Molecular and Cellular
Characterization of the Biological
Effects of Ruthenium(II) Complexes Incorporating 2‑Pyridyl-2-pyrimidine-4-carboxylic
Acid
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Abstract
A great majority of the Ru complexes currently studied
in anticancer
research exert their antiproliferative activity, at least partially,
through ligand exchange. In recent years, however, coordinatively
saturated and substitutionally inert polypyridyl Ru(II) compounds
have emerged as potential anticancer drug candidates. In this work,
we present the synthesis and detailed characterization of two novel
inert Ru(II) complexes, namely, [Ru(bipy)<sub>2</sub>(Cpp-NH-Hex-COOH)]<sup>2+</sup> (<b>2</b>) and [Ru(dppz)<sub>2</sub>(CppH)]<sup>2+</sup> (<b>3</b>) (bipy = 2,2′-bipyridine; CppH = 2-(2′-pyridyl)pyrimidine-4-carboxylic
acid; Cpp-NH-Hex-COOH = 6-(2-(pyridin-2-yl)pyrimidine-4-carboxamido)hexanoic
acid; dppz = dipyrido[3,2-<i>a</i>:2′,3′-<i>c</i>]phenazine). <b>3</b> is of particular interest as
it was found to have IC<sub>50</sub> values comparable to cisplatin,
a benchmark standard in the field, on three cancer cell lines and
a better activity on one cisplatin-resistant cell line than cisplatin
itself. The mechanism of action of <b>3</b> was then investigated
in detail and it could be demonstrated that, although <b>3</b> binds to calf-thymus DNA by intercalation, the biological effects
that it induces did not involve a nuclear DNA related mode of action.
On the contrary, confocal microscopy colocalization studies in HeLa
cells showed that <b>3</b> specifically targeted mitochondria.
This was further correlated by ruthenium quantification using High-resolution
atomic absorption spectrometry. Furthermore, as determined by two
independent assays, <b>3</b> induced apoptosis at a relatively
late stage of treatment. The generation of reactive oxygen species
could be excluded as the cause of the observed cytotoxicity. It was
demonstrated that the mitochondrial membrane potential in HeLa was
impaired by <b>3</b> as early as 2 h after its introduction
and even more with increasing time