N-methyl threonine analogues of deglycobleomycin A2: Synthesis and evaluation

Abstract

The synthesis of 5 and its D-allo-threonine epimer 6 and the comparison of their DNA cleavage efficiency and selectivity with that of deglycobleomycin A2 (3) are detailed. The studies illustrate that N-methylation of the L-threonine subunit within deglycobleomycin A2 dramatically reduces the DNA cleavage efficiency (10-15-fold), weakens and nearly abolishes the inherent DNA cleavage selectivity, but has little effect on the inherent oxidation capabilities of the activated Fe(III) complexes. The results are consistent with a previously unrecognized prominent role for the threonine NH and the potential importance of a hydrogen bond to the Fe(III) hydroperoxide complex of bleomycin or a subsequent activated complex implicated in recent structural models.