Redox-Active Antineoplastic Ruthenium Complexes with Indazole: Correlation of in Vitro Potency and Reduction Potential

Antineoplastic ruthenium(III) complexes are generally regarded
as prodrugs, being activated by reduction. Within a homologous series
of ruthenium(III) complexes, cytotoxic potency is therefore expected
to increase with increasing ease of reduction. Complexes of the general
formula [RuIIICl(6-n)(ind)n](3-n)- (n = 0−4; ind = indazole;
counterions = Hind+ or Cl-) and the compound trans-[RuIICl2(ind)4] have
been prepared and characterized electrochemically. Lever's parametrization
method predicts that a higher indazole-to-chloride ratio results in
a higher reduction potential, which is confirmed by cyclic voltammetry.
In vitro antitumor potencies of these complexes in colon cancer cells
(SW480) and ovarian cancer cells (CH1) vary by more than 2 orders
of magnitude and increase in the following rank order:  [RuIIICl6]3- < [RuIIICl4(ind)2]- < [RuIIICl5(ind)]2- ≪ [RuIIICl3(ind)3] < [RuIIICl2(ind)4]+ ≈ [RuIICl2(ind)4]. Thus, the observed differences in potency correlate with
reduction potentials largely, though not perfectly, pointing to the
influence of additional factors. Differences in the cellular uptake
(probably resulting from different lipophilicity) contribute to this
correlation but cannot solely account for it.