Structure-activity relationships for NAMI-A-type complexes (HL)[trans-RuCl4L(S-dmso)ruthenate(III)] (L = imidazole, indazole, 1,2,4-triazole, 4-amino-1,2,4-triazole, and 1-methyl-1,2,4-triazole): aquation, redox properties, protein binding, and antiproliferative activity.
Imidazolium [trans-tetrachloro(1H-imidazole)(S-dimethylsulfoxide)ruthenate(III)] (NAMI-A) and indazolium [trans-tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) are the most promising ruthenium complexes for anticancer chemotherapy. In this study, the azole ligand of NAMI-A was systematically varied (from imidazole of NAMI-A to indazole, 1,2,4-triazole, 4-amino-1,2,4-triazole, and 1-methyl-1,2,4-triazole), and the respective complexes were evaluated with regard to the rate of aquation and protein binding, redox potentials, and cytotoxicity by means of capillary zone electrophoresis, electrospray ionization mass spectrometry, cyclic voltammetry, and colorimetric microculture assays. Stability studies demonstrated low stability of the complexes at pH 7.4 and 37 degrees C and a high reactivity toward proteins (binding rate constants in the ranges of 0.02-0.34 and 0.01-0.26 min-1 for albumin and transferrin, respectively). The redox potentials (between 0.25 and 0.35 V) were found to be biologically accessible for activation of the complexes in the tumor, and the indazole-containing compound shows the highest antiproliferative activity in vitro.
Groessl
Michael
M
Institute of Inorganic Chemistry, University of Vienna, A-1090 Vienna, Austria.
Reisner
Erwin
E
Hartinger
Christian G
CG
Eichinger
Rene
R
Semenova
Olga
O
Timerbaev
Andrei R
AR
Jakupec
Michael A
MA
Arion
Vladimir B
VB
Keppler
Bernhard K
BK
D000418:Albumins / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003124:Colorimetry; D018360:Crystallography, X-Ray; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D019075:Electrophoresis, Capillary; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D011199:Potentiometry; D011485:Protein Binding; D012428:Ruthenium; D017975:Ruthenium Compounds; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D014168:Transferrin / Q000737:chemistry; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014867:Water / Q000737:chemistry
D000418:Albumins; D000970:Antineoplastic Agents; D007093:Imidazoles; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; D014168:Transferrin; D014230:Triazoles; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); D014867:Water; D012428:Ruthenium; D004121:Dimethyl Sulfoxide