TY - JOUR
T1 - Solid-phase synthesis and biochemical evaluation of conformationally constrained analogues of deglycobleomycin A5
AU - Cagir, Ali
AU - Tao, Zhi Fu
AU - Sucheck, Steven J.
AU - Hecht, Sidney M.
N1 - Funding Information:
We thank Dr. Christopher Leitheiser for advice on the solid phase synthesis of the deglycoBLM analogues. This work was supported by NIH Research Grants CA76297 and CA77284, awarded by the National Cancer Institute.
PY - 2003/11/17
Y1 - 2003/11/17
N2 - 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 Fe2+ and activating O2 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.
AB - 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 Fe2+ and activating O2 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.
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U2 - 10.1016/j.bmc.2003.08.033
DO - 10.1016/j.bmc.2003.08.033
M3 - Article
C2 - 14604681
AN - SCOPUS:0242329790
SN - 0968-0896
VL - 11
SP - 5179
EP - 5187
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 23
ER -