Development of 1,8-Naphthalimides as Clathrin Inhibitors

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• 作者：Kylie A. MacGregor ; Mark J. Robertson ; Kelly A. Young ; Lisa von Kleist ; Wiebke Stahlschmidt ; Ainslie Whiting ; Ngoc Chau ; Phillip J. Robinson ; Volker Haucke ; Adam McCluskey
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：January 9, 2014
• 年：2014
• 卷：57
• 期：1
• 页码：131-143
• 全文大小：649K
• ISSN：1520-4804

文摘

We reported the first small molecule inhibitors of the interaction between the clathrin N-terminal domain (TD) and endocyctic accessory proteins (i.e., clathrin inhibition1). Initial screening of a 17鈥?00 small molecule ChemBioNet library identified 1. Screening of an existing in-house propriety library identified four substituted 1,8-napthalimides as 80鈥?20 渭M clathrin inhibitors. Focused library development gave 3-sulfo-N-(4-aminobenzyl)-1,8-naphthalimide, potassium salt (18, IC₅₀ 鈮?18 渭M). A second library targeting the 4-aminobenzyl moiety was developed, and four analogues displayed comparable activity (26, 27, 28, 34 with IC₅₀ values of 22, 16, 15, and 15 渭M respectively) with a further four (24, 25, 32, 33) more active than 18 with IC₅₀ values of 10, 6.9, 12, and 10 渭M, respectively. Docking studies rationalized the structure鈥揳ctivity relationship (SAR) with the biological data. 3-Sulfo-N-benzyl-1,8-naphthalimide, potassium salt (25) with an IC_50聽鈮?6.9 渭M, is the most potent clathrin terminal domain鈥揳mphiphysin inhibitor reported to date.