title: Synthesis and biological evaluation of novel 7-acyl homocamptothecins as Topoisomerase I inhibitors.
abstract: A series of novel 7-acyl derivatives of homocamptothecin (hCPT) were designed and synthesized with the purpose to improve antitumor activity of hCPT, via Minisci free-radical reaction from 10-methoxyhomocamptothecin. All the compounds were evaluated for in vitro cytotoxicity against three cancer cell lines (A549, MDA-MB-435 and HCT116). For MDA-MB-435 cell line, compounds, 6a, 6b, 6k and all of 7-alkylcabonyl homocamptothecin derivatives showed higher in vitro inhibitory activities than topotecan (TPT). Furthermore, compounds 6d, 6e, and 6k showed highly potent inhibitory activities with the IC50 values from less than 1 nM to 2.2 nM. In Topoisomerase I (Topo I)-induced DNA cleavage assay, compounds 6a, 6d, and 6k, as compared to CPT, revealed higher Topo I inhibitory activity.
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Liu
authors.forename: Lingjian
authors.initials: L
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Chunlin
authors.initials: C
authors.lastname: Zhuang
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.forename: Pengfei
authors.initials: P
authors.lastname: Cheng
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yao
authors.forename: Wenya
authors.initials: W
authors.lastname: Wang
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: Wannian
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; C120029:homocamptothecin; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin