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 is the ability of these compounds to mediate photoactivated DNA cleavage. Chlorinated bithiazole analogues were shown to be much more active than an analogous brominated derivative. DNA strand scission activity was strictly light dependent and was accompanied by dechlorination of the bithiazole nucleus, apparently in a stoichiometric fashion. Inhibition of DNA cleavage in the presence of DMSO, as well as photoaddition to 1-octene by both brominated and chlorinated bithiazole derivatives, suggest strongly that the initial step in photoactivated DNA cleavage involves homolysis of the thiazole carbon-halogen bond. The chlorinated bithiazoles were found to mediate sequence selective cleavage of a (32)P-end labeled DNA, although the selectivity observed was not the same as that of bleomycin itself. The implications of this observation are discussed.
Quada
J C
JC
Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.
Boturyn
D
D
Hecht
S M
SM
D000475:Alkenes / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry; D001483:Base Sequence; D001665:Binding Sites; D001761:Bleomycin / Q000031:analogs & derivatives* / Q000737:chemistry; D001966:Bromine; D002713:Chlorine; D004247:DNA / Q000737:chemistry / Q000378:metabolism* / Q000528:radiation effects; D006868:Hydrolysis; D010782:Photolysis / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D000475:Alkenes; D000970:Antineoplastic Agents; D013844:Thiazoles; D001761:Bleomycin; D002713:Chlorine; C025703:bleomycetin; D004247:DNA; C037690:1-octene; D001966:Bromine