title: New tricks for an old natural product: discovery of highly potent evodiamine derivatives as novel antitumor agents by systemic structure-activity relationship analysis and biological evaluations.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Dong
authors.forename: Shengzheng
authors.initials: S
authors.lastname: Wang
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Miao
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yao
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Zizhao
authors.initials: Z
authors.lastname: Guo
authors.forename: Wannian
authors.initials: W
authors.lastname: Zhang
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D032086:Evodia / Q000737:chemistry*; D006801:Humans; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001688:Biological Products; D011799:Quinazolines; C049639:evodiamine