Synthesis and <i>in vitro</i> anticancer activity of certain novel 1-(2-methyl-6-arylpyridin-3-yl)-3-phenylureas as apoptosis-inducing agents
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In connection with our research program on the development of novel anticancer candidates, herein we report the design and synthesis of novel series of 1-(2-methyl-6-arylpyridin-3-yl)-3-phenylureas <b>5a–l</b>. The target pyridins were evaluated for their <i>in vitro</i> anticancer activity against two cancer cell lines: non-small cell lung cancer A549 cell line and colon cancer HCT-116 cell line. Compound <b>5l</b> emerged as the most active congener towards both A549 and HCT-116 cell lines with IC<sub>50</sub> values equal to 3.22 ± 0.2 and 2.71 ± 0.16 µM, respectively, which are comparable to those of Doxorubicin; 2.93 ± 0.28 and 3.10 ± 0.22, respectively. Furthermore, compound <b>5l</b> stood out as the most potent pyridine derivative (mean % GI = 40), at US-NCI Developmental Therapeutic Program anticancer assay, with broad-spectrum antitumor activity against the most tested cancer cell lines from all subpanels. Compound <b>5l</b> was able to provoke apoptosis in HCT-116 cells as evidenced by the decreased expression of the anti-apoptotic Bcl-2 protein, and the enhanced expression of the pro-apoptotic proteins levels; Bax, cytochrome C, p53, caspase-3 and caspase-9. Moreover, <b>5l</b> disrupted the HCT-116 cell cycle via alteration of the Sub-G<sub>1</sub> phase and arresting the G<sub>2</sub>-M stage. Also, <b>5l</b> showed a significant increase in the percent of annexinV-FITC positive apoptotic cells from 1.99 to 15.76%.
