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.

Structure-dependent in vitro cytotoxicity of the isomeric complexes [Ru(L)2Cl2] (L=o-tolylazopyridine and 4-methyl-2-phenylazopyridine) in comparison to [Ru(azpy)2Cl2]

“…The 2D NOESY NMR data show as most important cross-peaks: an interligand NOE between the H6 resonance and H14 resonance, and an interligand NOE between the H6 and CH 3 resonance. As it is known that in case of the a-Ru(azpy) 2 backbone, an H6-H(o) interligand NOE cross-peak is to be expected [11,36,37], these H6-H14 and H6-CH 3 NOEs confirm the a configuration. The fact that the H6 resonance gives an NOE to both the CH 3 signal, as well as to the H14 resonance, suggests the fast rotation of the phenyl rings in solution, a common feature of a isomeric complexes, despite the presence of the methyl groups.…”

“…The complexes a-and c-[Ru(azpy) 2 Cl 2 ] have a C 2 symmetry, causing the two azpy ligands in each isomer to be identical in NMR. It was proven that the a configuration shows a characteristic (intramolecular) interligand H6-H(o) (H(o)=H10/H14) NOE cross-peak [11,36,37]. 1 Moreover, the averaged interproton H6-H(o) distances from solid-state XRD-data appear to be useful for predicting NOEs in solution [11,36,37].…”

“…It was proven that the a configuration shows a characteristic (intramolecular) interligand H6-H(o) (H(o)=H10/H14) NOE cross-peak [11,36,37]. 1 Moreover, the averaged interproton H6-H(o) distances from solid-state XRD-data appear to be useful for predicting NOEs in solution [11,36,37]. The absence of interligand NOE cross-peaks between the aromatic resonances is characteristic for the c isomer [11].…”

New clues for platinum antitumor chemistry: Kinetically controlled metal binding to DNA

“…3 have generated tremendous synthetic activity. My lab has recently modified the azapyridine compounds and made them water soluble (91), which results in compounds with a high antitumor activity. Sadler and colleagues (92) have shown that even organometallic half-sandwich Ru compounds show activity and interesting DNA-binding properties.…”

Complexos de dirutênio com os fármacos ibuprofeno, ácido acetilsalicílico, naproxeno, indometacina, e com ácido y-linolêncio: Síntese, caracterização, avaliação da ação antiproliferativa sobre células tumorais e estudo da interação da unidade dimetálica com adenina e adenosina

“…9 10 11 Recentemente vários tipos de complexos de Ru (11) com ligantes arenos 12 13 ou ligantes bidentados heterocíclicos 14 No caso de compostos dinucleares os mais estudados são os de cobre, focalizando principalmente as propriedades antiinflamatórias e atuação destes complexos como miméticos da SOD. 41 Os AINEs com a função ácido carboxílico, foi lavado com 2-propanol e colocado no dessecador contendo P 2 0 S e sílica-gel.…”