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.