Inhibition of human collagenases by sulfur-based substrate analogs.
A series of sulfhydryl and novel sulfur-based substrate-analog inhibitors has been synthesized and tested against human fibroblast and neutrophil collagenases. Absolute stereospecific synthesis of several sulfhydryl inhibitors establishes that it is the diastereomers with the R-configuration of the P'1 residues, which correspond to the unnatural D-amino acid analogs, that are the most potent inhibitors. The corresponding disulfide, sulfonate, sulfinate, sulfide, sulfoxide and sulfone analogs exhibit widely variable levels of potency, but all less than the sulfhydryl compounds. No correlation between inhibitor potency and any single structural feature of these new compounds is apparent. However, differences in potency can be ascribed to the different affinities of these functional groups for zinc coordination and hydrogen bonding to nearby active site residues.
Schwartz
M A
MA
Department of Chemistry, Florida State University, Tallahassee 32306.
Venkataraman
S
S
Ghaffari
M A
MA
Libby
A
A
Mookhtiar
K A
KA
Mallya
S K
SK
Birkedal-Hansen
H
H
Van Wart
H E
HE
D000595:Amino Acid Sequence; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D003012:Microbial Collagenase / Q000037:antagonists & inhibitors* / Q000097:blood; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000201:enzymology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000494:pharmacology*
D009842:Oligopeptides; D013438:Sulfhydryl Compounds; D003012:Microbial Collagenase