期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 17, 页码 7593-7613出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm300605m
关键词
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资金
- National Natural Science Foundation of China [81222044, 30930107]
- 863 Hi-Tech Program of China [2012AA020302]
- Shanghai Rising-Star Program [12QH1402600]
- Science and Technology Commission of Shanghai [11431920402]
- Shanghai Municipal Health Bureau [XYQ2011038]
Evodiamine is a quinazolinocarboline alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus. Previously, we identified N13-substituted evodiamine derivatives as potent topoisomerase I inhibitors by structure-based virtual screening and lead optimization. Herein, a library of novel evodiamine derivatives bearing various substitutions or modified scaffold were synthesized. Among them, a number of evodiamine derivatives showed substantial increase of the antitumor activity, with GI(50) values lower than 3 nM. Moreover, these highly potent compounds can effectively induce the apoptosis of A549 cells. Interestingly, further computational target prediction calculations in combination with biological assays confirmed that the evodiamine derivatives acted by dual inhibition of topoisomerases I and II. Moreover, several hydroxyl derivatives, such as 10-hydroxyl evodiamine (10j) and 3-amino-10-hydroxyl evodiamine (18g), also showed good in vivo antitumor efficacy and low toxicity at the dose of 1 mg/kg or 2 mg/kg. They represent promising candidates for the development of novel antitumor agents.
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