title: Telomestatin: formal total synthesis and cation-mediated interaction of its seco-derivatives with G-quadruplexes.
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.
authors.affiliation: School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom.
authors.forename: Jörg
authors.initials: J
authors.lastname: Linder
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Garner
authors.forename: Huw E L
authors.initials: HE
authors.lastname: Williams
authors.forename: Mark S
authors.initials: MS
authors.lastname: Searle
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Moody
mesh_terms: D001483:Base Sequence; D055592:Biophysical Phenomena; D002414:Cations, Monovalent / Q000737:chemistry; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D008697:Methane / Q000031:analogs & derivatives / Q000737:chemistry; D008958:Models, Molecular; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012238:Rhodium / Q000737:chemistry
chemical_list: D002414:Cations, Monovalent; D008024:Ligands; D010080:Oxazoles; C431888:telomestatin; C030011:carbene; D012238:Rhodium; D008697:Methane