Solid-phase synthesis and biochemical evaluation of conformationally constrained analogues of deglycobleomycin A5.
Deglycobleomycin binds to and degrades the self-complementary oligonucleotide d(CGCTAGCG)(2) in a sequence selective fashion. A previous modeling study [J. Am. Chem. Soc. 120, (1998), 7450] had shown that, during binding to double stranded DNA, the conformation of the methylvalerate domain of deglycoBLM approximated that of S-proline. In the belief that an analogue of deglycoBLM structurally constrained to mimic the DNA-bound conformation might exhibit facilitated DNA binding and cleavage, an analogue of deglycoBLM was prepared in which the methylvalerate moiety was replaced by S-proline. This deglycoBLM analogue, as well as the related analogue containing R-proline, was synthesized on a TentaGel resin. Both of the analogues were found to be capable of binding Fe(2+) and activating O(2) for transfer to styrene. However, both deglycoBLM analogues exhibited diminished abilities to effect the relaxation of supercoiled plasmid DNA, and neither mediated sequence selective DNA cleavage.
Cagir
Ali
A
Departments of Chemistry and Biology, University of Virginia, Charlottesville, VA 22901, USA.
Tao
Zhi-Fu
ZF
Sucheck
Steven J
SJ
Hecht
Sidney M
SM
D001761:Bleomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry*; D004247:DNA / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction
D001761:Bleomycin; C033284:deglycobleomycin; D004247:DNA