期刊
MOLECULES
卷 27, 期 15, 页码 -出版社
MDPI
DOI: 10.3390/molecules27154898
关键词
1; 3-thiazole; 2-hydrazinyl-1; 3-thiazole; breast cancer; anticancer activity; antiproliferation; VEGFR-2 kinase activity; apoptosis; cell cycle arrest; molecular docking
资金
- Faculty of Pharmacy, Suez Canal University
- Faculty of Science, Port Said University, Egypt
- Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia [PNURSP2022R141]
- Taif University, Taif, Saudi Arabia [TURSP-2020/127]
A novel set of 1,3-thiazole derivatives was designed and synthesized, among which compound 4 showed the most potent antiproliferative activity against breast cancer cells and significant inhibitory activity towards VEGFR-2, suggesting it as a promising lead compound for developing potent anti-breast cancer compounds.
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 4 exhibited the most potent antiproliferative activity, with an IC50 of 5.73 and 12.15 mu M toward MCF-7 and MDA-MB-231 cells, respectively, compared to staurosporine (IC50 = 6.77 and 7.03 mu M, respectively). Exploring the mechanistic insights responsible for the antiproliferative activity of compound 4 revealed that compound 4 possesses a significant inhibitory activity toward the vascular endothelial growth factor receptor-2 (VEGFR-2) with (IC50 = 0.093 mu M) compared to Sorafenib (IC50 = 0.059 mu M). Further, compound 4 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 4 could be a promising lead compound for developing potent anti-breast cancer compounds.
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