SYNTHESIS AND EVALUATION OF THE FULLY FUNCTIONALIZED BLEOMYCIN A(2) METAL-BINDING DOMAIN-CONTAINING THE 2-O-(3-O-CARBAMOYL-ALPHA-D-MANNOPYRANOSYL)-ALPHA-L-GULOPYRANOSYL DISACCHARIDE

The synthesis of the full metal binding domain of bleomycin A(2) complete with linkage to the 2-O-(3-O-carbamoyl-alpha-D-mannopyranosyl)-alpha-L-gulopyranosyl disaccharide is detailed. Metal complexes (Fe(II), Fe(III)) of this full metal binding domain which includes the putative carbamoyl ligand residing in the disaccharide were found to cleave DNA in the presence of O-2 (Fe(II)) or H2O2 (Fe(III)) well above background cleavage and only 8-10x less efficiently than deglycobleomycin A(2) or 30-40x less efficiently than bleomycin A(2) and to do so in a nonsequence-specific manner with significantly reduced ratios of double versus single strand DNA cleavage (1:48 versus 1:6 for bleomycin A(2)). Thus, although the metal binding domain of bleomycin A(2) may play a role in determining 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 bleomycin A(2).