TY - JOUR
T1 - Triazole-Based Half-Sandwich Ruthenium(II) Compounds
T2 - From in Vitro Antiproliferative Potential to in Vivo Toxicity Evaluation
AU - Lenis-Rojas, Oscar A.
AU - Cabral, Rui
AU - Carvalho, Beatriz
AU - Friães, Sofia
AU - Roma-Rodrigues, Catarina
AU - Fernández, Jhonathan A. A.
AU - Vila, Sabela F.
AU - Sanchez, Laura
AU - Gomes, Clara S. B.
AU - Fernandes, Alexandra R.
AU - Royo, Beatriz
N1 - Funding Information:
info:eu-repo/grantAgreement/FCT/3599-PPCDT/125363/PT#
We are grateful to the Fundação da Ciência e a Tecnologia, FCT, fo rthe project MOSTMICRO-ITQB NOVA with references UIDB/04612/2020 and UIDP/04612/2020.
The NMR spectrometers at CERMAX are integrated in the national NMR Network and partially supported through project 022162.
We also thank the Analytic Services of ITQB and C. Almeida for elemental analysis and HRMS spectrometry. O.A.L.-R. acknowledges FCT, POPH- Programa Operacional Potencial Humano, and FSE (European Social Fund) for the CEEC 2017 Initiative.
Also, this work was supported by the Applied Molecular Biosciences Unit-UCIBIO which is financed by national funds from FCT (UIDP/04378/2020 and UIDB/04378/2020).
J.A.A.F. acknowledges Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES) and the program CAPES/PRINT Proc. 88887.470075/2019–00.
C.S.B.G. acknowledges the Associate Laboratory for Green Chemistry-LAQV, the Applied Molecular Biosciences Unit-UCIBIO (UIDB/50006/2020, UIDP/50006/2020, UIDB/04378/2020, UIDP/04378/2020).
Publisher Copyright:
©
PY - 2021/6/7
Y1 - 2021/6/7
N2 - A new series of half-sandwich ruthenium(II) compounds [(η6-arene)Ru(L)Cl][CF3SO3] bearing 1,2,3-triazole ligands (arene = p-cymene, L = L1 (1); arene = p-cymene, L = L2 (2); arene = benzene, L = L1 (3); arene = benzene, L2 (4); L1 = 2-[1-(p-tolyl)-1H-1,2,3-triazol-4-yl]pyridine and L2 = 1,1′-di-p-tolyl-1H,1′H-4,4′-bi(1,2,3-triazole) have been synthesized and fully characterized by 1H and 13C NMR and IR spectroscopy, mass spectrometry, and elemental analysis. The molecular structures of 1, 2, and 4 have been determined by single-crystal X-ray diffraction. The cytotoxic activity of 1-4 was evaluated using the MTS assay against human tumor cells, namely ovarian carcinoma (A2780), colorectal carcinoma (HCT116), and colorectal carcinoma resistant to doxorubicin (HCT116dox), and against normal primary fibroblasts. Whereas compounds 2 and 4 showed no cytotoxic activity toward tumor cell lines, compounds 1 and 3 were active in A2780, while showing no antiproliferative effect in human normal dermal fibroblasts at the IC50 concentrations of the A2780 cell line. Exposure of ovarian carcinoma cells to IC50 concentrations of compound 1 or 3 led to an accumulation of reactive oxygen species and an increase of apoptotic and autophagic cells. While compound 3 displayed low levels of angiogenesis induction, compound 1 showed an ability to induce cell cycle delay and to interfere with cell migration. When the in vivo toxicity studies using zebrafish and chicken embryos are considered, compounds 1 and 3, which were not lethal, are promising candidates as anticancer agents against ovarian cancer due to their good cytotoxic activity in tumor cells and their low toxicity both in vitro and in vivo.
AB - A new series of half-sandwich ruthenium(II) compounds [(η6-arene)Ru(L)Cl][CF3SO3] bearing 1,2,3-triazole ligands (arene = p-cymene, L = L1 (1); arene = p-cymene, L = L2 (2); arene = benzene, L = L1 (3); arene = benzene, L2 (4); L1 = 2-[1-(p-tolyl)-1H-1,2,3-triazol-4-yl]pyridine and L2 = 1,1′-di-p-tolyl-1H,1′H-4,4′-bi(1,2,3-triazole) have been synthesized and fully characterized by 1H and 13C NMR and IR spectroscopy, mass spectrometry, and elemental analysis. The molecular structures of 1, 2, and 4 have been determined by single-crystal X-ray diffraction. The cytotoxic activity of 1-4 was evaluated using the MTS assay against human tumor cells, namely ovarian carcinoma (A2780), colorectal carcinoma (HCT116), and colorectal carcinoma resistant to doxorubicin (HCT116dox), and against normal primary fibroblasts. Whereas compounds 2 and 4 showed no cytotoxic activity toward tumor cell lines, compounds 1 and 3 were active in A2780, while showing no antiproliferative effect in human normal dermal fibroblasts at the IC50 concentrations of the A2780 cell line. Exposure of ovarian carcinoma cells to IC50 concentrations of compound 1 or 3 led to an accumulation of reactive oxygen species and an increase of apoptotic and autophagic cells. While compound 3 displayed low levels of angiogenesis induction, compound 1 showed an ability to induce cell cycle delay and to interfere with cell migration. When the in vivo toxicity studies using zebrafish and chicken embryos are considered, compounds 1 and 3, which were not lethal, are promising candidates as anticancer agents against ovarian cancer due to their good cytotoxic activity in tumor cells and their low toxicity both in vitro and in vivo.
UR - http://www.scopus.com/inward/record.url?scp=85106348656&partnerID=8YFLogxK
U2 - 10.1021/acs.inorgchem.1c00527
DO - 10.1021/acs.inorgchem.1c00527
M3 - Article
C2 - 33973771
AN - SCOPUS:85106348656
SN - 0020-1669
VL - 60
SP - 8011
EP - 8026
JO - Inorganic Chemistry
JF - Inorganic Chemistry
IS - 11
ER -