Design, Synthesis, In Vitro Anticancer Evaluation and Molecular Modelling Studies of 3,4,5-Trimethoxyphenyl-Based Derivatives as Dual EGFR/HDAC Hybrid Inhibitors
Recently, combining histone deacetylase (HDAC) inhibitors with chemotherapeutic drugs or agents, in particular epidermal growth factor receptor (EGFR) inhibitors, is considered to be one of the most encouraging strategy to enhance the efficacy of the antineoplastic agents and decrease or avoid drug...
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| Autores principales: | , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/6b1935634bf64310b98e1acf2ad5f1f6 |
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| Sumario: | Recently, combining histone deacetylase (HDAC) inhibitors with chemotherapeutic drugs or agents, in particular epidermal growth factor receptor (EGFR) inhibitors, is considered to be one of the most encouraging strategy to enhance the efficacy of the antineoplastic agents and decrease or avoid drug resistance. Therefore, in this work, based on introducing 3,4,5-trimethoxy phenyl group as a part of the CAP moiety, in addition to incorporating 4–6 aliphatic carbons linker and using COOH or hydroxamic acid as ZBG, 12 novel EGFR/HDAC hybrid inhibitors <b>2a</b>–<b>c</b>, <b>3a</b>–<b>c</b>, <b>4a</b>–<b>c</b> and <b>5a</b>–<b>c</b> were designed, constructed, and evaluated for their anticancer activities against 4 cancer cell lines (HepG2, MCF-7, HCT116 and A549). Among all, hybrids with hydroxamic acid <b>4a</b>–<b>c</b> and <b>5a</b>, exhibited the highest inhibition against all cancer cell lines with IC<sub>50</sub> ranging from 0.536 to 4.892 μM compared to Vorinostat (SAHA) with IC<sub>50</sub> ranging from 2.43 to 3.63 μM and Gefitinib with IC<sub>50</sub> ranging from 1.439 to 3.366 μM. Mechanistically, the most potent hybrids <b>4a</b>–<b>c</b> and <b>5a</b> were further tested for their EGFR and HDACs inhibitory activities. The findings disclosed that hybrid <b>4b</b> displayed IC<sub>50</sub> = 0.063 µM on the target EGFR enzyme which is slightly less potent than the standard Staurosporine (IC<sub>50</sub> = 0.044 µM). Furthermore, hybrid <b>4b</b> showed less HDAC inhibitory activity IC<sub>50</sub> against HDAC1 (0.148), 2 (0.168), 4 (5.852), 6 (0.06) and 8 (2.257) than SAHA. In addition, the investigation of apoptotic action of the most potent hybrid <b>4b</b> showed a significant increase in Bax level up to 3.75-folds, with down-regulation in Bcl2 to 0.42-fold, compared to the control. Furthermore, hybrid <b>4b</b> displayed an increase in the levels of Caspases 3 and 8 by 5.1 and 3.15 folds, respectively. Additionally, the cell cycle analysis of hybrid <b>4b</b> revealed that it showed programmed cell death and cell cycle arrest at G1/S phase. Moreover, all these outcomes together with the molecular docking study recommended the rationalized target hybrids <b>4a</b>–<b>c</b> and <b>5a</b>, particularly <b>4b</b>, may be considered to be promising lead candidates for discovery of novel anticancer agents via dual inhibition of both EGFR/HDAC enzymes. |
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