期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 53, 期 7, 页码 2927-2941出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm901722v
关键词
-
资金
- Cancer Research UK [C180/A1060, C96/A 5008, C96/A6670]
- Spirogen Ltd (U.K.)
- Engineering and Physical Sciences Research Council [GR/R47646/01]
A comprehensive SA R investigation of the C2-position of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) monomer antitumor agents is reported, establishing the molecular requirements for optimal in vitro cytotoxicity and DNA-binding affinity. Both carbocyclic and heterocyclic C2-aryl substituents have been studied ranging from single aryl rings to fused ring systems, and also styryl substituents, establishing across a library of 80 analogues that C2-aryl and styryl substituents significantly enhance both DNA-binding affinity and in vitro cytotoxicity, with a correlation between the two. The optimal C2-grouping for both DNA-binding affinity and cytotoxicity was found to be the C2-quinolinyl moiety which, according to molecular modeling, is due to the overall fit of the molecule in the DNA minor groove, and potential specific contacts with functional groups in the floor and walls of the groove. This analogue (14l) was shown to delay tumor growth in a HCT-116 (bowel) human tumor xenograft model.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据