Ionic Immobilization, Diversification, and Release: Application to the Generation of a Library of Methionine Aminopeptidase Inhibitors

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• 作者：Punitha Vedantham ; Jennifer M. Guerra ; Frank Schoenen ; Min Huang ; Parul J. Gor ; Gunda I. Georg ; Jenna L. Wang ; Benjamin Neuenswander ; Gerald H. Lushington ; Lester A. Mitscher ; Qi-Zhuang Ye ; Paul R. Han
• 刊名：Journal of Combinatorial Chemistry
• 出版年：2008
• 出版时间：March 2008
• 年：2008
• 卷：10
• 期：2
• 页码：185 - 194
• 全文大小：925K
• 年卷期：v.10,no.2(March 2008)
• ISSN：1520-4774

文摘

Development of an ionic immobilization, diversification, and release method for the generation of methionine aminopeptidase inhibitors is reported. This method involves the immobilization of 5-bromofuran-2-carboxylic acid and 5-bromothiophene-2-carboxylic acid onto PS-BEMP, followed by Suzuki reaction on a resin-bound intermediate and subsequent release to provide products in moderate yields and excellent purities. Compound potencies were evaluated on the Co(II), Mn(II), Ni(II), and Fe(II) forms of Escherichia coli MetAP1. The furoic-acid analogs were found to be Mn(II) selective with IC₅₀ values in the low micromolar range. Qualitative SAR analysis, supplemented by molecular modeling studies, provides valuable information on structural elements responsible for potency and selectivity.