Models of bleomycin interactions with poly(dA-dT). Fluorescence and proton nuclear magnetic resonance studies of cationic thiazole amides related to bleomycin A2

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Abstract
The interaction of 8 2-substituted thiazole-4-carboxamides, structurally related to the cationic terminus of bleomycin [the antineoplastic drug] A2, with poly(dA-dT) was studied by using 3H-NMR and fluorescence spectroscopy. These analogs were used as probes of the complex formed between the parent drug molecule and poly(dA-dT). Aliphatic substituents on the 2'' position of 2,4''-bithiazole derivatives restrict the ability of the aromatic ring system to intercalate in the double-helical form of the polynucleotide. Absence or partial removal of the 2'' substituent enhances intercalation of the bithiazole system. The cationic side chain does not appear to be involved in the stabilization of any of these complexes, although it may be necessary for their formation. A 2,4'':2''4"-terthiazole derivative shows a substantial degree of intercalation which is accompanied by extensive immobilization of the cationic side chain. Insertion of the aromatic system into the nucleic acid probably causes the cationic side chain to be pulled in also. Monothiazole analogs do not appear to bind, indicating that at least 2 thiazole rings are necessary for binding or that proper spacing between the 2 side chains on either side of the thiazole system is important for binding. The relation of the interactions of these analogs to the biochemical and biological properties of the parent bleomycins is discussed, as is the possible use of these data in the design of synthetic bleomycin derivatives having varying affinities and specificities for [vertebrate] DNA.