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

Author(s)

Bernhard Keppler, Christian Hartinger, Michael Größl, Erwin Reisner, Rene Eichinger, Olga Semenova, Andrei Timerbaev, Michael Jakupec, Vladimir Arion

Abstract

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.

Organisation(s)

Department of Inorganic Chemistry

Journal

Journal of Medicinal Chemistry

Volume

50

Pages

2185-2193

No. of pages

9

ISSN

0022-2623

Publication date

2007

Peer reviewed

Yes

Austrian Fields of Science 2012

104003 Inorganic chemistry

Portal url

https://ucrisportal.univie.ac.at/en/publications/ce4685f7-cfb4-47b1-9530-8d902a3474cb