title: Heteroleptic mononuclear compounds of ruthenium(ii): synthesis, structural analyses, in vitro antitumor activity and in vivo toxicity on zebrafish embryos.
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 compounds 1a-5a with the general formula [Ru(bipy)2L][CF3SO3]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,1H and31P-{1H} 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 IC50of 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 LC50ranging from 8.67 mg L-1for compound 1a to 170.30 mg L-1for compound 2a.
authors.affiliation: Departamento de Química Fundamental & Centro de Investigaciones Científicas Avanzadas (CICA), Universidade da Coruña, 15008 A Coruña, Spain. lujjfs@udc.es.
authors.forename: O A
authors.initials: OA
authors.lastname: Lenis-Rojas
authors.forename: A R
authors.initials: AR
authors.lastname: Fernandes
authors.forename: C
authors.initials: C
authors.lastname: Roma-Rodrigues
authors.forename: P V
authors.initials: PV
authors.lastname: Baptista
authors.forename: F
authors.initials: F
authors.lastname: Marques
authors.forename: D
authors.initials: D
authors.lastname: Pérez-Fernández
authors.forename: J
authors.initials: J
authors.lastname: Guerra-Varela
authors.forename: L
authors.initials: L
authors.lastname: Sánchez
authors.forename: D
authors.initials: D
authors.lastname: Vázquez-García
authors.forename: M López
authors.initials: ML
authors.lastname: Torres
authors.forename: A
authors.initials: A
authors.lastname: Fernández
authors.forename: J J
authors.initials: JJ
authors.lastname: Fernández
mesh_terms: D015082:2,2'-Dipyridyl / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D004247:DNA / Q000737:chemistry; D053938:DNA Fragmentation; D004625:Embryo, Nonmammalian / Q000187:drug effects; D006801:Humans; D007928:Lethal Dose 50; D015394:Molecular Structure; D012428:Ruthenium / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D015027:Zebrafish
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D015082:2,2'-Dipyridyl; D012428:Ruthenium; D004247:DNA