title: New cytotoxic and water-soluble bis(2-phenylazopyridine)ruthenium(II) complexes.
abstract: New water-soluble bis(2-phenylazopyridine)ruthenium(II) complexes, all derivatives of the highly cytotoxic alpha-[Ru(azpy)(2)Cl(2)] (alpha denoting the coordinating pairs Cl, N(py), and N(azo) as cis, trans, cis, respectively) have been developed. The compounds 1,1-cyclobutanedicarboxylatobis(2-phenylazopyridine)ruthenium(II), alpha-[Ru(azpy)(2)(cbdca-O,O')] (1), oxalatobis(2-phenylazopyridine)ruthenium(II), alpha-[Ru(azpy)(2)(ox)] (2), and malonatobis(2-phenylazopyridine)ruthenium(II), alpha-[Ru(azpy)(2)(mal)] (3), have been synthesized and fully characterized. X-ray analyses of 1 and 2 are reported, and compound 1 is the first example in which the cbdca ligand is coordinated to a ruthenium center. The cytotoxicity of this series of water-soluble bis(2-phenylazopyridine) complexes has been determined in A2780 human ovarian carcinoma and A2780cisR, the corresponding cisplatin-resistant cell line. For comparison reasons, the cytotoxicity of the complexes alpha-[Ru(azpy)(2)Cl(2)], alpha-[Ru(azpy)(2)(NO(3))(2)], beta-[Ru(azpy)(2)Cl(2)] (beta indicating the coordinating pairs Cl, N(py), and N(azo) as cis, cis, cis, respectively), and beta-[Ru(azpy)(2)(NO(3))(2)] have been determined in this cell line. All the bis(2-phenylazopyridine)ruthenium(II) compounds display a promising cytotoxicity in the A2780 cell line (IC(50) = 0.9-10 microM), with an activity comparable to that of cisplatin and even higher than the activity of carboplatin. Interestingly, the IC(50) values of this series of ruthenium compounds (except the beta isomeric compounds) are similar in the cisplatin-resistant A2780cisR cell line compared to the normal cell line A2780, suggesting that the activity of these compounds might not be influenced by the multifactorial resistance mechanism that affect platinum anticancer agents.
authors.affiliation: Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Anna C G
authors.initials: AC
authors.lastname: Hotze
authors.forename: Marina
authors.initials: M
authors.lastname: Bacac
authors.forename: Aldrik H
authors.initials: AH
authors.lastname: Velders
authors.forename: Bart A J
authors.initials: BA
authors.lastname: Jansen
authors.forename: Huub
authors.initials: H
authors.lastname: Kooijman
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Spek
authors.forename: Jaap G
authors.initials: JG
authors.lastname: Haasnoot
authors.forename: Jan
authors.initials: J
authors.lastname: Reedijk
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012428:Ruthenium; D012995:Solubility; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014867:Water
chemical_list: C474153:1,1-cyclobutanedicarboxylatobis(2-phenylazopyridine)ruthenium(II); D000970:Antineoplastic Agents; D009942:Organometallic Compounds; C474155:malonatobis(2-phenylazopyridine)ruthenium(II); C474154:oxalatobis(2-phenylazopyridine)ruthenium(II); D014867:Water; D012428:Ruthenium; D002945:Cisplatin