Photoactivated DNA cleavage by compounds structurally related to the bithiazole moiety of bleomycin

The syntheses of several novel halogenated bithiazoles structurally related to the bithiazole moiety of bleomycin A(5) are described. Also described i s the ability of these compounds to mediate photoactivated DNA cleavage. Ch lorinated bithiazole analogues were shown to be much more active than an an alogous brominated derivative. DNA strand scission activity was strictly li ght dependent and was accompanied by dechlorination of the bithiazole nucle us, apparently in a stoichiometric fashion. Inhibition of DNA cleavage in t he presence of DMSO, as well as photoaddition to 1-octene by both brominate d and chlorinated bithiazole derivatives, suggest strongly that the initial step in photoactivated DNA cleavage involves homolysis of the thiazole car bon-halogen bond. The chlorinated bithiazoles were found to mediate sequenc e selective cleavage of a P-32-end labeled DNA, although the selectivity ob served was not the same as that of bleomycin itself. The implications of th is observation are discussed. (C) 2001 Elsevier Science Ltd. All rights res erved.