Novel fluoropeptidomimetics: synthesis, stability studies and protease inhibition

被引：9

作者：

Annedi, SC ^{[1
]}

Majumder, K ^{[1
]}

Wei, LH ^{[1
]}

Oyiliagu, CE ^{[1
]}

Samson, S ^{[1
]}

Kotra, LP ^{[1
]}

机构：

[1] Univ Toronto, Leslie Dan Fac Pharm, Mol Design & Informat Technol Ctr, Toronto, ON M5S 2S2, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2005年 / 13卷 / 08期

基金：

加拿大创新基金会; 加拿大健康研究院;

关键词：

fluoropeptidomimetics; protease inhibitors; chemistry and aqueous stability;

D O I：

10.1016/j.bmc.2005.02.011

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Designer fluoropeptidomimetics as protease inhibitors are revealed. The key peptidomimetic region in the inhibitors contains a ' CHF-S-' moiety and is designed to mimic the tetrahedral oxyanion species during the hydrolysis of a peptide bond. Designed fluoropeptidomimetics in aqueous methanol slowly (in several hours to days) yielded the corresponding methyl ether and/or the oxazole derivatives after cyclization. Alkyl substitutions at the C-2 position exhibited enhanced aqueous stability. Nature of '-CHF-S-' moiety and the stabilities of various fluoropeptidomimetics in aqueous solution are disclosed in detail. Fluoropeptidomimetics containing bulky substitutions at PI such as compounds 15 and 16 exhibited time-dependent loss of activities against chymotrypsin, up to 67% and 79% with a K-i of 63 and 120 mu M, respectively. Fluoropeptidomimetics are a novel class of protease inhibitors and the next generation of fluoropeptidomimetics should incorporate enhanced stability. (c) 2005 Elsevier Ltd. All rights reserved.

引用

页码：2943 / 2958

页数：16

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