Synthesis and in vitro anticancer activity of certain novel 1-(2-methyl-6-arylpyridin-3-yl)-3-phenylureas as apoptosis-inducing agents

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 34; no. 1; pp. 322 - 332
• Main Authors: Eldehna, Wagdy M., Hassan, Ghada S., Al-Rashood, Sara T., Al-Warhi, Tarfah, Altyar, Ahmed E., Alkahtani, Hamad M., Almehizia, Abdulrahman A., Abdel-Aziz, Hatem A.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.01.2019; Taylor & Francis Group
• Subjects: Anticancer agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; apoptosis; Apoptosis - drug effects; cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; Molecular Structure; pyridine-urea; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Research Paper; Structure-Activity Relationship; synthesis; Urea - analogs & derivatives; Urea - chemistry; Urea - pharmacology; synthesis; apoptosis; Anticancer agents; cell cycle; pyridine-urea
• ISSN: 1475-6366; 1475-6374; 1475-6374
• DOI: 10.1080/14756366.2018.1547286

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 5a-l. The target pyridins were evaluated for their in vitro anticancer activity against two cancer cell lines: non-small cell lung cancer A549 cell line and colon cancer HCT-116 cell line. Compound 5l emerged as the most active congener towards both A549 and HCT-116 cell lines with IC 50 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 5l 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 5l 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, 5l disrupted the HCT-116 cell cycle via alteration of the Sub-G 1 phase and arresting the G 2 -M stage. Also, 5l showed a significant increase in the percent of annexinV-FITC positive apoptotic cells from 1.99 to 15.76%.