Nucleic acids are important targets for drug discovery, and the development of selective probes to either visualize or selectively damage nucleic acids within the cell is an active area of research. G-rich regions are abundant in the human genome, and the presence of G-quadruplexes in telomeres and promoter regions of oncogenes make them potential therapeutic targets. Ru(II) polypyridyl complexes are able to bind nucleic acids, and have been shown to induce and/or stabilize G-quadruplex structures. We’ve reported Ru(II) complex photochemical “light switches” for DNA, which undergo slow photodecomposition upon irradiation in an aqueous environment, but when in the presence of DNA become light-triggered metalating agents, with selectivity for G-quadruplex structures. A family of Ru(II) complexes were synthesized through a common Ru(II) building block to increase the rate of production of “light switch” molecules. A rapid screening approach was developed to determine the “light switch” selectivity and reactivity of each Ru(II) complex for different nucleic acid sequences and structures. Hit compounds were identified and derivatives were designed, synthesized, and tested to improve selectivity for biologically relevant nucleic acid structures. Promising results suggest these derivatives could broaden the use of Ru(II) “light switch” compounds from <i>in vitro</i> to <i>in vivo </i>probes and DNA damaging agents.

Using a Ru(II) building block and a rapid screening approach to identify nucleic acid selective “light switch” compounds

251st National Meeting (2016)

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