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Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design, Synthesis, In Vitro, and In Silico Study
| Content Provider | MDPI |
|---|---|
| Author | Salem, Manar G. El-Maaty, Dina M. Abu El-Deen, Yassmina I. Mohey Elesawy, Basem H. Askary, Ahmad El Saleh, Asmaa Saied, Essa M. Behery, Mohammed El |
| Copyright Year | 2022 |
| Abstract | 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 µM toward MCF-7 and MDA-MB-231 cells, respectively, compared to staurosporine (IC50 = 6.77 and 7.03 µM, 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 µM) compared to Sorafenib (IC50 = 0.059 µM). 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. |
| Starting Page | 4898 |
| e-ISSN | 14203049 |
| DOI | 10.3390/molecules27154898 |
| Journal | Molecules |
| Issue Number | 15 |
| Volume Number | 27 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2022-07-31 |
| Access Restriction | Open |
| Subject Keyword | Molecules Medicinal Chemistry 1,3-thiazole 2-hydrazinyl-1,3-thiazole Breast Cancer Anticancer Activity Antiproliferation Vegfr-2 Kinase Activity Apoptosis Cell Cycle Arrest Molecular Docking |
| Content Type | Text |
| Resource Type | Article |
