Synthesis and evaluation of deglycobleomycin A2 analogues containing a tertiary N-methyl amide and simple ester replacement for the L-histidine secondary amide: direct functional characterization of the requirement for secondary amide metal complexation.
The synthesis and comparative examination of 3-5, analogues of deglycobleomycin A2 (2) which address the inferred importance of the L-histidine secondary amide directly, are detailed. The agent 3 lacks only the L-histidine beta-hydroxy group of deglycobleomycin A2 and the corresponding agents 4 and 5 incorporate a tertiary N-methyl amide and simple ester in place of the L-histidine secondary amide. The DNA cleavage properties of 3 proved essentially indistinguishable from those of deglycobleomycin A2 (2) confirming that the distinctions between bleomycin A2 (1) and deglycobleomycin (2) are due to the removal of the disaccharide and not the introduction of the L-histidine free beta-hydroxy group. The agents 4 and 5 containing a tertiary N-methyl amide and ester in place of the L-histidine secondary amide were found to cleave duplex DNA but to do so in a nonsequence selective fashion with a substantially reduced efficiency and a diminished double to single strand cleavage ratio that are only slightly greater than that of free iron itself. These latter observations establish the functional requirement for the L-histidine secondary amide and are consistent with the proposals that the L-histidine deprotonated secondary amide is required for functional metal chelation and activity.
Boger
D L
DL
Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, U.S.A.
Teramoto
S
S
Cai
H
H
D000577:Amides / Q000737:chemistry*; D001482:Base Composition; D001665:Binding Sites; D001761:Bleomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002614:Chelating Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004587:Electrophoresis, Agar Gel; D004952:Esters; D006639:Histidine / Q000737:chemistry*; D007502:Iron Chelating Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000577:Amides; D002614:Chelating Agents; D004952:Esters; D007502:Iron Chelating Agents; D001761:Bleomycin; D006639:Histidine; C033284:deglycobleomycin; D004247:DNA