Open AccessStructure–Activity Relationship for Thiirane-Based Gelatinase Inhibitors
Author(s) -
Mijoon Lee,
Masahiro Ikejiri,
Dennis Klimpel,
Márta Tóth,
Mana Espahbodi,
Dušan Hesek,
Christopher C. Forbes,
Malika Kumarasiri,
Bruce C. Noll,
Mayland Chang,
Shahriar Mobashery
Publication year - 2012
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml300050b
Subject(s) - thiirane , gelatinases , chemistry , metabolic stability , ring (chemistry) , gelatinase , stereochemistry , biotransformation , structure–activity relationship , sulfonyl , biochemistry , combinatorial chemistry , enzyme , organic chemistry , in vitro , alkyl
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 analogs, 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 alpha position of the sulfonyl group in the aliphatic side chain.