Ruthenium(II) polypyridyl complexes with benzothiophene and benzimidazole derivatives: Synthesis, antitumor activity, solution studies and biospeciation

• Published in: Journal of inorganic biochemistry 2023-01, Vol.238, p.112058-112058, Article 112058
• Main Authors: Dömötör, Orsolya, Teixeira, Ricardo G., Spengler, Gabriella, Avecilla, Fernando, Marques, Fernanda, Lenis-Rojas, Oscar A., Matos, Cristina P., de Almeida, Rodrigo F.M., Enyedy, Éva A., Tomaz, Ana Isabel
• Format: Article
• Language: English
• Subjects: Anticancer; Antineoplastic Agents - chemistry; Benzimidazoles - pharmacology; Cell Line, Tumor; Coordination Complexes - chemistry; Cytotoxicity; DNA binding; Female; Fluorescence lifetime; Humans; Ovarian Neoplasms; Ru(II) complexes; Ruthenium - chemistry; Thiophenes; X-ray crystal structures
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2022.112058

With the aim to incorporate pharmacophore motifs into the Ru(II)-polypyridyl framework, compounds [Ru(II)(1,10-phenantroline)2(2-(2-pyridyl)benzo[b]thiophene)](CF3SO3)2 (1) and [Ru(II)(1,10-phenantroline)2(2-(2-pyridyl)benzimidazole)](CF3SO3)2 (2) were prepared, characterized and tested for their antitumor potential. The solid-state structure of the compounds was confirmed by single-crystal X-ray diffraction analysis. The solution behavior of both complexes was investigated, namely their solubility, stability, and lipophilicity in physiological mimetic conditions, as well as an eventual uptake by passive diffusion. In vitro anticancer activity of the complexes on ovarian and different colon cancer cells and apoptosis induction by the complexes were studied. A slow transformation process was observed for complex 1 in aqueous solution when exposed to sunlight, while complex 2 undergoes deprotonation (pKa = 7.59). The lipophilicity of this latter complex depends strongly on the pH and ionic strength. In contrast, 1 is rather hydrophilic under various conditions. Complex 1 was highly cytotoxic on Colo-205 human colon (IC50 = 7.87 μM) and A2780 ovarian (IC50 = 2.2 μM) adenocarcinoma cell lines, while 2 displayed moderate anticancer activity (30.9 μM and 18.0 μM, respectively). The complexes induced late apoptosis and necrosis. Only a weak binding of the complexes to human serum albumin, the main transport protein in blood serum, was found. However, a more significant binding to calf thymus DNA was observed in UV–visible titrations and fluorometric dye displacement studies. Detailed analysis of fluorescence lifetime data collected for the latter systems reveals not only the partial intercalation of the complexes, but goes beyond the usual simplified interpretations. Anticancer activity in vitro of Ru(II)-phenanthroline complexes synthesized with benzothiophene and benzimidazole-derived co-ligands, their solution speciation and binding to human serum albumin and DNA in vitro. [Display omitted] •Structures revealed by various spectroscopic techniques and X-ray crystallography.•Stability and lipophilicity in aqueous solution assayed under different conditions.•Good cytotoxic activity on ovarian and colon cancer cell lines.•Weak binding towards human serum albumin.•Strong binding to calf thymus DNA, the binding mode is not clearly intercalation.