Ru-II(p‑cymene) compounds as effective and selective anticancer candidates with no toxicity in vivo
Autor(a) principal: | |
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Data de Publicação: | 2018 |
Outros Autores: | , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.21/8964 |
Resumo: | Ruthenium(II) complexes are currently considered a viable alternative to the widely used platinum complexes as efficient anticancer agents. We herein present the synthesis and characterization of half-sandwich ruthenium compounds with the general formula [Ru(p-cymene)(L-N,N)Cl][CF3SO3] (L = 3,6-di-2-pyridyl-1,2,4,5-tetrazine (1) 6,7-dimethyl-2,3-bis(pyridin-2-yl)quinoxaline (2)), which have been synthesized by substitution reactions from the precursor dimer [Ru(p-cymene)(Cl)(μ-Cl)]2 and were characterized by elemental analysis, mass spectrometry, 1H NMR, UV–vis, and IR spectroscopy, conductivity measurements, and cyclic voltammetry. The molecular structure for complex 2 was determined by single-crystal X-ray diffraction. The cytotoxic activity of these compounds was evaluated against human tumor cells, namely ovarian carcinoma A2780 and breast MCF7 and MDAMB231 adenocarcinoma cells, and against normal primary fibroblasts. Whereas the cytotoxic activity of 1 is moderate, IC50 values found for 2 are among the lowest previously reported for Ru(p-cymene) complexes. Both compounds present no cytotoxic effect in normal human primary fibroblasts when they are used at the IC50 concentration in A2780 and MCF7 cancer cells. Their antiproliferative capacity is associated with a combined mechanism of apoptosis and autophagy. A strong interaction with DNA was observed for both with a binding constant value of the same magnitude as that of the classical intercalator [Ru(phen)2(dppz)]2+. Both complexes bind to human serum albumin with moderate to strong affinity, with conditional binding constants (log Kb) of 4.88 for complex 2 and 5.18 for complex 1 in 2% DMSO/10 mM Hepes pH7.0 medium. The acute toxicity was evaluated in zebrafish embryo model using the fish embryo acute toxicity test (FET). Remarkably, our results show that compounds 1 and 2 are not toxic/lethal even at extremely high concentrations. The novel compounds reported herein are highly relevant antitumor metallodrug candidates, given their in vitro cytotoxicity toward cancer cells and the lack of in vivo toxicity. |
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Ru-II(p‑cymene) compounds as effective and selective anticancer candidates with no toxicity in vivoHalf-sandwich ruthenium compoundsHuman tumor cellsNormal primary fibroblastsRuthenium(II) complexes are currently considered a viable alternative to the widely used platinum complexes as efficient anticancer agents. We herein present the synthesis and characterization of half-sandwich ruthenium compounds with the general formula [Ru(p-cymene)(L-N,N)Cl][CF3SO3] (L = 3,6-di-2-pyridyl-1,2,4,5-tetrazine (1) 6,7-dimethyl-2,3-bis(pyridin-2-yl)quinoxaline (2)), which have been synthesized by substitution reactions from the precursor dimer [Ru(p-cymene)(Cl)(μ-Cl)]2 and were characterized by elemental analysis, mass spectrometry, 1H NMR, UV–vis, and IR spectroscopy, conductivity measurements, and cyclic voltammetry. The molecular structure for complex 2 was determined by single-crystal X-ray diffraction. The cytotoxic activity of these compounds was evaluated against human tumor cells, namely ovarian carcinoma A2780 and breast MCF7 and MDAMB231 adenocarcinoma cells, and against normal primary fibroblasts. Whereas the cytotoxic activity of 1 is moderate, IC50 values found for 2 are among the lowest previously reported for Ru(p-cymene) complexes. Both compounds present no cytotoxic effect in normal human primary fibroblasts when they are used at the IC50 concentration in A2780 and MCF7 cancer cells. Their antiproliferative capacity is associated with a combined mechanism of apoptosis and autophagy. A strong interaction with DNA was observed for both with a binding constant value of the same magnitude as that of the classical intercalator [Ru(phen)2(dppz)]2+. Both complexes bind to human serum albumin with moderate to strong affinity, with conditional binding constants (log Kb) of 4.88 for complex 2 and 5.18 for complex 1 in 2% DMSO/10 mM Hepes pH7.0 medium. The acute toxicity was evaluated in zebrafish embryo model using the fish embryo acute toxicity test (FET). Remarkably, our results show that compounds 1 and 2 are not toxic/lethal even at extremely high concentrations. The novel compounds reported herein are highly relevant antitumor metallodrug candidates, given their in vitro cytotoxicity toward cancer cells and the lack of in vivo toxicity.American Chemical SocietyRCIPLLenis-Rojas, Oscar A.Robalo, Maria PaulaTomaz, Ana IsabelCarvalho, AndreiaFernandes, AlexandraMarques, FernandaFOLGUEIRA, MONICAYáñez, JuliánVázquez-García, DignaLópez-Torres, MargaritaFernandez, AlbertoFernandez, Jesus J.2018-10-24T10:51:54Z2018-11-052018-11-05T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.21/8964engLENIS-ROJAS, Oscar A.; [et al] – Ru-II(p‑cymene) compounds as effective and selective anticancer candidates with no toxicity in vivo. Inorganic Chemistry. ISSN 0020-1669. Vol. 57, N.º 21 (2018), pp. 13150-131660020-166910.1021/acs.inorgchem.8b01270metadata only accessinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-08-03T09:57:03Zoai:repositorio.ipl.pt:10400.21/8964Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:17:38.201081Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Ru-II(p‑cymene) compounds as effective and selective anticancer candidates with no toxicity in vivo |
