Study of the anticancer properties of optically active titanocene oximato compounds

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

Resumen: New water soluble and optically active cyclopentadienyl titanium derivatives [(¿5-C5H5)2Ti{(1R, 4S)-¿ON, (R)NH}Cl] (R = Bn (Benzyl) 1a’, 2-pic (2-picolylamine) 1b’) have been synthesized. The novel compounds along with those previously described [(¿5-C5H5)2Ti{(1S, 4R)-¿ON, (R)NH}Cl] (R = Bn 1a, 2-pic 1b) were evaluated by polarimetry, ultra-violet and circular dichroism spectroscopy. The structure of 1b was determined by single crystal X-ray crystallography and showed a unique terminal monohapto Ti–O disposition of the oximato ligand. All enantiomers have been tested against several cancer cell lines in vitro: prostate PC-3 and DU-145, lung A-549, pancreas MiaPaca-2, colorectal HCT-116, leukemia Jurkat and cervical HeLa. In addition, 1a, 1b and 1b’ were tested against non-tumorigenic prostate RWPE-1 cell line. After 24 h of incubation, 1b and 1b’ were moderately active against Jurkat and A-549 cells. The anti-proliferative effect of titanium compounds on prostate PC-3, DU-145 and RWPE-1 cell lines was also assessed after 72 h of drug exposure. The cytotoxic profile of the enantiomers was similar, exception made for the PC-3 cells, with S, R-isomers exhibiting cytotoxicities 2 to 3 times higher than R, S-compounds. Under these conditions, derivative 1b showed calculated IC50 values better than those of Tacke''s Titanocene-Y (bis-[(p-methoxybenzyl)cyclopentadienyl]titanium(IV) dichloride) on both the prostate PC-3 and DU-145 cells. 1a and 1b cytotoxic behaviour shows certain selectiveness, with activities 2–4 times lower on normal prostate RWPE-1 than on cancer PC-3 cells. Furthermore, 1b produces higher cytotoxicity on prostate PC-3, DU-145 and RWPE-1 cells than the additive dose of titanocene dichloride and pro-ligand b·HCl. Additionally, compound-DNA interactions have been investigated by equilibrium dialysis, Fluorescence Resonance Energy Transfer (FRET) melting assays and viscometric titrations, which suggest that these metal complexes and/or their hydrolysis products bind DNA either in the minor groove or externally.

Idioma: Inglés

DOI: 10.1016/j.jorganchem.2018.12.011

Año: 2019

Publicado en: Journal of Organometallic Chemistry 881 (2019), 150-158
ISSN: 0022-328X

Factor impacto JCR: 2.304 (2019)

Categ. JCR: CHEMISTRY, ORGANIC rank: 26 / 57 = 0.456 (2019) - Q2 - T2
Categ. JCR: CHEMISTRY, INORGANIC & NUCLEAR rank: 20 / 45 = 0.444 (2019) - Q2 - T2

Factor impacto SCIMAGO: 0.506 - Materials Chemistry (Q2) - Inorganic Chemistry (Q2) - Physical and Theoretical Chemistry (Q2) - Organic Chemistry (Q2) - Biochemistry (Q3)

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)