SYNTHESIS AND EVALUATION OF THE FULLY FUNCTIONALIZED BLEOMYCIN A(2) METAL-BINDING DOMAIN-CONTAINING THE MOYL-ALPHA-D-MANNOPYRANOSYL)-ALPHA-L-GULOPYRANOSYL DISACCHARIDE

The synthesis of the full metal binding domain of bleomycin A(2) compl ete with linkage to the moyl-alpha-D-mannopyranosyl)-alpha-L-gulopyran osyl disaccharide is detailed. Metal complexes (Fe(II), Fe(III)) of th is full metal binding domain which includes the putative carbamoyl lig and residing in the disaccharide were found to cleave DNA in the prese nce of O-2 (Fe(II)) or H2O2 (Fe(III)) well above background cleavage a nd only 8-10x less efficiently than deglycobleomycin A(2) or 30-40x le ss efficiently than bleomycin A(2) and to do so in a nonsequence-speci fic manner with significantly reduced ratios of double versus single s trand DNA cleavage (1:48 versus 1:6 for bleomycin A(2)). Thus, althoug h the metal binding domain of bleomycin A(2) may play a role in determ ining the selectivity observed in DNA cleavage when incorporated into the full natural product structure, the metal binding domain alone or in the presence of noncovalently linked tri- and tetrapeptide S failed to exhibit the sequence-selective DNA cleavage characteristic of bleo mycin A(2).