Structure-Activity Relationship for Thiirane-Based Gelatinase Inhibitors

被引：31

作者：

Lee, Mijoon ^{[1
]}

Ikejiri, Masahiro ^{[1
]}

Klimpel, Dennis ^{[1
]}

Toth, Marta ^{[1
]}

Espahbodi, Mana ^{[1
]}

Hesek, Dusan ^{[1
]}

Forbes, Christopher ^{[1
]}

Kumarasiri, Malika ^{[1
]}

Noll, Bruce C. ^{[1
]}

Chang, Mayland ^{[1
]}

Mobashery, Shahriar ^{[1
]}

机构：

[1] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 06期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

Gelatinase; SAR; matrix metalloproteinases; QUADRUPOLE INTERACTIONS; MATRIX-METALLOPROTEINASE-9; POTENT; METASTASIS; METABOLISM; PHENOLS; DESIGN; ACIDS; MODEL;

D O I：

10.1021/ml300050b

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 a position of the sulfonyl group in the aliphatic side chain.

引用

页码：490 / 495

页数：6

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