Abstract
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 IC50 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-G1 phase and arresting the G2-M stage. Also, 5l showed a significant increase in the percent of annexinV-FITC positive apoptotic cells from 1.99 to 15.76%.
Highlights
Apoptosis, a self-automated cell death, represents the principal pathway in tissue homeostasis and in animal development; in addition, it is the main pathway for the clearance of aged or defective cells in the body
Based on the aforementioned findings and as a part of our ongoing quest towards developing potent anticancer agents[12,13,14,15,16,17,18,19,20], we report the synthesis and biological evaluation of novel series of 1-(2-methyl-6-arylpyridin-3-yl)-3-phenylureas 5a–l
All pyridines 5a–l were examined for their potential anti-proliferative activity against non-small cell lung cancer A549 cell line and colon cancer HCT-116 cell line
Summary
A self-automated cell death, represents the principal pathway in tissue homeostasis and in animal development; in addition, it is the main pathway for the clearance of aged or defective cells in the body. The second is the intrinsic mitochondrial apoptotic pathway that results from an intracellular cascade of events that are mainly produced by cellular stress, in which mitochondrial permeabilization plays a crucial role Both extrinsic and intrinsic pathways converge onto the activation of effector caspases, resulting in apoptotic cell death program. Our research group has explored the anticancer activity for novel series of 1–(2-methyl-6-(4-methoxy/3,4-dimethoxyphenyl)-pyridin-3-yl)-3-phenylureas[11]. All these derivatives were evaluated for their growth inhibitory activity against the proliferation of breast cancer cell line (MCF-7), where they displayed promising anti-proliferative activity. All pyridines 5a–l were examined for their potential anti-proliferative activity against non-small cell lung cancer A549 cell line and colon cancer HCT-116 cell line. White crystals (yield 70%), m.p. 223–225 C; IR (KBr, cmÀ1) 3393 (NH), 1731 (C1⁄4O); 1H NMR (CDCl3-d) d ppm: 2.64 (s, 3H, CH3), 6.30 (s, 1H, NH, D2O exchangeable), 6.61 (s, 1H, NH, D2O exchangeable), 7.15 (t, 2H, J 1⁄4 8.8 Hz, Ar-H), 7.38 (d, 1H, J 1⁄4 8.4 Hz, Ar-H), 7.46 (t, 1H, J 1⁄4 8.0 Hz, Ar-H), 7.60–7.65 (m, 2H, Ar-H), 7.71 (s, 1H, Ar-H), 7.98 (dd, 2H, J 1⁄4 8.8 Hz, J 1⁄4 5.6 Hz, Ar-H), 8.06 (d, 1H, J 1⁄4 8.4 Hz, Ar-H);13C NMR (DMSO-d6) d ppm: 21.34 (CH3), 115.36, 115.53, 117.69, 121.75, 128.04, 128.67, 130.06, 132.47, 135.00, 140.42, 148.02, 148.45, 152.62 (CO), 161.43, 163.38 (1⁄4C-F); HRMS (ESI) m/z calcd for [M þ H]þ (C20H16N3OF4): 390.12240, found: 390.12286
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