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 [Ru(III)Cl((6-n))(ind)n](3-n)- (n = 0-4; ind = indazole; counterions = Hind(+) or Cl(-)) and the compound trans-[Ru(II)Cl(2)(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: [Ru(III)Cl(6)](3-) < [Ru(III)Cl(4)(ind)(2)](-) < [Ru(III)Cl(5)(ind)](2-) << [Ru(III)Cl(3)(ind)(3)] < [Ru(III)Cl(2)(ind)(4)](+) approximately [Ru(II)Cl(2)(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.
Jakupec
Michael A
MA
Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria.
Reisner
Erwin
E
Eichinger
Anna
A
Pongratz
Martina
M
Arion
Vladimir B
VB
Galanski
Mathea Sophia
MS
Hartinger
Christian G
CG
Keppler
Bernhard K
BK
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004563:Electrochemistry; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012428:Ruthenium; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002614:Chelating Agents; D007093:Imidazoles; D008024:Ligands; D009942:Organometallic Compounds; D011355:Prodrugs; D012428:Ruthenium