Biological evaluation of water soluble arene Ru(II) enantiomers with amino-oxime ligands

de la Cueva-Alique, I. ; Sierra, S. ; Muñoz-Moreno, L. ; Pérez-Redondo, A. ; Bajo, A.M. ; Marzo, I. (Universidad de Zaragoza) ; Gude, L. ; Cuenca, T. ; Royo, E.

Resumen: New water soluble, enantiopure arene ruthenium compound SRuSN-(1R, 4S)-[(¿6-p-cymene)Ru{¿NH(Bn), ¿NOH}Cl]Cl (Bn = benzyl, 1a') has been synthesized. The novel compound along with that previously described RRuRN-(1S, 4R)-[(¿6-p-cymene)Ru{¿NH(Bn), ¿NOH}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.

Idioma: Inglés

DOI: 10.1016/j.jinorgbio.2018.02.018

Año: 2018

Publicado en: JOURNAL OF INORGANIC BIOCHEMISTRY 183 (2018), 32-42
ISSN: 0162-0134

Factor impacto JCR: 3.224 (2018)

Categ. JCR: CHEMISTRY, INORGANIC & NUCLEAR rank: 11 / 45 = 0.244 (2018) - Q1 - T1
Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 127 / 294 = 0.432 (2018) - Q2 - T2

Factor impacto SCIMAGO: 0.655 - Inorganic Chemistry (Q2) - Biochemistry (Q2)

Financiación: info:eu-repo/grantAgreement/ES/MICINN/CTQ2014-58270-R

Tipo y forma: Artículo (PostPrint)

Área (Departamento): Área Biología Celular (Dpto. Bioq.Biolog.Mol. Celular)