TY - JOUR
T1 - 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
AU - Groessl, Michael
AU - Reisner, Erwin
AU - Hartinger, Christian G.
AU - Eichinger, Rene
AU - Semenova, Olga
AU - Timerbaev, Andrei R.
AU - Jakupec, Michael A.
AU - Arion, Vladimir B.
AU - Keppler, Bernhard K.
N1 - CAN 147:22703 1-3 Pharmacology Institute of Inorganic Chemistry,University of Vienna,Vienna,Austria. Journal 938076-98-3P; 938077-00-0P Role: PAC (Pharmacological activity), PRP (Properties), RCT (Reactant), SPN (Synthetic preparation), THU (Therapeutic use), BIOL (Biological study), PREP (Preparation), USES (Uses), RACT (Reactant or reagent) (SAR of NAMI-A ruthenium complexes: aquation, redox properties, protein binding, and antitumor action); 201653-76-1; 783324-95-8; 783325-20-2 Role: PAC (Pharmacological activity), PRP (Properties), THU (Therapeutic use), BIOL (Biological study), USES (Uses) (SAR of NAMI-A ruthenium complexes: aquation, redox properties, protein binding, and antitumor action); 938077-02-2P; 938077-04-4P Role: PRP (Properties), SPN (Synthetic preparation), PREP (Preparation) (SAR of NAMI-A ruthenium complexes: aquation, redox properties, protein binding, and antitumor action); 584-13-4 (4H-1,2,4-Triazol-4-amine); 1100-88-5; 6086-21-1; 135908-81-5 Role: RCT (Reactant), RACT (Reactant or reagent) (SAR of NAMI-A ruthenium complexes: aquation, redox properties, protein binding, and antitumor action)
PY - 2007/5/3
Y1 - 2007/5/3
N2 - 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 °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. © 2007 American Chemical Society.
AB - 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 °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. © 2007 American Chemical Society.
KW - Antitumor agents
KW - Cytotoxic agents
KW - Human
KW - Neoplasm
KW - Redox potential
KW - Stability
KW - Structure-activity relationship (SAR of NAMI-A ruthenium complexes: aquation, redox properties, protein binding, and antitumor action)
KW - Albumins
KW - Transferrins Role: BSU (Biological study, unclassified), BIOL (Biological study) (binding to
KW - SAR of NAMI-A ruthenium complexes: aquation, redox properties, protein binding, and antitumor action)
KW - Mammary gland (carcinoma
KW - Carcinoma
KW - Colon neoplasm (colon carcinoma
KW - Carcinoma (mammary
KW - Crystal structure (of NAMI-A ruthenium complexes: SAR, aquation, redox properties, protein binding, and antitumor action)
KW - structure ruthenium complex aquation redox potential protein cancer antitumor
U2 - 10.1021/jm061081y
DO - 10.1021/jm061081y
M3 - Article
SN - 0022-2623
VL - 50
SP - 2185
EP - 2193
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 9
ER -