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.

 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 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 .

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

• Legal notice:
  

  Copyright (c) Pielaszek Research, all rights reserved.
  The above materials, including auxiliary resources, are subject to Publisher's copyright and the Author(s) intellectual rights. Without limiting Author(s) rights under respective Copyright Transfer Agreement, no part of the above documents may be reproduced without the express written permission of Pielaszek Research, the Publisher. Express permission from the Author(s) is required to use the above materials for academic purposes, such as lectures or scientific presentations.
  In every case, proper references including Author(s) name(s) and URL of this webpage: https://science24.com/paper/25137 must be provided.

1. New camptothecin derivatives alkylating DNA oligomers: the synthesis, physicochemical data and application as Topo I inhibitors
2. New generation of topoisomerase I inhibitors  from camptothecin family spontaneously covalently binding to DNA oligomers.
3. 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.
4. Diffusion ordered  NMR spectroscopy  application  to medicines control and research  
5. JS-1, a novel isoquinoline alkaloid with antimicrobial activity isolated from Streptomyces sp. 8812
6. Novel medium for monomer proteins structure elucidation. Human insulin structure in water/ acetonitrile solvent. Search for nonamyloidogenic conditions
7. NMR INVESTIGATIONS OF HUMAN INSULIN AGGREGATION AND STRUCTURE
8. ¹H AND ¹³C NMR DATA FOR INDOLO[2,3-b]QUINOLINES - AMINOGLYCOSIDE HYBRIDS, A NOVEL POTENT ANTICANCER DRUG FAMILY .