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Selective G-Quadruplex DNA Recognition by a New Class of Designed Cyanines
Department of Chemistry, Georgia State University, 50 Decatur St., Atlanta, GA 30303, USA
Center for Diagnostics and Therapeutics, Georgia State University, 100 Piedmont Ave SE, Atlanta, GA 30303, USA
Department of Biology, Georgia State University, 495 Petit Science Center, 100 Piedmont Ave., Atlanta, GA 30303, USA
* Authors to whom correspondence should be addressed.
Received: 30 August 2013; in revised form: 26 October 2013 / Accepted: 29 October 2013 / Published: 4 November 2013
Abstract: A variety of cyanines provide versatile and sensitive agents acting as DNA stains and sensors and have been structurally modified to bind in the DNA minor groove in a sequence dependent manner. Similarly, we are developing a new set of cyanines that have been designed to achieve highly selective binding to DNA G-quadruplexes with much weaker binding to DNA duplexes. A systematic set of structurally analogous trimethine cyanines has been synthesized and evaluated for quadruplex targeting. The results reveal that elevated quadruplex binding and specificity are highly sensitive to the polymethine chain length, heterocyclic structure and intrinsic charge of the compound. Biophysical experiments show that the compounds display significant selectivity for quadruplex binding with a higher preference for parallel stranded quadruplexes, such as cMYC. NMR studies revealed the primary binding through an end-stacking mode and SPR studies showed the strongest compounds have primary KD values below 100 nM that are nearly 100-fold weaker for duplexes. The high selectivity of these newly designed trimethine cyanines for quadruplexes as well as their ability to discriminate between different quadruplexes are extremely promising features to develop them as novel probes for targeting quadruplexes in vivo.
Keywords: G-quadruplex; cyanines; c-myc; telomere; end-stacking; halogenation; nuclear magnetic resonance; surface plasmon resonance; thermal melting
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Nanjunda, R.; Owens, E.A.; Mickelson, L.; Dost, T.L.; Stroeva, E.M.; Huynh, H.T.; Germann, M.W.; Henary, M.M.; Wilson, W.D. Selective G-Quadruplex DNA Recognition by a New Class of Designed Cyanines. Molecules 2013, 18, 13588-13607.
Nanjunda R, Owens EA, Mickelson L, Dost TL, Stroeva EM, Huynh HT, Germann MW, Henary MM, Wilson WD. Selective G-Quadruplex DNA Recognition by a New Class of Designed Cyanines. Molecules. 2013; 18(11):13588-13607.
Nanjunda, Rupesh; Owens, Eric A.; Mickelson, Leah; Dost, Tyler L.; Stroeva, Ekaterina M.; Huynh, Hang T.; Germann, Markus W.; Henary, Maged M.; Wilson, W. D. 2013. "Selective G-Quadruplex DNA Recognition by a New Class of Designed Cyanines." Molecules 18, no. 11: 13588-13607.