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Ru-II(p‑cymene) compounds as effective and selective anticancer candidates with no toxicity in vivo

2018-11-05Journal article Restricted access
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dc.contributor.authorLenis-Rojas, Oscar A.
dc.contributor.authorRobalo, Maria Paula
dc.contributor.authorTomaz, Ana Isabel
dc.contributor.authorCarvalho, Andreia
dc.contributor.authorFernandes, Alexandra
dc.contributor.authorMarques, Fernanda
dc.contributor.authorFOLGUEIRA, MONICA
dc.contributor.authorYáñez, Julián
dc.contributor.authorVázquez-García, Digna
dc.contributor.authorLópez-Torres, Margarita
dc.contributor.authorFernandez, Alberto
dc.contributor.authorFernandez, Jesus J.
dc.date.accessioned2018-10-24T10:51:54Z
dc.date.available2018-10-24T10:51:54Z
dc.date.issued2018-11-05
dc.description.abstractRuthenium(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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationLENIS-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. 13150-13166pt_PT
dc.identifier.doi10.1021/acs.inorgchem.8b01270pt_PT
dc.identifier.issn0020-1669
dc.identifier.issn1520-510X
dc.identifier.urihttp://hdl.handle.net/10400.21/8964
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherAmerican Chemical Societypt_PT
dc.relationIF/01179/2013pt_PT
dc.relationPOCI-01-0145-FEDER-007728pt_PT
dc.relation.publisherversionhttps://pubs.acs.org/doi/pdf/10.1021/acs.inorgchem.8b01270pt_PT
dc.subjectHalf-sandwich ruthenium compoundspt_PT
dc.subjectHuman tumor cellspt_PT
dc.subjectNormal primary fibroblastspt_PT
dc.titleRu-II(p‑cymene) compounds as effective and selective anticancer candidates with no toxicity in vivopt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FMulti%2F04349%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/RECI%2FQEQ-QIN%2F0189%2F2012/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FMulti%2F04378%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FQUI%2F00100%2F2013/PT
oaire.citation.endPage13166pt_PT
oaire.citation.issue21
oaire.citation.startPage13150pt_PT
oaire.citation.titleInorganic Chemistrypt_PT
oaire.citation.volume57
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person.familyNameRobalo
person.familyNameTomaz
person.familyNameFernandes
person.familyNameMarujo Marques
person.familyNameFOLGUEIRA
person.familyNameYáñez
person.familyNameDigna
person.familyNameLópez-Torres
person.familyNameFernández Sánchez
person.givenNameMaria Paula
person.givenNameAna Isabel
person.givenNameAlexandra
person.givenNameFernanda
person.givenNameMONICA
person.givenNameJulián
person.givenNameVazquez
person.givenNameMargarita
person.givenNameJesús José
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project.funder.identifierhttp://doi.org/10.13039/501100001871
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project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsclosedAccesspt_PT
rcaap.typearticlept_PT
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