The more acidic extracellular environment of solid tumors, relative to that of the normal cells, can be explored in the design of tumor-specific DNA cleaving agents. Because control of reactivity and selectivity becomes especially challenging when chemical processes have to work in the complexity of biological environments, we designed a group of �switchable� molecular systems for pH-gated ds DNA-cleavage which combine a potent DNA-photocleaver and a pH-regulated part derived from a dipeptide. The basic amino groups are protonated throughout all biologically relevant pH range; whereas the pH-gating amines undergo protonation at the pH threshold which separates cancer (pH 7). Control over the reactivity and selectivity is achieved via transformation of the initial protonation state (a monocation or a dication) into a trication at the relatively acidic pH. This change leads to an extraordinary increase in the efficiency of ds DNA cleavage leading to the ds:ss ratios comparable with the most efficient non-enzymatic ds DNA cleavers.

Engineering pH-gated transitions for selective and efficient double strand DNA photocleavage in hypoxic tumors

243rd National Meeting (2012)

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