TY - JOUR
T1 - Dinuclear RuII(bipy)2 Derivatives: Structural, Biological, and in Vivo Zebrafish Toxicity Evaluation
AU - Lenis-Rojas, Oscar A.
AU - Roma-Rodrigues, Catarina
AU - Fernandes, Alexandra R.
AU - Marques, Fernanda
AU - Pérez-Fernández, David
AU - Guerra-Varela, Jorge
AU - Sánchez, Laura
AU - Vázquez-García, Digna
AU - López-Torres, Margarita
AU - Fernández, Alberto A.
AU - Fernández, Jesús J.
N1 - info:eu-repo/grantAgreement/FCT/5876/147258/PT#
info:eu-repo/grantAgreement/FCT/5876/147266/PT#
UDC and USC authors acknowledge the financial support received from the Xunta de Galicia (Galicia, Spain) under the Grupos de Referencia Competitiva Programme: Project RC2014/042 (UDC) and Project GRC2014/010 (USC).
UCIBIO authors were cofinanced by the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007728).
D.V.-G. gratefully acknowledges the Xunta de Galicia support through EM2014/056 project. D.P.F. would like to thank M. Villar and V. Perez for technical assistance. O.A.L.-R. acknowledges the Fundacion Gil-Davila for a grant.
PY - 2017/6/19
Y1 - 2017/6/19
N2 - Ruthenium-based drugs exhibit interesting properties as potential anticancer pharmaceuticals. We herein present the synthesis and characterization of a new family of ruthenium complexes with formulas [{Ru(bipy)2}2(μ-L)][CF3SO3]4 (L = bptz, 1a) and [{Ru(bipy)2}2(μ-L)][CF3SO3]2 (L = arphos, 2a; dppb, 3a; dppf, 4a), which were synthesized from the Ru(II) precursor compound cis-Ru(bipy)2Cl2. The complexes were characterized by elemental analysis, mass spectrometry, 1H and 31P{1H} NMR, IR spectroscopy, and conductivity measurements. The molecular structures for three Ru(II) compounds were determined by single-crystal X-ray diffraction. The newly developed compounds interact with CT-DNA by intercalation, in particular, 2a, 3a, and 4a, which also seemed to induce some extent of DNA degradation. This effect seemed to be related with the formation of reactive oxygen species. The cytotoxic activity was evaluated against A2780, MCF7, and MDAMB231 human tumor cells. Compounds 2a and 4a were the most cytotoxic with activity compared to cisplatin (∼2 μM, 72 h) in the A2780 cisplatin sensitive cells. All the compounds induced A2780 cell death by apoptosis, however, to a lesser extent for compounds 4a and 2a. For these compounds, the mechanism of cell death in addition to apoptosis seemed to involve autophagy. In vivo toxicity was evaluated using the zebrafish embryo model. LC50 estimates varied from 5.397 (3a) to 39.404 (1a) mg/L. Considering the in vivo toxicity in zebrafish embryos and the in vitro cytotoxicity in cancer cells, compound 1a seems to be the safest having no effect on dechirionation and presenting a good antiproliferative activity against ovarian carcinoma cells.
AB - Ruthenium-based drugs exhibit interesting properties as potential anticancer pharmaceuticals. We herein present the synthesis and characterization of a new family of ruthenium complexes with formulas [{Ru(bipy)2}2(μ-L)][CF3SO3]4 (L = bptz, 1a) and [{Ru(bipy)2}2(μ-L)][CF3SO3]2 (L = arphos, 2a; dppb, 3a; dppf, 4a), which were synthesized from the Ru(II) precursor compound cis-Ru(bipy)2Cl2. The complexes were characterized by elemental analysis, mass spectrometry, 1H and 31P{1H} NMR, IR spectroscopy, and conductivity measurements. The molecular structures for three Ru(II) compounds were determined by single-crystal X-ray diffraction. The newly developed compounds interact with CT-DNA by intercalation, in particular, 2a, 3a, and 4a, which also seemed to induce some extent of DNA degradation. This effect seemed to be related with the formation of reactive oxygen species. The cytotoxic activity was evaluated against A2780, MCF7, and MDAMB231 human tumor cells. Compounds 2a and 4a were the most cytotoxic with activity compared to cisplatin (∼2 μM, 72 h) in the A2780 cisplatin sensitive cells. All the compounds induced A2780 cell death by apoptosis, however, to a lesser extent for compounds 4a and 2a. For these compounds, the mechanism of cell death in addition to apoptosis seemed to involve autophagy. In vivo toxicity was evaluated using the zebrafish embryo model. LC50 estimates varied from 5.397 (3a) to 39.404 (1a) mg/L. Considering the in vivo toxicity in zebrafish embryos and the in vitro cytotoxicity in cancer cells, compound 1a seems to be the safest having no effect on dechirionation and presenting a good antiproliferative activity against ovarian carcinoma cells.
UR - http://www.scopus.com/inward/record.url?scp=85020908951&partnerID=8YFLogxK
U2 - 10.1021/acs.inorgchem.7b00790
DO - 10.1021/acs.inorgchem.7b00790
M3 - Article
C2 - 28585811
AN - SCOPUS:85020908951
SN - 0020-1669
VL - 56
SP - 7127
EP - 7144
JO - Inorganic Chemistry
JF - Inorganic Chemistry
IS - 12
ER -
