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Nucleic Acids Research Advance Access published online on April 22, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm188
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Structural Biology

Defining the mode, energetics and specificity with which a macrocyclic hexaoxazole binds to human telomeric G-quadruplex DNA

Christopher M. Barbieri1, Annankoil R. Srinivasan1, Suzanne G. Rzuczek2, Joseph E. Rice2, Edmond J. LaVoie2,3 and Daniel S. Pilch1,3,4,*

1Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854-5635, 2Department of Pharmaceutical Chemistry, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854-8020, 3The Cancer Institute of New Jersey, New Brunswick, NJ 08901 and 4Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854-8087, USA

*To whom correspondence should be addressed. Tel: +1-732-235-3352; Fax: +1-732-235-4073; Email: pilchds{at}umdnj.edu

Received January 9, 2007. Revised March 9, 2007. Accepted March 15, 2007.

Oxazole-containing macrocycles represent a promising class of anticancer agents that target G-quadruplex DNA. We report the results of spectroscopic studies aimed at defining the mode, energetics and specificity with which a hexaoxazole-containing macrocycle (HXDV) binds to the intramolecular quadruplex formed by the human telomeric DNA model oligonucleotide d(T2AG3)4 in the presence of potassium ions. HXDV binds solely to the quadruplex nucleic acid form, but not to the duplex or triplex form. HXDV binds d(T2AG3)4 with a stoichiometry of two drug molecules per quadruplex, with these binding reactions being coupled to the destacking of adenine residues from the terminal G-tetrads. HXDV binding to d(T2AG3)4 does not alter the length of the quadruplex. These collective observations are indicative of a nonintercalative ‘terminal capping’ mode of interaction in which one HXDV molecule binds to each end of the quadruplex. The binding of HXDV to d(T2AG3)4 is entropy driven, with this entropic driving force reflecting contributions from favorable drug-induced alterations in the configurational entropy of the host quadruplex as well as in net hydration. The ‘terminal capping’ mode of binding revealed by our studies may prove to be a general feature of the interactions between oxazole-containing macrocyclic ligands (including telomestatin) and intramolecular DNA quadruplexes.


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