Telomestatin: Formal total synthesis and cation-mediated interaction of its seco-derivatives with G-quadruplexes

Jörg Linder, Thomas P. Garner, Huw E.L. Williams, Mark S. Searle, Christopher J. Moody

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

The structurally unique natural product telomestatin incorporates seven oxazole rings and one sulfur-containing thiazoline in a macrocyclic arrangement. The compound is a potent inhibitor of the enzyme telomerase and therefore provides a structural framework for developing new potential therapeutic agents for cancer. An efficient formal total synthesis of telomestatin is reported in which the key steps are the use of dirhodium-(II)-catalyzed reactions of diazocarbonyl compounds to generate six oxazole rings, demonstrating the power of rhodium carbene methodology in organic chemical synthesis. CD spectroscopy establishes that seco-derivatives of telomestatin are potent stabilizers of G-quadruplex structures derived from the human telomeric repeat sequence. Mass spectrometry studies, confirmed by molecular dynamics simulations, provide the first evidence that high affinity binding to terminal G-tetrads in both 1:1 and 2:1 ligand complexes is mediated through the macrocycle coordinating a monovalent cation, with selectivity for the antiparallel structure.

Original languageEnglish (US)
Pages (from-to)1044-1051
Number of pages8
JournalJournal of the American Chemical Society
Volume133
Issue number4
DOIs
StatePublished - Feb 2 2011

ASJC Scopus subject areas

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

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