Iminochromene Inhibitors of Dynamins I and II GTPase Activity and Endocytosis

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• 作者：Timothy A. Hill ; Anna Mariana ; Christopher P. Gordon ; Luke R. Odell ; Mark J. Robertson ; Andrew B. McGeachie ; Ngoc Chau ; James A. Daniel ; Nick N. Gorgani ; Phillip J. Robinson ; Adam McCluskey
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：May 27, 2010
• 年：2010
• 卷：53
• 期：10
• 页码：4094-4102
• 全文大小：848K
• 年卷期：v.53,no.10(May 27, 2010)
• ISSN：1520-4804

文摘

Herein we report the synthesis of discrete iminochromene (“iminodyn”) libraries (14−38) as potential inhibitors of dynamin GTPase. Thirteen iminodyns were active (IC₅₀ values of 260 nM to 100 μM), with N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (17), N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (22), and N,N-(ethane-1,2-diyl)bis(7,8-dihydroxy-2-iminochromene-3-carboxamide) (23) (IC₅₀ values of 330 ± 70, 450 ± 50, and 260 ± 80 nM, respectively) being the most potent. Five of the most potent iminodyns all inhibited dynamins I and II approximately equally. Iminodyn-22 displayed uncompetitive inhibition with respect to GTP. Selected iminodyns were evaluated for their ability to block receptor mediated endocytosis (RME, mediated by dynamin II) and synaptic vesicle endocytosis (SVE, mediated by dynamin I), with 17 showing no activity while 22 returned RME and SVE IC₅₀ values of 10.7 ± 4.5 and 99.5 ± 1.7 μM, respectively. The iminodyns reported herein represent a new chemical class of the first nanomolar potent dynamin inhibitors that are also effective endocytosis inhibitors.