RESUMEN
In the search of new bioorganometallic compounds as potential inhibitors of human (h) carbonic anhydrases (hCAs, EC 4.2.1.1), heterobinuclear ruthenium(II) complexes based on organometallic-acylhydrazones have been obtained. The complexes (1a-b, 2a-b) were prepared by reaction between the corresponding organometallic-acylhydrazone of the general formula [{(η5-C5H4)CH=N-NH-C(O)-C6H4-4-SO2NH2}]MLn or [{(η5-C5H4)CH=N-NH-C(O)-CH2CH2-NH-C6H4-4-SO2NH2}]MLn (where MLn = Re(CO)3; FeCp) and [Ru(p-cymene)Cl2]2. All compounds were characterized by conventional spectroscopic techniques and cyclic voltammetry. Biological evaluation as CA inhibitors (CAIs) was carried out and showed derivatives 1a, 2a and 2b to behave as selective inhibition against the tumors associate isoforms hCA IX and XII making them interesting candidates for preclinical evaluation in various hypoxic tumors in which the two enzymes are overexpressed.
Asunto(s)
Anhidrasas Carbónicas , Neoplasias , Antígenos de Neoplasias/química , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/química , Humanos , Ligandos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
AIMS: Ruthenium (II) complexes are promising anticancer molecules due its pharmacological properties and selectivity to cells tumor. The aim of this work was to study the cytotoxic activity, and apoptosis induction of two new ruthenium complexes on a human gastric cancer cell line. MAIN METHODS: Two ruthenium(II) complexes were synthesized: [(H2pbbzim)Ru(tpy-Ph-COOCH3)](Cl)2 (Ru-UCN1), and [(tpy)Ru(tpy-Ph-bzH)](Cl)2 (Ru-UCN3), and their anticancer capacity determined by cytotoxic assays, gene expression analysis, caspase activation and confocal microscopy. KEY FINDINGS: Ru-UCN3 is more notably cytotoxic than cisplatin in human gastric cancer cells AGS at 24â¯h, while Ru-UCN1 is more active against gastric cancer cells than cisplatin at 48â¯h. The complexes induce apoptosis as shown by RT-qPCR, protease activity, and confocal microscopy. Ru-UCN1 induces the overexpression of pro-apoptotic genes at 3 and 6â¯h, whereas Ru-UCN3 induces overexpression of these genes at 12 and 24â¯h. Ru-UCN1 treatment shows a strong activation of caspases 3/7 at 24â¯h, which was not observed for Ru-UCN3 treatment in the same timeframe. SIGNIFICANCE: Taken together, this data suggests that Ru-UCN1 and to a lesser extent, Ru-UCN3, may be interesting anticancer agents for gastric cancer.
Asunto(s)
Compuestos de Rutenio/farmacología , Neoplasias Gástricas/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Rutenio/farmacología , Rutenio/uso terapéutico , Compuestos de Rutenio/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
The aim of this work was the synthesis, characterization, and cytotoxicity evaluation of three new Ru(II) complexes with a general formula [Ru(Spy)(bipy)(P-P)]PF6 [Spy = pyridine-6-thiolate; bipy = 2,2'-bipyridine; P-P = 1,2-bis(diphenylphosphine)ethane (1); 1,3-bis(diphenylphosphine) propane (2); and 1,1'-bis(diphenylphosphino)ferrocene] (4). Complex (3) with the 1,4-bis(diphenylphosphine)butane ligand, already known from the literature, was also synthesized, to be better studied here. The cytotoxicities of the complexes toward two kinds of cancerous cells (K562 and S-180 cells) were evaluated and compared to normal cells (L-929 and PBMC) by MTT assay. The complex [Ru(Spy)(bipy)(dppb)]PF6 (3) was selected to study both the cellular and molecular mechanisms underlying its promising anticancer action in S-180 cells. The results obtained from this study indicated that complex (3) induces cell cycle arrest in the G0/G1 phase in S-180 cells associated with a decrease in the number of cells in S phase. After 24 and 48 h of exposure to complex (3), the cell viability decreased when compared to the negative control. Complex (3) does not appear to be involved in the DNA damage, but induced changes in the mitochondrial membrane potential in S-180 cells. Furthermore, there was also an increase in the gene expression of Bax, Caspase 9, and Tp53. According to our results, complex (3) induces cell apoptosis through p53/Bax-dependent intrinsic pathway and suppresses the expression of active antiapoptotic Bcl-2 protein.