Biological evaluation of water soluble arene Ru(II) enantiomers with amino-oxime ligands
Authors
Cueva Alique, Isabel de la; Sierra Tornero, Sara; Muñoz Moreno, Laura; Pérez Redondo, Adrián; Bajo Chueca, Ana María; [et al.]Identifiers
Permanent link (URI): http://hdl.handle.net/10017/60452DOI: 10.1016/j.jinorgbio.2018.02.018
ISSN: 0162-0134
Date
2018-06Affiliation
Universidad de Alcalá. Departamento de Bioquímica y Biología Molecular; Universidad de Alcalá. Departamento de Biología de Sistemas; Universidad de Alcalá. Departamento de Química Orgánica y Química InorgánicaFunders
Ministerio de Economía y Competitividad
Comunidad Autónoma de Madrid
Universidad de Alcalá
Bibliographic citation
Journal of Inorganic Biochemistry, 2018, v. 183, p. 32-42
Keywords
Anticancer
Antimetastatic
Chiral
Cytotoxicity
DNA
In vivo.
Project
info:eu-repo/grantAgreement/MINECO//CTQ2014-58270-R/ES/
info:eu-repo/grantAgreement/CAM//I3 Program/ES/
info:eu-repo/grantAgreement/UAH//CCG2015%2FEXP-082/ES/
info:eu-repo/grantAgreement/UAH//CCG2015%2FBIO-010/ES/
info:eu-repo/grantAgreement/UAH//CCG2016%2FEXP-044/ES/
info:eu-repo/grantAgreement/UAH//CCG2016%2FEXP-028/ES/
Document type
info:eu-repo/semantics/article
Version
info:eu-repo/semantics/aceptedVersion
Rights
Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)
© Elsevier
Access rights
info:eu-repo/semantics/openAccess
Abstract
New water soluble, enantiopure arene ruthenium compound SRuSN-(1R,4S)-[(η6-p-cymene)Ru{ĸNH(Bn),ĸNOH}Cl]Cl (Bn = benzyl, 1a′) has been synthesized. The novel compound along with that previously described RRuRN-(1S,4R)-[(η6-p-cymene)Ru{ĸNH(Bn),ĸNOH}Cl]Cl (1a) was evaluated by polarimetry, ultra-violet and circular dichroism spectroscopy. The structure of novel ruthenium derivative 1a′ was determined by single crystal X-ray crystallography. Both enantiomers have been tested against several cancer cell lines in vitro: prostate PC-3, lung A-549, pancreas MIA PaCa-2, colorectal HCT-116, leukemia Jurkat and cervical HeLa. Both enantiomers are active and versatile cytotoxic agents, showing IC50 values from 2 to 12 times lower than those found for cisplatin in the different cell lines evaluated. The mechanism of cell death induced by the metal compounds was analyzed in A-549 and Jurkat cell lines. Derivatives 1a and 1a′ induced apoptotic cell death of A-549 cells while dose-dependent cell death mechanisms have been found in the Jurkat cell line. Compound-DNA interactions have been investigated by equilibrium dialysis, Fluorescence Resonance Energy Transfer (FRET) melting assays and viscometric titrations, revealing moderate binding affinity of 1a and 1a′ towards duplex DNA. Finally, the efficacy of 1a in a preliminary in vivo assay of PC-3 xenografts in nude mice has been evaluated, resulting in a promising inhibition of tumor growth by 45%. Analysis of tumor tissue also showed a significant decrease of levels of crucial molecules in the invasive phenotype of PC-3 cells.
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