Heteroleptic mononuclear compounds of ruthenium(ii): synthesis, structural analyses, in vitro antitumor activity and in vivo toxicity on zebrafish embryos

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 compounds 1a-5a with the general formula [Ru(bipy) L][CF SO ] (bipy = 2...

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Published in:Dalton transactions : an international journal of inorganic chemistry 2016-12, Vol.45 (47), p.19127-19140
Main 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
Format: Article
Language:English
Subjects:
2,2'-Dipyridyl - chemistry
2,2'-Dipyridyl - pharmacology
2,2'-Dipyridyl - toxicity
Animals
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Antineoplastic Agents - toxicity
Apoptosis - drug effects
Biocompatibility
Cancer
Cell Line
Cell Line, Tumor
Cell Survival - drug effects
Coordination Complexes - chemistry
Coordination Complexes - pharmacology
Coordination Complexes - toxicity
DNA - chemistry
DNA Fragmentation
Embryo, Nonmammalian - drug effects
Embryos
Humans
In vitro testing
Lethal Dose 50
Molecular Structure
Ruthenium - chemistry
Ruthenium - pharmacology
Ruthenium - toxicity
Synthesis
Toxicity
Tumors
Zebrafish
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Summary: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 compounds 1a-5a with the general formula [Ru(bipy) L][CF SO ] (bipy = 2,2'-bipyridine; L = bidentate ligand: N,N; N,P; P,P; P,As) which have been characterized by elemental analysis, ES-MS, H and P-{ 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. Compound 5a was the most cytotoxic compound against A2780 and MCF7 tumor cells with an IC 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 order 1a > 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, compound 1a 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 LC ranging from 8.67 mg L for compound 1a to 170.30 mg L for compound 2a.
ISSN:1477-9226
1477-9234
DOI:10.1039/c6dt03591d