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Titolo:
Protease inhibitors: Synthesis of potent bacterial collagenase and matrix metalloproteinase inhibitors incorporating N-4-nitrobenzylsulfonylglycine 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:
JOURNAL OF MEDICINAL CHEMISTRY
fascicolo: 9, volume: 43, anno: 2000,
pagine: 1858 - 1865
SICI:
0022-2623(20000504)43:9<1858:PISOPB>2.0.ZU;2-V
Fonte:
ISI
Lingua:
ENG
Soggetto:
CARBONIC-ANHYDRASE INHIBITORS; HUMAN NEUTROPHIL COLLAGENASE; LOWERING AROMATIC/HETEROCYCLIC SULFONAMIDES; CLOSTRIDIUM-HISTOLYTICUM; INDIVIDUAL COLLAGENASES; DRUG DESIGN; ACID; SELECTIVITY; DERIVATIVES; BINDING;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
47
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: Synthesis of potent bacterial collagenase and matrix metalloproteinase inhibitors incorporating N-4-nitrobenzylsulfonylglycine hydroxamate moieties", J MED CHEM, 43(9), 2000, pp. 1858-1865

Abstract

A series of compounds was prepared by reaction of alkyl/arylsulfonyl halides with N-4-nitrobenzylglycine, followed by conversion of the COOK to the CONHOH group, with hydroxylamine in the presence of carbodiimides. Other structurally related compounds were obtained by reaction of N-4-nitrobenzylglycine with aryl isocyanates, arylsulfonyl isocyanates, or benzo;yl isothiocyanate, followed by the similar conversion of the COOK into the CONHOH moiety. Another subseries of derivatives was prepared from sulfanilyl- or metanilyl-4-nitrobenzylglycine by reaction with arylsulfonyl isocyanates, followed by conversion of the COOK to 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 best inhibitors of MMP-1, a short pocket enzyme, were those involving pentafluorophenylsulfonyl or3-trifluoromethylphenylsulfonyl moieties at P-1, (K-I's of 3-5 nM). For MMP-2, MMP-8, and MMP-9 (deep-pocket enzymes), best inhibitors were especially those containing long perfluoroalkylsulfonyl and substituted-arylsulfonylmoieties, such as pentafluorophenylsulfonyl, 3- and 4-protected-aminophenylsulfonyl, 3- and 4-carboxyphenylsulfonyl, arylsulfonylureido, or arylsulfonylureidosulfanilyl/metanilyl moieties, at P-1. Bulkier groups in this position, such as 1- and 2-naphthyl, substituted-naphthyl, or quinolin-8-yl moieties among others, led to less effective MMP/ChC inhibitors. Best ChC inhibitors were again those containing pentafluorophenylsulfonyl or 3- and 4-protected-aminophenylsulfonyl P-1 anchoring groups, suggesting that this protease is also a short-pocket wider-neck one (more similar to MMP-1). This study also proves that the 4-nitrobenzyl moiety is an efficient Pz anchoring moiety and that sulfonylureido, ureido, or carboxythioureido substitutions at P-1 are also tolerated for obtaining potent sulfonylated amino acid hydroxamate-like MMP/ChC inhibitors.

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Documento generato il 04/12/20 alle ore 13:10:26