title: Novel 4-(4-substituted amidobenzyl)furan-2(5H)-one derivatives as topoisomerase I inhibitors.
abstract: In this study, two series of novel 4-(4-substituted amidobenzyl)furan-2(5H)-one derivatives containing an α,β-unsaturated lactone fragment were synthesized and screened for Topo I inhibition and antitumor activity. The topoisomerase I inhibitory activities and cytotoxicities against three human cancer cell lines (MCF-7,Hela,A549) were evaluated. The results revealed that series 2, compounds bearing an exocyclic double bond on the furanone ring, generally showed more potent activity than series 1, compounds lacking an exocyclic double bond. Several compounds of series 2 possess significant Topo I inhibitory activity and potent antiproliferative activity against cancer cell lines. Further mechanism studies of the most active compound of series 2 (B-15) indicated that synthetic compounds can not only stabilize the drug-enzyme-DNA covalent ternary complex as well as camptothecin, but also interfere with the binding between Topo I and DNA. The binding patterns of these compounds with Topo I and structure-activity relationships are discussed.
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
authors.forename: Cheng-Kang
authors.initials: CK
authors.lastname: Peng
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zeng
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
authors.forename: Xing-Jun
authors.initials: XJ
authors.lastname: Xu
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
authors.forename: Yi-Qun
authors.initials: YQ
authors.lastname: Chang
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
authors.forename: Wen
authors.initials: W
authors.lastname: Hou
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
authors.forename: Kuo
authors.initials: K
authors.lastname: Lu
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Lin
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
authors.forename: Ping-Hua
authors.initials: PH
authors.lastname: Sun
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou 510632, PR China. Electronic address: linjing_jnu@163.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Lin
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou 510632, PR China. Electronic address: twmchen@jnu.edu.cn.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053837:DNA Cleavage / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005663:Furans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D009690:Nucleic Acid Conformation; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I
keywords: Antitumor; Furan-2(5H)-one; Topoisomerase I; α, β-unsaturated lactones