N-methyl threonine analogues of deglycobleomycin A2: synthesis and evaluation.
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.
Boger
D L
DL
Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA.
Teramoto
S
S
Cai
H
H
D010584:Bacteriophage phi X 174 / Q000235:genetics; D001761:Bleomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000378:metabolism; D004278:DNA, Superhelical / Q000378:metabolism; D004279:DNA, Viral / Q000378:metabolism; D008958:Models, Molecular; D010084:Oxidation-Reduction; D020058:Styrene; D013343:Styrenes / Q000378:metabolism
D004277:DNA, Single-Stranded; D004278:DNA, Superhelical; D004279:DNA, Viral; D013343:Styrenes; D001761:Bleomycin; D020058:Styrene; C033284:deglycobleomycin