title: Scaffold Diversity Inspired by the Natural Product Evodiamine: Discovery of Highly Potent and Multitargeting Antitumor Agents.
abstract: A critical question in natural product-based drug discovery is how to translate the product into drug-like molecules with optimal pharmacological properties. The generation of natural product-inspired scaffold diversity is an effective but challenging strategy to investigate the broader chemical space and identify promising drug leads. Extending our efforts to the natural product evodiamine, a diverse library containing 11 evodiamine-inspired novel scaffolds and their derivatives were designed and synthesized. Most of them showed good to excellent antitumor activity against various human cancer cell lines. In particular, 3-chloro-10-hydroxyl thio-evodiamine (66c) showed excellent in vitro and in vivo antitumor efficacy with good tolerability and low toxicity. Antitumor mechanism and target profiling studies indicate that compound 66c is the first-in-class triple topoisomerase I/topoisomerase II/tubulin inhibitor. Overall, this study provided an effective strategy for natural product-based drug discovery.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University , 325 Guohe Road, Shanghai 200433, People's Republic of China.|School of Pharmacy, Fourth Military Medical University , 169 Changle West Road, Xi'an, 710032, People's Republic of China.
authors.forename: Shengzheng
authors.initials: S
authors.lastname: Wang
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: Kun
authors.initials: K
authors.lastname: Fang
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.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University , 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors.forename: Shuqiang
authors.initials: S
authors.lastname: Chen
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: Na
authors.initials: N
authors.lastname: Liu
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: Zhenyuan
authors.initials: Z
authors.lastname: Miao
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: Jianzhong
authors.initials: J
authors.lastname: Yao
authors.affiliation: School of Pharmacy, East China University of Science & Technology , 130 Meilong Road, Shanghai 200237, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
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: Wannian
authors.initials: W
authors.lastname: Zhang
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: Chunquan
authors.initials: C
authors.lastname: Sheng
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000737:chemistry; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D015195:Drug Design; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D032086:Evodia / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001688:Biological Products; D011799:Quinazolines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D050257:Tubulin Modulators; C049639:evodiamine