Redox behavior of tumor-inhibiting ruthenium(III) complexes and effects of physiological reductants on their binding to GMP.
Biotransformation of ruthenium(III) anticancer complexes as hypothesized in the activation-by-reduction theory is the central topic of the present paper. The redox behavior of tetrachlorobis(azole)ruthenate(III)-type complexes was studied by NMR spectroscopy and square wave voltammetry. The influence of reducing agents on the binding behavior toward the DNA-modeling nucleotide GMP was determined by capillary electrophoresis, accompanied by identification of arising peaks by online coupling to electrospray ionization mass spectrometry. The determination of redox potentials revealed that the biologically relevant reductants ascorbic acid and glutathione are capable of reducing the studied Ru(III) complexes under physiological conditions. Characteristic differences in reduction kinetics dependent on the pH value can be explained by higher reduction strength of ascorbic acid and glutathione at higher pH compared to the pH-independent redox response of ruthenium(III) complexes. Binding behavior of (H2ind)[trans-RuCl4(Hind)2] (Hind = 1H-indazole) toward GMP was found to be increased upon addition of two equivalents of glutathione but not of ascorbic acid. In contrast, only a minor influence on the GMP-binding under reductive conditions was found for (H2im)[trans-RuCl4(Him)2] (KP418, Him = 1H-imidazole).
Institute of Inorganic Chemistry-Bioinorganic, Environmental and Radiochemistry, Faculty of Chemistry, University of Vienna, Währinger Str. 42, A-1090, Vienna, Austria.
Petra
P
Schluga
Christian G
CG
Hartinger
Alexander
A
Egger
Erwin
E
Reisner
Mathea S
MS
Galanski
Michael A
MA
Jakupec
Bernhard K
BK
Keppler
D000970:Antineoplastic Agents / Q000737:chemistry*; D001205:Ascorbic Acid / Q000737:chemistry; D001665:Binding Sites; D019075:Electrophoresis, Capillary / Q000379:methods; D005978:Glutathione / Q000737:chemistry; D006150:Guanine Nucleotides / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007191:Indazoles / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D010084:Oxidation-Reduction; D017975:Ruthenium Compounds / Q000737:chemistry*; D012680:Sensitivity and Specificity; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013329:Structure-Activity Relationship; D013997:Time Factors
D000970:Antineoplastic Agents; D006150:Guanine Nucleotides; D007191:Indazoles; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C521720:imidazolium tetrachlorobis(1H-imidazole)ruthenate(III); C499292:indazolium trans-(tetrachlorobis(1H-indazole)ruthenate (III)); D005978:Glutathione; D001205:Ascorbic Acid