Telomestatin: Formal Total Synthesis and Cation-Mediated Interaction of Its seco-Derivatives with G-Quadruplexes

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• 作者：J枚rg Linder ; Thomas P. Garner ; Huw E. L. Williams ; Mark S. Searle ; Christopher J. Moody
• 刊名：Journal of the American Chemical Society
• 出版年：2011
• 出版时间：February 2, 2011
• 年：2011
• 卷：133
• 期：4
• 页码：1044-1051
• 全文大小：1069K
• 年卷期：v.133,no.4(February 2, 2011)
• ISSN：1520-5126

文摘

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.