Design, Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents.

Three novel pyrazolo-[4,3-e][1,2,4]triazolopyrimidine derivatives (1, 2, and 3) were designed, synthesized, and evaluated for their in vitro biological activity. All three compounds exhibited different levels of cytotoxicity against cervical and breast cancer cell lines. However, compound 1 showed the best antiproliferative activity against all tested tumor cell lines, including HCC1937 and HeLa cells, which express high levels of wild-type epidermal growth factor receptor (EGFR). Western blot analyses demonstrated that compound 1 inhibited the activation of EGFR, protein kinase B (Akt), and extracellular signal-regulated kinase (Erk)1/2 in breast and cervical cancer cells at concentrations of 7 and 11 µM, respectively. The results from docking experiments with EGFR suggested the binding of compound 1 at the ATP binding site of EGFR. Furthermore, the crystal structure of compound 3 (7-(4-bromophenyl)-9-(pyridin-4-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine) was determined by single crystal X-ray analysis. Our work represents a promising starting point for the development of a new series of compounds targeting EGFR.

Novel imidazo[1,2-a]pyridine inhibits AKT/mTOR pathway and induces cell cycle arrest and apoptosis in melanoma and cervical cancer cells.

The present study aimed to investigate the anti-cancer activity of imidazo[1,2-a]pyridine 5-7 in the A375 and WM115 melanoma and HeLa cervical cancer cell lines. The viability of cancer cells was analyzed by the MTT assay. Apoptosis was quantified by flow cytometry following staining of the cells with AnnexinV/propidium iodide (PI). The cell cycle was evaluated by flow cytometry after staining of cells with PI. The three compounds inhibited the proliferation of all cells for half maximal inhibitory concentration ranging from 9.7 to 44.6 µM following 48-h treatment. In addition, all cancer cells were more sensitive to compound 6 compared with the other compounds. Treatment with compound 6 induced G2/M cell cycle arrest and a significant increased level of intrinsic apoptosis in all tested cells. Furthermore, compound 6 reduced the levels of phospho (p)-protein kinase B and p-mechanistic target of rapamycin, and increased levels of the cell cycle inhibitors p53 and p21 and of the apoptosis-associated proteins BCL2 associated X protein and active caspase-9. Silencing p53 in A375 melanoma cells reduced compound 6-induced apoptosis, which suggested that compound 6 may induce p53-partially mediated apoptosis. These results demonstrated that imidazo[1,2-a]pyridines 5-7 are potential effective compounds in the treatment of melanoma and cervical cancers.