Studies on the mechanism of action of azinomycin B: definition of regioselectivity and sequence selectivity of DNA cross-link formation and clarification of the role of the naphthoate.
Evaluation of the sequence selectivity, noncovalent association, and orientation of the DNA cross-linking agent azinomycin B on its duplex DNA receptor is described. A strong correlation between sequence nucleophilicity and cross-linking yield was observed, and steric effects due to the thymine C5-methyl group were identified. Detailed studies on the role of the azinomycin naphthoate using viscometry, fluorescence contact energy transfer, and DNA unwinding assays point to a nonintercalative binding mode for this group. A kinetic assay for agent regioselectivity was used to determine the orientation of binding and covalent cross-link formation.
Coleman
Robert S
RS
Department of Chemistry, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210-1185, USA. coleman@chemistry.ohio-state.edu
Perez
Ronelito J
RJ
Burk
Christopher H
CH
Navarro
Antonio
A
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000737:chemistry* / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D006020:Glycopeptides; D036341:Intercellular Signaling Peptides and Proteins; D009281:Naphthalenes; D010455:Peptides; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D003432:Cross-Linking Reagents; D006020:Glycopeptides; D036341:Intercellular Signaling Peptides and Proteins; D009281:Naphthalenes; D010455:Peptides; C051055:azinomycin B; D004247:DNA