Structure–Activity Relationship for Thiirane-Based Gelatinase Inhibitors

An extensive structure–activity relationship study with the template of 2-(4-phenoxyphenylsulfonylmethyl)­thiirane (1), a potent and highly selective inhibitor for human gelatinases, is reported herein. Syntheses of 65 new analogues, each in multistep processes, allowed for exploration of key structural components of the molecular template. This study reveals that the presence of the sulfonylmethylthiirane and the phenoxyphenyl group were important for gelatinase inhibition. However, para- and some meta-substitutions of the terminal phenyl ring enhanced inhibitory activity and led to improve metabolic stability. This agrees with the result from metabolism studies with compound 1 that the primary route of biotransformation is oxidation, mainly at the para position of the phenyl ring and the α position of the sulfonyl group in the aliphatic side chain.