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

• Published in: Journal of medicinal chemistry 2005-04, Vol.48 (8), p.2831-2837
• Main Authors: JAKUPEC, Michael A., REISNER, Erwin, EICHINGER, Anna, PONGRATZ, Martina, ARION, Vladimir B., GALANSKI, Markus, HARTINGER, Christian G., KEPPLER, Bernhard K.
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Chelating Agents - chemical synthesis; Chelating Agents - chemistry; Chelating Agents - pharmacology; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Electrochemistry; General aspects; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Ligands; Medical sciences; Molecular Structure; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Oxidation-Reduction; Pharmacology. Drug treatments; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Ruthenium; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0490742

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.