C-lysine conjugates as ph-controlled, light-activated reagents for double stranded dna cleavage and associated methods

Abstract

Compounds and methods for double-stranded DNA cleavage of light-activated lysine conjugates are enhanced at the slightly acidic pH suitable for selective targeting of cancer cells by the presence of two amino groups of different basicities. The first amino group plays an auxiliary role enhancing solubility and affinity to DNA whereas the second amino group which is positioned next to the light-activated DNA-cleaver undergoes protonation at the desired pH threshold. Protonation results in two synergetic effects which account for the increased DNA-cleaving ability at the lower pH: tighter binding to DNA at the lower pH; and the unproductive pathway which quenches the excited state of the photocleaver through intramolecular electron transfer is eliminated once the donor amino group next to the chromophore is protonated. The utility of these molecules for phototherapy of cancer is confirmed by the drastic increase in toxicity of five conjugates against cancer cell lines upon photoactivation.