RESUMEN
Complexes of yttrium(III) and dysprosium(III) with the traditional Chinese medicine active ingredient oxoglaucine (OG), namely [Y(OG)2(NO3)3]·CH3OH (1) and [Dy(OG)2(NO3)3]·H2O (2), were synthesized and characterized by elemental analysis, IR, ESI-MS, (1)H and (13)C NMR as well as single-crystal X-ray diffraction analysis. In vitro the complexes exhibited higher anticancer activity than the free ligand OG against the tested cancer cell lines. Among the tested cell lines, HepG2 is the most sensitive to the complexes. Complex 2 can trigger DNA damage in HepG2 cells, resulting in cell cycle arrest in the S phase and leading to cell apoptosis. The S phase cell-cycle arrest is caused via the ATM (ataxia-telangiectasia mutated)-Chk2-Cdc25A pathway. Chk2 is phosphorylated and activated in an ATM-dependent manner. It, in turn, phosphorylates Cdc25A phosphatise on serine124, causing the inactivation of Cdc25A in ubiquitin-mediated proteolytic degradation. The cyclin-Cdk complexes of the S phase could also be inhibited by limited supply of cyclins A and E. This irreversible cell cycle arrest process ultimately induces mitochondria-involved apoptotic cell death via the activation of Bcl-2 protein. Complex e2 ffectively inhibited tumour growth in the BEL-7402 xenograft mouse model and exhibited higher safety in vivo than cisplatin.
Asunto(s)
Antineoplásicos , Apomorfina/análogos & derivados , Complejos de Coordinación , Disprosio , Inhibidores de Topoisomerasa , Itrio , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apomorfina/química , Apomorfina/farmacología , Apomorfina/uso terapéutico , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/uso terapéutico , ADN/metabolismo , Daño del ADN , Disprosio/química , Disprosio/farmacología , Disprosio/uso terapéutico , Humanos , Medicina Tradicional China , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Fase S/efectos de los fármacos , Solubilidad , Inhibidores de Topoisomerasa/química , Inhibidores de Topoisomerasa/farmacología , Inhibidores de Topoisomerasa/uso terapéutico , Carga Tumoral/efectos de los fármacos , Agua/química , Difracción de Rayos X , Itrio/química , Itrio/farmacología , Itrio/uso terapéuticoRESUMEN
[Zn2(ClQ)4(CH3OH)2] (1), [Zn(BrQ)2(H2O)2] (2), [Zn2(ClIQ)4] (3) and [Cu(BrQ)2] (4) (H-ClQ = 5,7-dichloro-8-hydroxylquinoline, H-BrQ = 5,7-dibromo-8-hydroxylquinoline, and H-ClIQ = 5-chloro-7-iodo-8-hydroxylquinoline) were synthesized. Compounds 1-4 showed high anti-proliferative cytotoxicities against BEL-7404, SK-OV-3, NCI-H460 tumor cells, and HL-7702 normal cells in vitro, with IC50 values in the 1.4 nM to 32.13 µM range. Compounds 2-4 exhibited significantly enhanced cytotoxicity against BEL-7404 cell line, comparing with free 5,7-dihalo-8-quinolinol. Western blotting analysis showed that 2, 3 depleted mutant p53 protein in MDA-MB-231, and compound 2 decreased the ratio of Bcl-2/Bax in NCI-H460 significantly. The binding abilities of 1-4 to DNA were stronger than that of free quinolinol ligand. Intercalation is the probable binding mode for the complexes and free quinolinol ligands with DNA.
Asunto(s)
Antineoplásicos/farmacología , Cobre/química , Compuestos Organometálicos/farmacología , Quinolinas/química , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/biosíntesisRESUMEN
New platinum(II) complexes containing aminophosphonate ester were synthesized and fully characterized, which were found to possess better solubility in both organic solvents and water than cisplatin. These platinum(II) complexes exhibited considerable cytotoxicity against tumor cells MG-63, SK-OV-3, HepG2, BEL-7404 and low cytotoxicity to normal human liver cells HL-7702. Their antitumor activities were achieved through the induction of cell apoptosis and the cell cycle arrest at G1 phase. The electrophoretic mobility studies and CD spectral analysis revealed that the binding mode of complex 6 to DNA might be different from that of cisplatin.
Asunto(s)
Antineoplásicos/farmacología , Ésteres/química , Compuestos Organometálicos/farmacología , Organofosfonatos/química , Platino (Metal)/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Modelos Moleculares , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/químicaRESUMEN
Six new platinum(II) complexes with mono-aminophosphonate ester were synthesized and characterized by elemental analysis, (1)H NMR, ESI-MS as well as single crystal X-ray diffraction analysis. They are mononuclear structures. In all the crystal structures of complexes 1-6, the platinum centre adopts an approximately square-planar geometry, which were found to possess excellent solubility in both organic solvents and water and exhibit considerable cytotoxicity against MG-63, SK-OV-3 and HepG2 cell lines, but low cytotoxicity towards normal human liver cell HL-7702. In contrast to cisplatin, their antitumour activities are achieved through the induction of cell apoptosis by G1 cell-cycle arrest.