RESUMEN
OBJECTIVE: This study aimed at synthesizing 13 series of novel derivatives with 2-phenylacrylonitrile, evaluating antitumor activity both in vivo and in vitro, and obtaining novel tubulin inhibitors. METHOD: The 13 series of 2-phenylacrylonitrile derivatives were synthesized by Knoevenagel condensation and the anti-proliferative activities were determined by MTT assay. The cell cycle and apoptosis were analyzed by flow cytometer. Quantitative cell migration was performed using 24-well Boyden chambers. The proteins were detected by western blotting. in vitro kinetics of microtubule assembly was measured using ELISA kit for Human ß-tubulin (TUBB). Molecular docking was done by Discovery Studio (DS) 2017 Client online tool. RESULTS: Among the derivatives, compound 1g2a possessed strong inhibitory activity against HCT116 (IC50 = 5.9 nM) and BEL-7402 (IC50 = 7.8 nM) cells. Compound 1g2a exhibited better selective antiproliferative activities and specificities than all the positive control drugs, including taxol. Compound 1g2a inhibited proliferation of HCT116 and BEL-7402 cells by arresting them in the G2/M phase of the cell cycle, inhibited the migration of HCT116 and BEL-7402 cells and the formation of cell colonies. Compound 1g2a showed excellent tubulin polymerization inhibitory activity on HCT116 and BEL-7402 cells. The results of molecular docking analyses showed that 1g2a may inhibit tubulin to exert anticancer effects. CONCLUSION: Compound 1g2a shows outstanding antitumor activity both in vivo and in vitro and has the potential to be further developed into a highly effective antitumor agent with little toxicity to normal tissues.
Asunto(s)
Antineoplásicos , Moduladores de Tubulina , Humanos , Moduladores de Tubulina/farmacología , Relación Estructura-Actividad , Proliferación Celular , Tubulina (Proteína)/metabolismo , Simulación del Acoplamiento Molecular , Ensayos de Selección de Medicamentos Antitumorales , Antineoplásicos/farmacología , Línea Celular Tumoral , ApoptosisRESUMEN
To identify anticancer agents with high potency and low toxicity, a series of (Z)-styrylbenzene derivatives were synthesised and evaluated for anticancer activities using a panel of nine cancer cell lines and two noncancerous cell lines. Most derivatives exhibited significant anti-proliferative activities against five cancer cell lines, including MGC-803 and BEL-7402. (Z)-3-(p-Tolyl)-2-(3,4,5-trimethoxyphenyl)acrylonitrile (6h) showed a strong inhibitory effect on MGC-803 cells (IC50 < 0.01 µM) and exhibited stronger anti-proliferative activity than taxol (IC50 < 0.06 ± 0.01 µM). The IC50 value of 6h in L-02 cells was 10,000-fold higher than in MGC-803 cells. Compound 6h inhibited proliferation of BEL-7402 cells by arresting at the G2/M phase through up-regulation of cyclin B1 expression, down-regulation of cyclin A and D1 expression, and induction of apoptosis. In addition, 6h inhibited the migration of BEL-7402 cells and the formation of cell colonies.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Estilbenos/síntesis química , Estilbenos/farmacología , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Estereoisomerismo , Estilbenos/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Eighteen novel 2,3-diphenyl acrylonitrile derivatives bearing halogens were designed, synthesized, and evaluated for biological activity. Preliminary in vitro results indicated that the majority of the compounds with a para-substituted halogen had considerable antiproliferative activity against five human cancer cell lines, including MGC-803, AGS, and BEL-7402, with IC50 values in the range of 0.46-100 µm. No significant toxic effects on the non-cancerous human liver cell line L-02 were observed. The selective inhibitory activities against cancer cells were significantly better than that of the control lead compound CA-4 and CA-4P. Particularly, potent activities were found for the derivatives of 3-(4-halogen phenyl)-2-(3,4,5-trimethoxyphenyl)acrylonitrile, such as 5c (4-fluoro), 5f (4-bromo), 5h (4-chloro), and 5k (4-trifluoro- methyl), for AGS with IC50 values of 0.75 ± 0.24, 0.68 ± 0.21, 0.41 ± 0.05, and 1.49 ± 0.92 µm, respectively. The antiproliferative effects of 5f were attributed to cell-cycle arrest in the G2 /M phase, induction of cellular apoptosis, suppression of cell migration, and inhibition of cell colony formation in AGS cells.