1,8-萘二甲酰亚胺衍生物：针对发动蛋白I GTP酶活性的新型先导化合物

1,8-Naphthalimide derivatives: new leads against dynamin I GTPase activity.

作者信息

Abdel-Hamid Mohammed K, Macgregor Kylie A, Odell Luke R, Chau Ngoc, Mariana Anna, Whiting Ainslie, Robinson Phillip J, McCluskey Adam

机构信息

Centre for Chemical Biology, Chemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia.

出版信息

Org Biomol Chem. 2015 Aug 7;13(29):8016-28. doi: 10.1039/c5ob00751h. Epub 2015 Jun 29.

DOI:10.1039/c5ob00751h

PMID:26118967

Abstract

Fragment-based in silico screening against dynamin I (dynI) GTPase activity identified the 1,8-naphthalimide framework as a potential scaffold for the design of new inhibitors targeting the GTP binding pocket of dynI. Structure-based design, synthesis and subsequent optimization resulted in the development of a library of 1,8-naphthalimide derivatives, called the Naphthaladyn™ series, with compounds 23 and 29 being the most active (IC50 of 19.1 ± 0.3 and 18.5 ± 1.7 μM respectively). Compound 29 showed effective inhibition of clathrin-mediated endocytosis (IC50(CME) 66 μM). The results introduce 29 as an optimised GTP-competitive lead Naphthaladyn™ compound for the further development of naphthalimide-based dynI GTPase inhibitors.

摘要

基于片段的计算机模拟筛选针对动力蛋白I（dynI）的GTP酶活性，确定了1,8-萘二甲酰亚胺骨架是设计靶向dynI的GTP结合口袋的新型抑制剂的潜在支架。基于结构的设计、合成及后续优化导致了一个1,8-萘二甲酰亚胺衍生物库的开发，称为萘达因™系列，化合物23和29活性最高（IC50分别为19.1±0.3和18.5±1.7μM）。化合物29显示出对网格蛋白介导的内吞作用的有效抑制（IC50（CME）66μM）。结果表明29是一种优化的GTP竞争性先导萘达因™化合物，用于基于萘二甲酰亚胺的dynI GTP酶抑制剂的进一步开发。