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

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

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

     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.

     dumbbell_decamer.jpg     

 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.

CPT_GEN_ANALOGS_REDUCED.jpg 

 

In a lecture there will be presented selected topics of tautomerism and chemistry of topotecan (TPT) from campthotecin family administered clinically as Hycamtin TM. The characteristics of molecular complex of NICK I and parent TPT inhibitor from camptothecin family will be discussed.

The design of NICK II model dumbbell DNA will be presented and molecular complexes of parent genistein and derivatives will be discussed .

Auxiliary resources (full texts, presentations, posters, etc.)
  1. FULLTEXT: Molecular complexes of topo I and II inhibitors from camptothecin and flavonoid families with model DNA oligomers. Search for sequence specific binding. Verification of biological assays on atomic coordinates level., PDF document, version 1.3, 0.3MB
  2. FULLTEXT: Molecular complexes of topo I and II inhibitors from camptothecin and flavonoid families with model DNA oligomers. Search for sequence specific binding. Verification of biological assays on atomic coordinates level., PDF document, version 1.3, 0.6MB
 

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Presentation: Invited oral at VIII Multidyscyplinarna Konferencja Nauki o Leku, by Lech Kozerski
See On-line Journal of VIII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2011-10-19 09:17
Revised:   2011-10-20 08:59
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