Sroor Farid M, El-Sayed Ahmed F, Mahmoud Khaled
Organometallic and Organometalloid Chemistry Department, National Research Centre, 12622 Cairo, Egypt.
Microbial Genetics Department, Biotechnology Research Institute, National Research Centre, Giza, Egypt; Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo, Egypt.
Bioorg Chem. 2024 Dec;153:107944. doi: 10.1016/j.bioorg.2024.107944. Epub 2024 Nov 6.
To investigate the therapeutic potential of 5-Fluorouracil-based analogues, a straightforward synthetic technique was employed to synthesize a novel series of 5-arylurea uracil derivatives (AUFU01-03) and aryl-urea derivatives bearing perfluorophenyl (AUPF01-03). Reliable tools such as infrared (IR), Nuclear Magnetic Resonance (NMR) spectra, and elemental analyses were utilized to confirm the chemical structures and purity of these compounds. In comparison to healthy noncancerous control skin fibroblast cells (BJ-1), we examined the antiproliferative efficacy of compounds (AUFU01-03) and (AUPF01-03) against specific human malignant cell lines of the breast (MCF-7), and colon (HCT-116). Based on the MTT experiment results, compounds AUFU03 and AUPF01-03 possessed highly cytotoxic effects. Among these, cytotoxicity was demonstrated by compounds AUPF01-03 with IC values (AUPF01, IC = 167 ± 0.57 µM, AUPF02, IC = 23.4 ± 0.68 µM and AUPF03, IC = 28.8 ± 1.13 µM, respectively, on MCF-7), relative to 5-Fluorouracil as reference drug (IC = 160.7 ± 0.22 µM). Compound AUPF01 showed safety on BJ-1 cells up to a concentration of 100 µM (% cytotoxicity = 3.9 ± 0.42 %), so AUPF01 was selected for further studies. At the gene, the expression levels of BCL-2 gene were decreased significantly in MCF-7 + 5-FU and reached the lowest level in MCF-7 + AUPF01. In contrast, the expression levels of pro-apoptotic genes (p53 and BAX) were increased in MCF-7 + 5-FU, and reached a significantly higher level in MCF-7 + AUPF01. Apoptosis/necrosis assays demonstrated that AUPF01 induced S and G2/M phase cell cycle arrest in MCF-7 cells. Moreover, the efficacy of these compounds against anti-cancer protein receptors was assessed using molecular docking. The results indicated that compound AUPF01 exhibited high binding energies, effectively interacting with the active sites of crucial proteins such as EGFR, CDK2, ERalfa, BAX1, BCL2, and P53. These interactions involved a diverse range of chemical bonding types, suggesting the potential of these substances to inhibit enzyme activities. Moreover, computational ADMET analyses of these compounds demonstrated compliance with Lipinski's criteria, indicating favorable physicochemical properties. Additionally, molecular dynamics (MD) simulations revealed stable complexes of AUPF01 with EGFR, CDK2, ERalfa, BAX1, BCL2, and P53, as evidenced by (RMSD) values, RMSF values, and (SASA) values for the respective complexes.
为了研究基于5-氟尿嘧啶的类似物的治疗潜力，采用了一种直接的合成技术来合成一系列新型的5-芳基脲尿嘧啶衍生物（AUFU01 - 03）和带有全氟苯基的芳基脲衍生物（AUPF01 - 03）。利用可靠的工具如红外（IR）、核磁共振（NMR）光谱和元素分析来确认这些化合物的化学结构和纯度。与健康的非癌对照皮肤成纤维细胞（BJ - 1）相比，我们检测了化合物（AUFU01 - 03）和（AUPF01 - 03）对特定的人类乳腺癌（MCF - 7）和结肠癌（HCT - 116）恶性细胞系的抗增殖功效。基于MTT实验结果，化合物AUFU03和AUPF01 - 03具有高度细胞毒性作用。其中，化合物AUPF01 - 03表现出细胞毒性，在MCF - 7细胞上的IC值分别为（AUPF01，IC = 167 ± 0.57 μM，AUPF02，IC = 23.4 ± 0.68 μM，AUPF03，IC = 28.8 ± 1.13 μM），相对于作为参考药物的5-氟尿嘧啶（IC = 160.7 ± 0.22 μM）。化合物AUPF01在浓度高达100 μM时对BJ - 1细胞显示出安全性（细胞毒性百分比 = 3.9 ± 0.42%），因此选择AUPF01进行进一步研究。在基因水平上，MCF - 7 + 5 - FU组中BCL - 2基因的表达水平显著降低，并在MCF - 7 + AUPF01组中达到最低水平。相反，促凋亡基因（p53和BAX）的表达水平在MCF - 7 + 5 - FU组中升高，并在MCF - 7 + AUPF01组中达到显著更高水平。凋亡/坏死分析表明AUPF01在MCF - 7细胞中诱导S期和G2/M期细胞周期停滞。此外，使用分子对接评估了这些化合物对抗癌蛋白受体的功效。结果表明化合物AUPF01表现出高结合能，有效地与关键蛋白如EGFR、CDK2、ERalfa、BAX1、BCL2和P53的活性位点相互作用。这些相互作用涉及多种化学键类型，表明这些物质具有抑制酶活性的潜力。此外，对这些化合物的计算ADMET分析表明符合Lipinski标准，表明具有良好的物理化学性质。另外，分子动力学（MD）模拟显示AUPF01与EGFR、CDK2、ERalfa、BAX1、BCL2和P53形成稳定的复合物，各个复合物的（RMSD）值、RMSF值和（SASA）值证明了这一点。
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