Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt.
Biochemistry Department, Faculty of Pharmacy, Suez Canal University, Ismailia 415222, Egypt.
Molecules. 2022 Jul 31;27(15):4898. doi: 10.3390/molecules27154898.
Breast cancer is the most common cancer in women, responsible for over half a million deaths in 2020. Almost 75% of FDA-approved drugs are mainly nitrogen- and sulfur-containing heterocyclic compounds, implying the importance of such compounds in drug discovery. Among heterocycles, thiazole-based heterocyclic compounds have demonstrated a broad range of pharmacological activities. In the present study, a novel set of 1,3-thiazole derivatives was designed and synthesized based on the coupling of acetophenone derivatives, and phenacyl bromide was substituted as a key reaction step. The activity of synthesized compounds was screened against the proliferation of two breast cancer cell lines (MCF-7 and MDA-MB-231). Almost all compounds exhibited a considerable antiproliferative activity toward the breast cancer cells as compared to staurosporine, with no significant cytotoxicity toward the epithelial cells. Among the synthesized compounds, compound exhibited the most potent antiproliferative activity, with an IC of 5.73 and 12.15 µM toward MCF-7 and MDA-MB-231 cells, respectively, compared to staurosporine (IC = 6.77 and 7.03 µM, respectively). Exploring the mechanistic insights responsible for the antiproliferative activity of compound revealed that compound possesses a significant inhibitory activity toward the vascular endothelial growth factor receptor-2 (VEGFR-2) with (IC = 0.093 µM) compared to Sorafenib (IC = 0.059 µM). Further, compound showed the ability to induce programmed cell death by triggering apoptosis and necrosis in MCF-7 cells and to induce cell cycle arrest on MCF-7 cells at the G1 stage while decreasing the cellular population in the G2/M phase. Finally, detailed in silico molecular docking studies affirmed that this class of compounds possesses a considerable binding affinity toward VEGFR2 proteins. Overall, these results indicate that compound could be a promising lead compound for developing potent anti-breast cancer compounds.
乳腺癌是女性最常见的癌症，2020 年导致超过 50 万人死亡。近 75%的 FDA 批准药物主要是含氮和硫的杂环化合物，这表明此类化合物在药物发现中的重要性。在杂环中，噻唑基杂环化合物表现出广泛的药理活性。在本研究中，设计并合成了一组新型 1,3-噻唑衍生物，基于苯乙酮衍生物的偶联，并用苯乙腈溴化物取代作为关键反应步骤。合成化合物的活性通过筛选对两种乳腺癌细胞系（MCF-7 和 MDA-MB-231）的增殖进行筛选。与司莫司汀相比，几乎所有化合物对乳腺癌细胞均显示出相当大的抗增殖活性，对上皮细胞无明显细胞毒性。在所合成的化合物中，化合物 表现出最强的抗增殖活性，对 MCF-7 和 MDA-MB-231 细胞的 IC 分别为 5.73 和 12.15 µM，而司莫司汀的 IC 分别为 6.77 和 7.03 µM。探讨化合物 抗增殖活性的机制研究表明，与索拉非尼（IC = 0.059 µM）相比，化合物 对血管内皮生长因子受体-2（VEGFR-2）具有显著的抑制活性（IC = 0.093 µM）。此外，化合物 在 MCF-7 细胞中通过触发细胞凋亡和坏死以及在 MCF-7 细胞中诱导细胞周期停滞在 G1 期同时减少 G2/M 期的细胞群体来显示诱导程序性细胞死亡的能力。最后，详细的计算机分子对接研究证实，这类化合物对 VEGFR2 蛋白具有相当大的结合亲和力。总的来说，这些结果表明，化合物 可能是开发有效的抗乳腺癌化合物的有前途的先导化合物。
