Molecular complexes of topo I and topo II inhibitors from camptothecin and flavonoid families with model DNA oligomers. Search from sequence specific binding. Verification of biological assay on atomic coordinates level.

Beata Naumczuk 1Karolina Hyz 1Wojciech Bocian 2Elżbieta Bednarek 2Jerzy Sitkowski 1,2Lech Kozerski 1,2

1. Instytut Chemii Organicznej Polskiej Akademii Nauk (ICHOPAN), Kasprzaka 44/52, Warszawa 01-224, Poland
2. Narodowy Instytut Lekow (NIL), Chełmska 30/34, Warszawa 00-725, Poland

Abstract

The role of topoisomerases I and II inhibitors involves the ternary complexes composed of enzyme/DNA/Inhibitor. Topoisomerases are essentially enzymes which, inter alia, relax the torsional strain in supercoiled DNA generated in replication process. The enzyme cleaves one strand, creating a nick, and thus enables the rotation around the uncleaved strand followed by ligation of the broken strand and restoring DNA duplex.

    Topotecan is in clinacl use as an antitumor agent Hycamtin TM. It act by binding to the covalent complex formed between nicked DNA and topoisomerase I and acting as a poison.

     Human topo I involves Tyr 723 , of which OH group attacks phosphate in the  main chain forming 3’-phosphotyrosine. After relaxation, strain free DNA duplex is restored in nucleophilic attack of free 5’-OH group on phosphorous atom in 3’-phosphotyrosine. Dumbbell DNA (NICK I)  mimics nicked DNA in a ternary complex and was designed by us as  a general model of DNA duplex for screening its interactions with topo I inhibitors from camtothecin group.

     Similarly to topo I , topo II generates nicks separated by four base pairs in both strands forming doubly broken duplex covalently linked to topo II through 5’-phosphotyrosines. Dumbbell DNA (NICK II)  mimics doubly nicked DNA and was designed by us as an adequate general model of DNA duplex for screening its interactions with topo II inhibitors from flavonoid  group of derivatives.

    
 

The essential role of inhibitor in a ternary complex is specific binding in a nick, either covalently or noncovalently, and preventing its ligation and further proliferation of cytotoxic DNA. 

The chemical basis of  selected compounds from both classes of inhibitors is shown below.

In a poster will be presented characteristics of molecular complexe of NICK I and parent TPT inhibitor from camptothecin family and also design of NICK II model dumbbell DNA and molecular complexes of parent genistein and its derivatives.

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Presentation: Poster at VIII Multidyscyplinarna Konferencja Nauki o Leku, by Beata Naumczuk
See On-line Journal of VIII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2012-03-02 12:45
Revised:   2012-03-09 06:38
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