Alteration of the selectivity of DNA cleavage by a deglycobleomycin analogue containing a trithiazole moiety

Craig J. Thomas, Michael M. McCormick, Corine Vialas, Zhi Fu Tao, Christopher J. Leitheiser, Michael J. Rishel, Xihan Wu, Sidney M. Hecht

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

The bleomycin (BLM) group of antitumor antibiotics effects DNA cleavage in a sequence-selective manner. Previous studies have indicated that the metal-binding and bithiazole moieties of BLM are both involved in the binding of BLM to DNA. The metal-binding domain is normally the predominant structural element in determining the sequence selectivity of DNA binding, but it has been shown that replacement of the bithiazole moiety with a strong DNA binder can alter the sequence selectivity of DNA binding and cleavage. To further explore the mechanism by which BLM and DNA interact, a trithiazole-containing deglycoBLM analogue was synthesized and tested for its ability to relax supercoiled DNA and cleave linear duplex DNA in a sequence-selective fashion. Also studied was cleavage of a novel RNA substrate. Solid-phase synthesis of the trithiazole deglycoBLM A5 analogue was achieved using a TentaGel resin containing a Dde linker and elaborated from five key intermediates. The ability of the resulting BLM analogue to relax supercoiled DNA was largely unaffected by introduction of the additional thiazole moiety. Remarkably, while no new sites of DNA cleavage were observed for this analogue, there was a strong preference for cleavage at two 5′-GT-3′ sites when a 5′-32P end-labeled DNA duplex was used as a substrate. The alteration of sequence selectivity of cleavage was accompanied by some decrease in the potency of DNA cleavage, albeit without a dramatic diminution. In common with BLM, the trithiazole analogue of deglycoBLM A5 effected both hydrolytic cleavage of RNA in the absence of added metal ion and oxidative cleavage in the presence of Fe2+ and O2. In comparison with BLM A5, the relative efficiencies of hydrolytic cleavage at individual sites were altered.

Original languageEnglish (US)
Pages (from-to)3875-3884
Number of pages10
JournalJournal of the American Chemical Society
Volume124
Issue number15
DOIs
StatePublished - Apr 17 2002
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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