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

63 Citations (Scopus)

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
Externally publishedYes

Fingerprint

G-Quadruplexes
Oxazoles
Cations
Positive ions
Derivatives
Organic chemicals
Rhodium
Organic Chemicals
Mass spectrometry
Molecular dynamics
Synthetic Chemistry Techniques
Monovalent Cations
Sulfur
Enzymes
Telomerase
Ligands
Spectroscopy
Enzyme Inhibitors
Molecular Dynamics Simulation
Biological Products

ASJC Scopus subject areas

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

Cite this

Telomestatin : Formal total synthesis and cation-mediated interaction of its seco-derivatives with G-quadruplexes. / Linder, Jörg; Garner, Thomas P.; Williams, Huw E L; Searle, Mark S.; Moody, Christopher J.

In: Journal of the American Chemical Society, Vol. 133, No. 4, 02.02.2011, p. 1044-1051.

Research output: Contribution to journalArticle

Linder, Jörg ; Garner, Thomas P. ; Williams, Huw E L ; Searle, Mark S. ; Moody, Christopher J. / Telomestatin : Formal total synthesis and cation-mediated interaction of its seco-derivatives with G-quadruplexes. In: Journal of the American Chemical Society. 2011 ; Vol. 133, No. 4. pp. 1044-1051.
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