoromethyl-phenylsulfonyl at P-1' (K-I of 3-5 nM). For MMP-2, MMP-8 and MMP-9 (deep-pocket enzymes), the best inhibitors were those containing perfluoroalkylsulfonyl- and substituted-arylsulfonyl moieties, such as pentafluorophenylsulfonyl, 3- and 4-protected-aminophenylsulfonyl-, 3- and 4-carboxy-phenylsulfonyl-, arylsulfonylureido- or arylsulfonylureido-sulfanilyl-/metanilyl moieties at P-1'. Bulkier groups in this position, such as 1- and 2-naphthyl-, substituted-naphthyl or quinoline-8-yl- moieties, among others, led to less effective MMP/ChC inhibitors. The best ChC inhibitors were again thosecontaining pentafluorophenylsulfonyl, 3- and 4-protected-aminophenylsulfonyl P-1. groups. This study demonstrates that the 4-nitrobenzyl moiety, investigated here for the first time, is an efficient P-2' anchoring moiety, whereas the beta-alanyl scaffold can successfully replace the alpha-amino acyl one, for obtaining potent MMP/ChC inhibitors. (C) 2000 Elsevier Science B. V. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 01/12/20 alle ore 07:57:56