article · Journal of Enzyme Inhibition and Medicinal Chemistry
A newly synthesised series of chemical compounds, specifically 1-(2-methyl-6-arylpyridin-3-yl)-3-phenylureas, has been developed and evaluated for anticancer activity. In laboratory testing against non-small cell lung cancer and colon cancer cell lines, a lead compound designated as 5l demonstrated potent cell-killing capability comparable to the standard chemotherapy drug doxorubicin. Broad screening through the United States National Cancer Institute Developmental Therapeutics Program confirmed that this lead molecule possesses broad-spectrum antitumor activity across multiple cancer types. Detailed cellular analysis revealed that compound 5l triggers programmed cell death, or apoptosis, in colon cancer cells. It achieves this by reducing the levels of protective proteins and increasing key proteins that promote cellular destruction, including p53, cytochrome C, and caspases. Additionally, the compound arrests the cell division cycle at the G2-M phase and increases the proportion of apoptotic cells.
Developing effective anticancer drugs remains a critical medical challenge, as many existing therapies face resistance or cause severe side effects. Identifying new chemical structures that can reliably trigger programmed cell death and arrest cancer cell division helps expand the pipeline of potential oncology treatments, offering alternative avenues for targeting lung and colon malignancies.
This work represents early-stage laboratory research that could interest biotechnology and pharmaceutical developers seeking new oncology leads. The findings identify a potential small-molecule candidate for further preclinical optimisation. Because testing remains limited to in vitro cell models, substantial development, including animal testing for toxicity and pharmacokinetic viability, is necessary before real-world therapeutic use can be considered.
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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 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<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 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<sub>1</sub> phase and arresting the G<sub>2</sub>-M stage. Also, 5l showed a significant increase in the percent of annexinV-FITC positive apoptotic cells from 1.99 to 15.76%.
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DOI: 10.1080/14756366.2018.1547286
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