Heteroleptic mononuclear compounds of ruthenium(ii): synthesis, structural analyses, in vitro antitumor activity and in vivo toxicity on zebrafish embryos. Issue 47 (21st November 2016)

• Record Type: Journal Article
• Authors: Lenis-Rojas, O. A.; Fernandes, A. R.; Roma-Rodrigues, C.; Baptista, P. V.; Marques, F.; Pérez-Fernández, D.; Guerra-Varela, J.; Sánchez, L.; Vázquez-García, D.; Torres, M. López; Fernández, A.; Fernández, J. J.
• Is Part Of: Dalton transactions. Volume 45:Issue 47(2016)
• Page Start: 19127
• Page End: 19140
• Publication Date: 2016-11-21
• Subjects: Chemistry, Inorganic -- Periodicals; Chemistry, Physical and theoretical -- Periodicals; Chemistry, Inorganic -- Periodicals; 546.05
• DOI: 10.1039/c6dt03591d
• Languages: English
• ISSNs: 1477-9226

Abstract

Abstract : Cytotoxic properties, DNA-interaction and in vivo toxicity were evaluated in Ru(ii ) compounds. Abstract : The limitations of platinum complexes in cancer treatment have motivated the extensive investigation into other metal complexes such as ruthenium. We herein present the synthesis and characterization of a new family of ruthenium compounds1a–5a with the general formula [Ru(bipy)2 L][CF3 SO3 ]2 (bipy = 2, 2′-bipyridine; L = bidentate ligand: N, N ; N, P ; P, P ; P, As ) which have been characterized by elemental analysis, ES-MS, 1 H and 31 P–{ 1 H} NMR, FTIR and conductivity measurements. The molecular structures of four Ru(ii ) complexes were determined by single crystal X-ray diffraction. All compounds displayed moderate cytotoxic activity in vitro against human A2780 ovarian, MCF7 breast and HCT116 colorectal tumor cells. Compound5a was the most cytotoxic compound against A2780 and MCF7 tumor cells with an IC50 of 4.75 ± 2.82 μM and 20.02 ± 1.46 μM, respectively. The compounds showed no cytotoxic effect on normal human primary fibroblasts but rather considerable selectivity for A2780, MCF7 and HCT116 tumor cells. All compounds induce apoptosis and autophagy in A2780 ovarian carcinoma cells and some nuclear DNA fragmentation. All compounds interact with CT-DNA with intrinsic binding constants in the order1a >4a >2a >3a >5a . The observed hyperchromic effect may be due to the electrostatic interaction between positively charged cations and the negatively charged phosphate backbone at the periphery of the double helix-CT-DNA. Interestingly, compound1a shows a concentration dependent DNA double strand cleavage. In addition in vivo toxicity has been evaluated on zebrafish embryos unveiling the differential toxicity between the compounds, with LC50 ranging from 8.67 mg L −1 for compound1a to 170.30 mg L −1 for compound2a .