title: Synthesis and biological evaluation of 6-substituted indolizinoquinolinediones as catalytic DNA topoisomerase I inhibitors.
abstract: In our previous work, indolizinoquinolinedione derivative 1 was identified as a Top1 catalytic inhibitor. Herein, a series of 6-substituted indolizinoquinolinedione derivatives were synthesized through modification of the parent compound 1. Top1 cleavage and relaxation assays indicate that none of these novel compounds act as classical Top1 poison, and that the compounds with alkylamino terminus at C-6 side chain, including 8, 11-16, 18-21, 25, 26 and 28-30, are the most potent Top1 catalytic inhibitors. Top1-mediated unwinding assay demonstrated that 14, 22 and 26 were Top1 catalytic inhibitors without Top1-mediated unwinding effect. Moreover, MTT results showed that compounds 26, 28-30 exhibit significant cytotoxicity against human leukemia HL-60 cells, and that compound 26 exerts potent cytotoxicity against A549 lung cancer cells at nanomolar range.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Le-Mao
authors.initials: LM
authors.lastname: Yu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Xiao-Ru
authors.initials: XR
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: College of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
authors.forename: Hong-Yu
authors.initials: HY
authors.lastname: Wei
authors.affiliation: College of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
authors.forename: Xi-Xin
authors.initials: XX
authors.lastname: He
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Lian-Quan
authors.initials: LQ
authors.lastname: Gu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Zhi-Shu
authors.initials: ZS
authors.lastname: Huang
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4255, United States.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: lssalk@mail.sysu.edu.cn.
authors.forename: Lin-Kun
authors.initials: LK
authors.lastname: An
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D055162:Biocatalysis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007212:Indolizines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D007212:Indolizines; C000607743:N-(3-(4-methylpiperazin-1-yl)propyl)-5,12-dioxo-5,12-dihydroindolizino(2,3-g)quinoline-6-carboxamide; D015363:Quinolones; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I
keywords: Anticancer; DNA topoisomerase; Indolizinoquinolinedione; Inhibitor