Solution Structure of an Intramolecular (3 + 1) Human Telomeric G-Quadruplex Bound to a Telomestatin Derivative
- 2 August 2013
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 135 (36), 13495-13501
- https://doi.org/10.1021/ja405843r
Abstract
Guanine-rich human telomeric DNA can adopt secondary structures known as G-quadruplexes, which can be targeted by small molecules to achieve anticancer effects. So far, the structural information on complexes between human telomeric DNA and ligands is limited to the parallel G-quadruplex conformation, despite the high structural polymorphism of human telomeric G-quadruplexes. No structure has been yet resolved for the complex with telomestatin, one of the most promising G-quadruplex-targeting anticancer drug candidates. Here we present the first high-resolution structure of the complex between an intramolecular (3 + 1) human telomeric G-quadruplex and a telomestatin derivative, the macrocyclic hexaoxazole L2H2-6M(2)OTD. This compound is observed to interact with the G-quadruplex through π-stacking and electrostatic interactions. This structural information provides a platform for the design of topology-specific G-quadruplex-targeting compounds and is valuable for the development of new potent anticancer drugs.Keywords
This publication has 69 references indexed in Scilit:
- Solution Structure of a 2:1 Quindoline–c-MYC G-Quadruplex: Insights into G-Quadruplex-Interactive Small Molecule Drug DesignJournal of the American Chemical Society, 2011
- The R.E.D. tools: advances in RESP and ESP charge derivation and force field library buildingPhysical Chemistry Chemical Physics, 2010
- G-quadruplex nucleic acids as therapeutic targetsCurrent Opinion in Chemical Biology, 2009
- Targeting human telomeric G-quadruplex DNA with oxazole-containing macrocyclic compoundsBiochimie, 2008
- Ring-closing metathesis for the synthesis of a highly G-quadruplex selective macrocyclic hexaoxazole having enhanced cytotoxic potencyBioorganic & Medicinal Chemistry Letters, 2008
- Lysinyl macrocyclic hexaoxazoles: Synthesis and selective G-quadruplex stabilizing propertiesBioorganic & Medicinal Chemistry Letters, 2008
- A hitchhiker's guide to G-quadruplex ligandsOrganic & Biomolecular Chemistry, 2007
- Development and testing of a general amber force fieldJournal of Computational Chemistry, 2004
- Telomeres shorten during ageing of human fibroblastsNature, 1990
- Comparison of simple potential functions for simulating liquid waterThe Journal of Chemical Physics, 1983