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Mechanistic Investigation into DNA Modification by a Ru II ,Rh III Bimetallic Complex
Author(s) -
RodríguezCorrales José Á.,
Wang Jing,
Winkel Brenda S. J.,
Brewer Karen J.
Publication year - 2018
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201800369
Subject(s) - chemistry , photosensitizer , covalent bond , dna , bimetallic strip , photodynamic therapy , reactive oxygen species , stereochemistry , ligand (biochemistry) , biophysics , combinatorial chemistry , photochemistry , catalysis , biochemistry , receptor , biology , organic chemistry
Despite significant progress in the treatment of cancer, there remains an urgent need for more effective therapies that also have less impact on patient wellbeing. Photodynamic therapy employs targeted light activation of a photosensitizer in selected tissues, thereby reducing off‐target toxicity. Our group previously reported a Ru II ,Rh III bimetallic architecture that displays multifunctional covalent photomodification of DNA in the therapeutic window in an oxygen‐independent manner, features that are essential for treating deep and hypoxic tumors. Herein, we explore the mechanism by which a new analogue, [(phen) 2 Ru(dpp)Rh(phen)Cl 2 ] 3+ , or Ru II ‐Rh III , interacts with DNA. We established that Ru II ‐Rh III exhibits “light switch” behavior in the presence of DNA, undergoing strong electrostatic interactions that might involve groove binding. Furthermore, these noncovalent interactions play a major role in the covalent photobinding and photocleavage of DNA, which occur according to an oxygen‐independent mechanism. Polymerase chain reaction (PCR) revealed that covalent modification of DNA by Ru II ‐Rh III , especially photobinding, is critical to inhibiting amplification, thus suggesting that the complex could exert its toxic activity by interfering with DNA replication in cells. This new structural motif, with phenanthroline at all three terminal ligand positions, has a number of properties that are promising for the continued refinement of photodynamic‐therapy strategies.