title: Synthesis and biological assays of 9-(acylamino) homocamptothecins as DNA topoisomerase I inhibitors.
abstract: In an effort to improve the stability of homocamptothecin and reduce the toxicity, novel homocamptothecin analogs with acylamino groups at C(9) were designed and synthesized. The cytotoxic activities of all the synthetic compounds against three cancer cell lines were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, and irinotecan was used as reference compound. Compound 7c with a piperidinylacetamido group and 10a with phenylacetamido group at C(9) showed potent activities both in vitro and in vivo. In addition, they also revealed remarkable topoisomerase I inhibitions which were exhibited with well-established bonds with amino acid residues Arg364 and Asp533 in the active pocket. On the basis of the biological activities, 7c and 10a would be potential candidates for further studies.
authors.affiliation: School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Dong
authors.forename: Lingjian
authors.initials: L
authors.lastname: Zhu
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Liu
authors.forename: Chunlin
authors.initials: C
authors.lastname: Zhuang
authors.forename: Zizhao
authors.initials: Z
authors.lastname: Guo
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yao
authors.forename: Chunquan
authors.initials: C
authors.lastname: Sheng
authors.forename: Huojun
authors.initials: H
authors.lastname: Zhang
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Miao
authors.forename: Wannian
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D053837:DNA Cleavage / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000737:chemistry* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D014183:Transplantation, Heterologous
chemical_list: C588288:7-methyl-9-((2-(2-methylpiperidin-1-yl)acetyl)amino)homocamptothecin; C588287:9-(benzoylamino)-7-methylhomocamptothecin; D059004:Topoisomerase I Inhibitors; C120029:homocamptothecin; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin
keywords: Antitumor activity; Cytotoxic activity; Friedländer condensation; Homocamptothecin; Inhibitors; Structureactivity relationship (SAR); Topoisomerase I