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New camptothecin derivatives alkylating DNA oligomers: the synthesis, physicochemical data and application as Topo I inhibitors

Beata Naumczuk 1Robert Kawęcki 1Elżbieta Bednarek 2Wojciech Bocian 1,2Jerzy Sitkowski 1,2Lech Kozerski 1,2

1. Polish Academy of Science, Institute of Organic Chemistry, Kasprzaka 44/52, Warszawa 01-224, Poland
2. National Medicines Institut (NIL), Chełmska 30/34, Warsaw 00-725, Poland


     Topoisomerases are essential enzymes, which relieve the torsional stress produced in DNA during replication by cutting DNA on one strand, allowing the broken strand to rotate around the uncut strand. Inhibition of Topo I is one of the strategies in the design of anti-cancer drugs, whose goal is create a stable covalent ternary complex DNA-Topo I-drug. (shown below)

     Derivatives belonging to the camptothecin family, such as Topotecan ( Hycamtin TM) and Irinotecan ( CamptosurTM ) are the Topoisomerase I inhibitors. They are used in clinical treatment as anti-cancer agents. These derivatives can intercalate into the nick site generated by Topo I and stabilise the DNA-Topo I complex, however this is weak interaction with DNA.

     In this presentation will be presented new water soluble camptothecin derivatives, their synthesis and physicochemical data. It was already established that these derivatives have better biological activity against colon cancer and breast cancer cell lines than Irinotecan, which is used in clinical treatment. We have also evidence that the new derivatives alkylate DNA oligomers. This was established using the PFGSE NMR and MALDI-TOF MS techniques.

     Sponsored by grant 2012/07/B/ST4/00566


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Submitted: 2014-03-13 13:57
Revised:   2014-05-02 13:15