title: Synthesis and antitumor activity of the hexacyclic camptothecin derivatives.
abstract: A series of hexacyclic camptothecin derivatives were synthesized to test for antitumor activity as topoisomerase I inhibitor. The strategy of synthesis was used for the formation of additional furan and dihydrofuran rings fused with 9- and 10-positions of camptothecin. All of the hexacyclic camptothecins were assayed for cytotoxicity against four human tumor cell lines, HL60, BEL-7402, HCT-116, and HeLa, and showed very impressive cytotoxicity activity in vitro. Enzyme activity of the hexacyclic camptothecins was evaluated, being equal or superior to that of SN-38. The stability of four compounds was assessed in human plasma. Two of these compounds were chosen to test for antitumor activity in vivo against Sarcoma-180. The results suggested that additional furan and dihydrofuran rings could improve the antitumor activity in vitro and vivo, though the stability of the lactone ring did not increase.
authors.affiliation: Shanghai Institute of Materia Medica, SIBS, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, 555, Zuchongzhi Road, Zhangjiang High-Tech Park, Shanghai 201203, China.
authors.forename: Heyong
authors.initials: H
authors.lastname: Gao
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Hongwu
authors.initials: H
authors.lastname: Shen
authors.forename: Tao
authors.initials: T
authors.lastname: Pang
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Chenghui
authors.initials: C
authors.lastname: Xu
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.forename: Chuan
authors.initials: C
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D051379:Mice; D012510:Sarcoma 180 / Q000188:drug therapy; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D002166:Camptothecin