title: Novel securinine derivatives as topoisomerase I based antitumor agents.
abstract: DNA topoisomerase I (Topo I) has been validated as a target for anticancer agents. In this study, a series of novel securinine derivatives bearing β'-hydroxy-α,β-unsaturated ketone moiety were designed and synthesized via a Baylis-Hillman reaction for screening as Topo I inhibitors and antitumor agents. Their topoisomerase I inhibitory activity as well as their cytotoxicity against four human cancer cell lines (A549, HeLa, HepG2, SH-SY5Y) were evaluated, and two pairs of diastereomers 4a-1 and 4a-6 with significant Topo I inhibitory activity and potent anti-proliferative activity against cancer cell lines were identified. The diastereomers were separated, and absolute configurations of five pairs of diastereomers were identified based on X-ray crystallographic analysis and circular dichroism (CD) spectra analysis. Further mechanism studies of the most active compounds 4a-1-R and 4a-1-S indicated that this kind of securinine derivative exhibits a different inhibitory mechanism from that of camptothecin, an established Topo I inhibitor. Unlike camptothecin, compounds 4a-1-R and 4a-1-S specifically inhibits the combination of Topo I and DNA rather than forming the drug-enzyme-DNA covalent ternary complex. In addition, molecular docking and molecular dynamic studies revealed the binding patterns of these compounds with Topo I.
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: Zhen-Ya
authors.initials: ZY
authors.lastname: Wang
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. 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.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
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: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
authors.forename: Ren-Wang
authors.initials: RW
authors.lastname: Jiang
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: twmchen@jnu.edu.cn.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001381:Azepines / Q000737:chemistry* / 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*; D015195:Drug Design; D006572:Heterocyclic Compounds, Bridged-Ring / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D006572:Heterocyclic Compounds, Bridged-Ring; D007783:Lactones; D010880:Piperidines; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; C000785:securinine
keywords: Antitumor agent; Baylis-Hillman reaction; Securinine derivatives; Topoisomerase I