title: Halogenated pentamethine cyanine dyes exhibiting high fidelity for G-quadruplex DNA.
abstract: Design and optimization of quadruplex-specific small molecules is developing into an attractive strategy for anti-cancer therapeutics with some promising candidates in clinical trials. A number of therapeutically favorable features of cyanine molecules can be effectively exploited to develop them as promising quadruplex-targeting agents. Herein, the design, synthesis and evaluation of a series of dimethylindolenine cyanine dyes with varying halogen substitutions are reported. Their interactions with telomeric and c-myc quadruplexes as well as a reference duplex sequence have been evaluated using thermal melting, biosensor-surface plasmon resonance, circular dichroism, isothermal titration calorimetry and mass spectrometry. Thermal melting analysis indicates that these ligands exhibit significant quadruplex stabilization and a very low duplex binding, with the dimethyl incorporation of paramount importance for decreased duplex affinity. Circular dichroism studies showed that the interaction of cyanines with quadruplex structures are primarily through stacking at one or both ends of the terminal tetrads with the two (trimethylammonium)propyl groups interacting in the accessible quadruplex grooves. Surface plasmon resonance and mass spectral studies shows the formation of an initial strong 1:1 complex followed by a significantly weaker secondary binding. Isothermal calorimetry studies show that the interaction of cyanines is predominantly entropy driven. In line with the design principles, this work provides new insights for further developing potent, highly selective cyanines as promising quadruplex-specific agents.
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Rupesh
authors.initials: R
authors.lastname: Nanjunda
authors.forename: Eric A
authors.initials: EA
authors.lastname: Owens
authors.forename: Leah
authors.initials: L
authors.lastname: Mickelson
authors.forename: Sergey
authors.initials: S
authors.lastname: Alyabyev
authors.forename: Nancy
authors.initials: N
authors.lastname: Kilpatrick
authors.forename: Siming
authors.initials: S
authors.lastname: Wang
authors.forename: Maged
authors.initials: M
authors.lastname: Henary
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
mesh_terms: D002151:Calorimetry; D002232:Carbocyanines / Q000737:chemistry*; D002942:Circular Dichroism; D005456:Fluorescent Dyes / Q000737:chemistry*; D054856:G-Quadruplexes; D016259:Genes, myc; D006219:Halogens / Q000737:chemistry; D006801:Humans; D013058:Mass Spectrometry; D008958:Models, Molecular; D020349:Surface Plasmon Resonance; D013816:Thermodynamics
chemical_list: D002232:Carbocyanines; D005456:Fluorescent Dyes; D006219:Halogens