Design and Synthesis of Sulfur Based Inhibitors of Matrix Metalloproteinase-1

Abstract

Fibroblast collagenase (MMP-1), a member of the matrix metalloproteinases family, is believed to be a pathogenesis of arthritis, by cleaving triple-helical type II collagen in cartilage. From the similarity of the active site zinc binding mode with hydroxamate, we designed and synthesized α-mercaptocarbonyl possessing compounds (3—5), which incorporated various peptide sequences as enzyme recognition sites. The P₄–P₁ peptide incorporating compound (3) exhibited as potent inhibition as the hydroxamate (1) and the carboxylate (2) type inhibitors, with an IC₅₀ of 10⁻⁶ M order against MMP-1. But the inhibitor (3) related compounds (6—8) displayed decreased or no inhibitory potencies. These results suggest that the existence of both the carbonyl and thiol groups might be critical for the inhibition, and the distance between the two functional groups is important for inhibitory potency. For P_n′ peptide incorporating compounds (4a—k), except for 4h and 4k, all compounds showed IC₅₀ values under sub-nanomolar. Among them, for potent inhibition, Leu was better than Phe and Val as the P₁′ amino acid, and the P₂′ position amino acid was necessary, and preferentially Phe. Insertion of the P_n peptide into 4d or 4k, giving compounds 5a—c, did not increase the activities of 4d and 4k. Substitution of the mercapto group with other functional groups lost the activity of compound 4a. The stereochemical preference at the thiol-attached position was also determined by preparation of both isomers of 4a. It was found that the S configuration compound (36b) is approximately 100 times more potent than the corresponding R-isomer (36a).