Bleomycin: new perspectives on the mechanism of action.
The bleomycin group antitumor antibiotics have long been of interest as a consequence of their efficacy in the treatment of certain tumors, not to mention their unique structures and properties in mediating dioxygen activation and sequence selective degradation of DNA. At a chemical level, the structure originally assigned to bleomycin was subsequently reassigned and the new structure has been confirmed by total synthesis. Through the elaboration of structurally modified bleomycin congeners and fragments, synthetic efforts have also facilitated an understanding of the contribution of individual structural domains in bleomycin to sequence selective DNA binding and cleavage, and have also provided insights into the nature of the chemical processes by which DNA degradation takes place. Within the last several years, it has also become apparent that bleomycin can mediate the oxidative degradation of all major classes of cellular RNAs; it seems entirely plausible that RNA may also represent an important locus of action for this class of antitumor agent. In parallel with ongoing synthetic and mechanistic efforts using classical methods, the study of bleomycins attached to solid supports has been shown to provide important mechanistic insights, and the actual elaboration of modified bleomycins by solid phase synthesis constitutes a logical extension of such efforts.
Hecht
S M
SM
Departments of Chemistry and Biology, University of Virginia, Charlottesville, Virginia 22901, USA. sidhecht@virginia.edu
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D001761:Bleomycin / Q000737:chemistry / Q000494:pharmacology*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D010084:Oxidation-Reduction; D012313:RNA / Q000737:chemistry / Q000187:drug effects; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D012313:RNA