Protease inhibitors. Part 12. Synthesis of potent matrix metalloproteinase and bacterial collagenase inhibitors incorporating sulfonylated N-4-nitrobenzyl-beta-alanine hydroxamate moieties.
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 those containing 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.
Università degli Studi, Laboratorio di Chimica Inorganica e Bioinorganica, Florence, Italy.
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D001190:Arylsulfonates / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors; D003012:Microbial Collagenase / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology
D001190:Arylsulfonates; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D003012:Microbial Collagenase