4.7 Article

Cytotoxicity, cellular uptake, and DNA interactions of new monodentate ruthenium(II) complexes containing terphenyl arenes

Journal

JOURNAL OF MEDICINAL CHEMISTRY
Volume 51, Issue 17, Pages 5310-5319

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/jm8003043

Keywords

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Funding

  1. Ministry of Education [MSMT LC06030, 6198959216, ME08017, OC08003]
  2. Academy of Sciences of the Czech Republic [1QS500040581, KAN200200651, AV0Z50040507, AV0Z50040702]
  3. Grant Agency of the CR [203/06/1239]
  4. Ministry of Health of the CR [NR8562-4/2005]

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We have compared the cancer cell cytotoxicity, cell uptake., and DNA binding properties of the isomeric terphenyl complexes [(eta(6)-arene)Ru(en)Cl](+), where the arene is ortho- (2), meta- (3), or para-terphenyl (1) (o-, m-, or p-terp). Complex 1, the X-ray crystal structure of which confirms that it has the classical piano-stool geometry, has a similar potency to cisplatin but is not cross-resistant and has a much higher activity than 2 or 3. The extent of Ru uptake into A2780 or A2780cis cells does not correlate with potency. Complex I binds to DNA rapidly and quantitatively, preferentially to guanine residues, and causes significant DNA unwinding. Circular and linear dichroism, competitive binding experiments with ethidium bromide, DNA melting, and surface-enhanced Raman spectroscopic data are consistent with combined intercalative and monofunctional (coordination) binding mode of complex 1. This unusual DNA binding mode may therefore make a major contribution to the high potency of complex 1.

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