Solid-phase synthesis and biochemical evaluation of conformationally constrained analogues of deglycobleomycin A5

Ali Cagir, Zhi Fu Tao, Steven J. Sucheck, Sidney M. Hecht

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5179-5187
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume11
Issue number23
DOIs
StatePublished - Nov 17 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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