C-lysine conjugates: pH-controlled light-activated reagents for efficient double-stranded DNA cleavage with implications for cancer therapy

Wang Yong Yang, Boris Breiner, Serguei V. Kovalenko, Chi Ben, Mani Singh, Shauna N. LeGrand, Qing Xiang Amy Sang, Geoffrey F. Strouse, John A. Copland, Igor V. Alabugin

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Double-stranded DNA cleavage of light-activated lysine conjugates is strongly enhanced at the slightly acidic pH (<7) suitable for selective targeting of cancer cells. This enhancement stems from the presence of two amino groups of different basicities. The first amino group plays an auxiliary role by 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. This protonation results in two synergetic effects which account for the increased DNA-cleaving ability at the lower pH. First, lysine conjugates show tighter binding to DNA at the lower pH, which is consistent with the anticipated higher degree of interaction between two positively charged ammonium groups with the negatively charged phosphate backbone of DNA. Second, 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. Experiments in the presence of traps for diffusing radicals show that reactive oxygen species do not contribute significantly to the mechanism of DNA cleavage at the lower pH, which is indicative of tighter binding to DNA under these conditions. This feature is valuable not only because many solid tumors are hypoxic but also because cleavage which does not depend on diffusing species is more localized and efficient. Sequence-selectivity experiments suggest combination of PET and base alkylation as the chemical basis for the observed DNA damage. 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.

Original languageEnglish (US)
Pages (from-to)11458-11470
Number of pages13
JournalJournal of the American Chemical Society
Volume131
Issue number32
DOIs
StatePublished - Aug 19 2009

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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