Quantitative structure-activity relationship analysis of cation-substituted polyaromatic compounds as potentiators (amplifiers) of bleomycin-mediated degradation of DNA

A set of 21 polyheteroaromatic compounds substituted with flexible cationic groups and of similar molecular size has been analyzed for binding with DNA and for effects of the bleomycin-mediated degradation of the DNA double helix. Increases in apparent rates of the DNA digestion were observed in all...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1991-02, Vol.34 (2), p.580-588
Main Authors: Strekowski, Lucjan, Wilson, W. David, Mokrosz, Jerzy L, Mokrosz, Maria J, Harden, Donald B, Tanious, Farial A, Wydra, Roman L, Crow, Sidney A
Format: Article
Language:English
Subjects:
Amplifiers, Electronic
Antineoplastic agents
Binding Sites
Biological and medical sciences
Bleomycin - chemical synthesis
Bleomycin - metabolism
Bleomycin - pharmacology
Chemical Phenomena
Chemistry
DNA - drug effects
DNA - metabolism
General aspects
Medical sciences
Pharmacology. Drug treatments
Structure-Activity Relationship
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Summary:A set of 21 polyheteroaromatic compounds substituted with flexible cationic groups and of similar molecular size has been analyzed for binding with DNA and for effects of the bleomycin-mediated degradation of the DNA double helix. Increases in apparent rates of the DNA digestion were observed in all cases under the experimental conditions of noncompetitive binding of these compounds and bleomycin to DNA. Surprisingly, the quantitative structure-activity relationship analysis revealed two distinct correlations despite close structural similarities for the set of bleomycin amplifiers. These unusual results are explained in terms of the formation of two stereochemically different ternary complexes of activated bleomycin-DNA-amplifier. The relevance of this finding for the design of new bleomycin amplifiers is discussed.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00106a017