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

Michael Groessl, Erwin Reisner, Christian G. Hartinger, Rene Eichinger, Olga Semenova, Andrei R. Timerbaev, Michael A. Jakupec, Vladimir B. Arion, Bernhard K. Keppler

    Research output: Contribution to journalArticlepeer-review

    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.
    Original languageEnglish
    Pages (from-to)2185-2193
    Number of pages8
    JournalJournal of Medicinal Chemistry
    Volume50
    Issue number9
    DOIs
    Publication statusPublished - 3 May 2007

    Keywords

    • Antitumor agents
    • Cytotoxic agents
    • Human
    • Neoplasm
    • Redox potential
    • Stability
    • Structure-activity relationship (SAR of NAMI-A ruthenium complexes: aquation, redox properties, protein binding, and antitumor action)
    • Albumins
    • Transferrins Role: BSU (Biological study, unclassified), BIOL (Biological study) (binding to
    • SAR of NAMI-A ruthenium complexes: aquation, redox properties, protein binding, and antitumor action)
    • Mammary gland (carcinoma
    • Carcinoma
    • Colon neoplasm (colon carcinoma
    • Carcinoma (mammary
    • Crystal structure (of NAMI-A ruthenium complexes: SAR, aquation, redox properties, protein binding, and antitumor action)
    • structure ruthenium complex aquation redox potential protein cancer antitumor

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