Dual PI3K/Akt Inhibitors Bearing Coumarin-Thiazolidine Pharmacophores as Potential Apoptosis Inducers in MCF-7 Cells
Breast cancer is the most common malignancy worldwide; therefore, the development of new anticancer agents is essential for improved tumor control. By adopting the pharmacophore hybridization approach, two series of 7-hydroxyl-4-methylcoumarin hybridized with thiosemicarbazone (<b>V-VI</b&g...
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| Main Authors: | , , , , , , , , |
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| Format: | Book |
| Published: |
MDPI AG,
2022-03-01T00:00:00Z.
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| Online Access: | Connect to this object online. |
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| Summary: | Breast cancer is the most common malignancy worldwide; therefore, the development of new anticancer agents is essential for improved tumor control. By adopting the pharmacophore hybridization approach, two series of 7-hydroxyl-4-methylcoumarin hybridized with thiosemicarbazone (<b>V-VI</b>) and thiazolidin-4-one moieties (<b>VII-VIII</b>) were prepared. The in vitro anticancer activity was assessed against MCF-7 cells adopting the MTT assay. Nine compounds showed significant cytotoxicity. The most promising compound, <b>VIIb</b>, induced remarkable cytotoxicity (IC<sub>50</sub> of 1.03 + 0.05 µM). Further investigations were conducted to explore its pro-apoptotic activity demonstrating S-phase cell cycle arrest. Apoptosis rates following <b>VIIb</b> treatment revealed a 5-fold and 100-fold increase in early and late apoptotic cells, correspondingly. Moreover, our results showed caspase-9 dependent apoptosis induction as manifested by an 8-fold increase in caspase-9 level following <b>VIIb</b> treatment. Mechanistically, <b>VIIb</b> was found to target the PI3K-α/Akt-1 axis, as evidenced by enzyme inhibition assay results reporting significant inhibition of examined enzymes. These findings were confirmed by Western blot results indicating the ability of <b>VIIb</b> to repress levels of Cyclin D1, p-PI3K, and p-Akt. Furthermore, docking studies showed that <b>VIIb</b> has a binding affinity with the PI3K binding site higher than the original ligands X6K. Our results suggest that <b>VIIb</b> has pharmacological potential as a promising anti-cancer compound by the inhibition of the PI3K/Akt axis. |
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| Item Description: | 10.3390/ph15040428 1424-8247 |