Synthesis,topoisomerase-targeting activity and growth inhibition of lycobetaine analogs |
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Authors: | Simone A Baechler Markus Fehr Michael Habermeyer Andreas Hofmann Karl-Heinz Merz Heinz-Herbert Fiebig Doris Marko Gerhard Eisenbrand |
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Institution: | 1. Department of Food Chemistry and Toxicology, University of Vienna, Waehringerstr. 38, A-1090 Vienna, Austria;2. Institute of Applied Biosciences and Section of Food Toxicology, University of Karlsruhe (TH), Adenauerring 20, D-76131 Karlsruhe, Germany;3. Department of Chemistry, Division of Food Chemistry and Toxicology, University of Kaiserslautern, Erwin-Schroedinger Str. 52, D-67663 Kaiserslautern, Germany;4. Oncotest GmbH, Am Flughafen 12, D-79108 Freiburg, Germany |
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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. |
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