title |
Ru-II(p‑cymene) compounds as effective and selective anticancer candidates with no toxicity in vivo |
spellingShingle |
Ru-II(p‑cymene) compounds as effective and selective anticancer candidates with no toxicity in vivo Lenis-Rojas, Oscar A. Half-sandwich ruthenium compounds Human tumor cells Normal primary fibroblasts |
title_short |
Ru-II(p‑cymene) compounds as effective and selective anticancer candidates with no toxicity in vivo |
title_full |
Ru-II(p‑cymene) compounds as effective and selective anticancer candidates with no toxicity in vivo |
title_fullStr |
Ru-II(p‑cymene) compounds as effective and selective anticancer candidates with no toxicity in vivo |
title_full_unstemmed |
Ru-II(p‑cymene) compounds as effective and selective anticancer candidates with no toxicity in vivo |
title_sort |
Ru-II(p‑cymene) compounds as effective and selective anticancer candidates with no toxicity in vivo |
author |
Lenis-Rojas, Oscar A. |
author_facet |
Lenis-Rojas, Oscar A. Robalo, Maria Paula Tomaz, Ana Isabel Carvalho, Andreia Fernandes, Alexandra Marques, Fernanda FOLGUEIRA, MONICA Yáñez, Julián Vázquez-García, Digna López-Torres, Margarita Fernandez, Alberto Fernandez, Jesus J. |
author_role |
author |
author2 |
Robalo, Maria Paula Tomaz, Ana Isabel Carvalho, Andreia Fernandes, Alexandra Marques, Fernanda FOLGUEIRA, MONICA Yáñez, Julián Vázquez-García, Digna López-Torres, Margarita Fernandez, Alberto Fernandez, Jesus J. |
author2_role |
author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
RCIPL |
dc.contributor.author.fl_str_mv |
Lenis-Rojas, Oscar A. Robalo, Maria Paula Tomaz, Ana Isabel Carvalho, Andreia Fernandes, Alexandra Marques, Fernanda FOLGUEIRA, MONICA Yáñez, Julián Vázquez-García, Digna López-Torres, Margarita Fernandez, Alberto Fernandez, Jesus J. |
dc.subject.por.fl_str_mv |
Half-sandwich ruthenium compounds Human tumor cells Normal primary fibroblasts |
topic |
Half-sandwich ruthenium compounds Human tumor cells Normal primary fibroblasts |
description |
Ruthenium(II) complexes are currently considered a viable alternative to the widely used platinum complexes as efficient anticancer agents. We herein present the synthesis and characterization of half-sandwich ruthenium compounds with the general formula [Ru(p-cymene)(L-N,N)Cl][CF3SO3] (L = 3,6-di-2-pyridyl-1,2,4,5-tetrazine (1) 6,7-dimethyl-2,3-bis(pyridin-2-yl)quinoxaline (2)), which have been synthesized by substitution reactions from the precursor dimer [Ru(p-cymene)(Cl)(μ-Cl)]2 and were characterized by elemental analysis, mass spectrometry, 1H NMR, UV–vis, and IR spectroscopy, conductivity measurements, and cyclic voltammetry. The molecular structure for complex 2 was determined by single-crystal X-ray diffraction. The cytotoxic activity of these compounds was evaluated against human tumor cells, namely ovarian carcinoma A2780 and breast MCF7 and MDAMB231 adenocarcinoma cells, and against normal primary fibroblasts. Whereas the cytotoxic activity of 1 is moderate, IC50 values found for 2 are among the lowest previously reported for Ru(p-cymene) complexes. Both compounds present no cytotoxic effect in normal human primary fibroblasts when they are used at the IC50 concentration in A2780 and MCF7 cancer cells. Their antiproliferative capacity is associated with a combined mechanism of apoptosis and autophagy. A strong interaction with DNA was observed for both with a binding constant value of the same magnitude as that of the classical intercalator [Ru(phen)2(dppz)]2+. Both complexes bind to human serum albumin with moderate to strong affinity, with conditional binding constants (log Kb) of 4.88 for complex 2 and 5.18 for complex 1 in 2% DMSO/10 mM Hepes pH7.0 medium. The acute toxicity was evaluated in zebrafish embryo model using the fish embryo acute toxicity test (FET). Remarkably, our results show that compounds 1 and 2 are not toxic/lethal even at extremely high concentrations. The novel compounds reported herein are highly relevant antitumor metallodrug candidates, given their in vitro cytotoxicity toward cancer cells and the lack of in vivo toxicity. |
publishDate |
2018 |
dc.date.none.fl_str_mv |
2018-10-24T10:51:54Z 2018-11-05 2018-11-05T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.21/8964 |
url |
http://hdl.handle.net/10400.21/8964 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
LENIS-ROJAS, Oscar A.; [et al] – Ru-II(p‑cymene) compounds as effective and selective anticancer candidates with no toxicity in vivo. Inorganic Chemistry. ISSN 0020-1669. Vol. 57, N.º 21 (2018), pp. 13150-13166 0020-1669 10.1021/acs.inorgchem.8b01270 |
dc.rights.driver.fl_str_mv |
metadata only access info:eu-repo/semantics/openAccess |
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metadata only access |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
American Chemical Society |
publisher.none.fl_str_mv |
American Chemical Society |
dc.source.none.fl_str_mv |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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