title: Bleomycin analogues. Phenylthiazole models of the bithiazole moiety of bleomycin A2.
abstract: Amides of 2-phenylthiazole-4-carboxylic acid, 2'-phenyl-2,4'-bithiazole-4-carboxylic acid and 4,4'-biphenylcarboxylic acid containing the (3-aminopropyl)dimethylsulfonium chloride side chain of bleomycin A2 have been prepared and their binding to poly(dA-dT) has been studied by proton nuclear magnetic resonance spectroscopy. Both the phenylthiazole and phenylbithiazole derivatives exhibit high-field shifts for their hydrogens in the presence of the polynucleotide which are considerably larger than those observed in the analogous completely heterocyclic systems studied previously (Sakai, T.T.; Riordan, J.M.; Glickson, J.D. Biochemistry 1982, 21, 805). The intercalative nature of the binding of these analogues was further indicated by viscometric measurements using calf thymus DNA. The data show that a phenyl ring allows the aromatic systems to interact with the base pairs of the polynucleotide to a greater extent than a thiazole ring in the same position. Possible models for the interaction of these derivatives with DNA are considered. The hydrogens of the biphenyl derivative show an interaction that is substantially less than those observed in the heterocycle-containing systems, suggesting that the ring system is oriented improperly or that the ring system is nonplanar. The analogous phenyl (benzoyl) compound does not bind, showing the requirement for an extended aromatic system for intercalation. The utility of these observations for the design of possible synthetic analogues of the bleomycins is discussed. None of the derivatives exhibited toxicity when tested against L1210 leukemia cells in culture.
mesh_terms: D000818:Animals; D001761:Bleomycin; D002455:Cell Division / Q000187:drug effects; D007939:Leukemia L1210 / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D011067:Poly dA-dT; D013844:Thiazoles; D014783:Viscosity
chemical_list: D013844:Thiazoles; D001761:Bleomycin; D011067:Poly dA-dT