Interaction of bleomycin A2 with deoxyribonucleic acid: DNA unwinding and inhibition of bleomycin-induced DNA breakage by cationic thiazole amides related to bleomycin A2.
The association of the antitumor antibiotic bleomycin A2 with DNA has been investigated by employing several 2-substituted thiazole-4-carboxamides, structurally related to the cationic terminus of the drug. With a 5'-32P-labeled DNA restriction fragment from plasmid pBR322 as substrate, these compounds have been shown to inhibit bleomycin-induced DNA breakage. Analogues possessing 2'-aromatic substituents on the bithiazole ring were more potent inhibitors than those carrying 2'-aliphatic groups, e.g., the acetyl dipeptide A2. The degree of inhibition was similar at all scission sites on DNA, and inclusion of the analogues did not induce bleomycin cleavage at new sites. DNA binding of bithiazole derivatives has also been studied by two complementary topological methods. Two-dimensional gel electrophoresis using a population of DNA topoisomers and DNA relaxation experiments involving calf thymus DNA topoisomerase I and pBR322 DNA reveal that bleomycin bithiazole analogues unwind closed circular duplex DNA. The inhibition and unwinding studies together support recent NMR studies suggesting that both bleomycin A2 and synthetic bithiazole derivatives bind to DNA by an intercalative mechanism. The results are discussed in relation to the DNA breakage properties of bleomycin A2.
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Kuroda
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Sakai
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D000818:Animals; D001761:Bleomycin; D002417:Cattle; D004262:DNA Restriction Enzymes; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004926:Escherichia coli; D009682:Magnetic Resonance Spectroscopy; D010957:Plasmids; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000201:enzymology
D001761:Bleomycin; D004262:DNA Restriction Enzymes; D004264:DNA Topoisomerases, Type I