title: Synthesis, topoisomerase-targeting activity and growth inhibition of lycobetaine analogs.
abstract: The plant alkaloid lycobetaine has potent topoisomerase-targeting properties and shows anticancer activity. Based on these findings, several lycobetaine analogs were synthesized mainly differing in their substituents at 2, 8 and 9 position and their biological activities were evaluated. The topoisomerase-targeting properties and cytotoxicity of these structural analogs were assessed in the human gastric carcinoma cell line GXF251L. Performing a plasmid relaxation assay, an increased inhibition of topoisomerase I was found with N-methylphenanthridinium chlorides bearing a 8,9-methylenedioxy moiety or a methoxy group in 2-position. Furthermore, quaternized phenanthridinium derivatives bearing either a 2-methoxy or a 8,9-methylenedioxy moiety in conjunction with a 2-hydroxy or 2-methoxy group display potent topoisomerase II inhibition as shown by decatenation of kinetoplast DNA. In general, the N-methylphenanthridinium chlorides possess more potency in inhibiting topoisomerase I than topoisomerase II. All quaternized derivatives also exhibited potent inhibition of tumor cell growth in the low micromolar concentration range. Hence, N-methylphenanthridinium compounds were found to represent a promising class of compounds, potently inhibiting both, topoisomerases I and II, and may be further developed into clinically useful topoisomerase inhibitors.
authors.affiliation: Department of Food Chemistry and Toxicology, University of Vienna, Waehringerstr. 38, A-1090 Vienna, Austria.
authors.forename: Simone A
authors.initials: SA
authors.lastname: Baechler
authors.forename: Markus
authors.initials: M
authors.lastname: Fehr
authors.forename: Michael
authors.initials: M
authors.lastname: Habermeyer
authors.forename: Andreas
authors.initials: A
authors.lastname: Hofmann
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Merz
authors.forename: Heinz-Herbert
authors.initials: HH
authors.lastname: Fiebig
authors.forename: Doris
authors.initials: D
authors.lastname: Marko
authors.forename: Gerhard
authors.initials: G
authors.lastname: Eisenbrand
mesh_terms: D047151:Amaryllidaceae Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; 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; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D047151:Amaryllidaceae Alkaloids; D000970:Antineoplastic Agents; D007212:Indolizines; D059004:Topoisomerase I Inhibitors; C016175:ungeremine; D004264:DNA Topoisomerases, Type I