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Selection of evodiamine as a novel topoisomerase I inhibitor by structure-based virtual screening and hit optimization of evodiamine derivatives as antitumor agents.

Abstract：

:Human topoisomerase I (TopoI) is recognized as a valuable target for the development of effective antitumor agents. Structure-based virtual screening was applied to the discovery of structurally diverse TopoI inhibitors. From 23 compounds selected by virtual screening, a total of 14 compounds were found to be TopoI inhibitors. Five hits (compounds 1, 14, 20, 21, and 23) also showed moderate to good in vitro antitumor activity. These novel structures can be considered as good starting points for the development of new antitumor lead compounds. Hit 20 (evodiamine) was chosen for preliminary structure-activity relationship studies. Various groups, including alkyl, benzoyl, benzyl and ester, were introduced to the indole nitrogen atom of evodiamine. The substituted benzoyl groups were found to be favorable for the antitumor activity and spectrum. The 4-Cl benzoyl derivative, compound 29u, was the most active one with IC(50) values in the range 0.049-2.6 μM.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Dong G,Sheng C,Wang S,Miao Z,Yao J,Zhang W

doi

10.1021/jm100387d

subject

Has Abstract

pub_date

2010-11-11 00:00:00

pages

7521-31

issue

21

eissn

0022-2623

issn

1520-4804

journal_volume

53

pub_type

杂志文章

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