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:	Tarek S. Ibrahim, Azizah M. Malebari, Mamdouh F. A. Mohamed
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cancer hybrid compounds EGFR HDAC inhibitors chalcone dual inhibitors Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/6b1935634bf64310b98e1acf2ad5f1f6
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spelling	oai:doaj.org-article:6b1935634bf64310b98e1acf2ad5f1f62021-11-25T18:39:57ZDesign, Synthesis, In Vitro Anticancer Evaluation and Molecular Modelling Studies of 3,4,5-Trimethoxyphenyl-Based Derivatives as Dual EGFR/HDAC Hybrid Inhibitors10.3390/ph141111771424-8247https://doaj.org/article/6b1935634bf64310b98e1acf2ad5f1f62021-11-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1177https://doaj.org/toc/1424-8247Recently, 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.Tarek S. IbrahimAzizah M. MalebariMamdouh F. A. MohamedMDPI AGarticlecancerhybrid compoundsEGFRHDAC inhibitorschalconedual inhibitorsMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1177, p 1177 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cancer hybrid compounds EGFR HDAC inhibitors chalcone dual inhibitors Medicine R Pharmacy and materia medica RS1-441
spellingShingle	cancer hybrid compounds EGFR HDAC inhibitors chalcone dual inhibitors Medicine R Pharmacy and materia medica RS1-441 Tarek S. Ibrahim Azizah M. Malebari Mamdouh F. A. Mohamed Design, Synthesis, In Vitro Anticancer Evaluation and Molecular Modelling Studies of 3,4,5-Trimethoxyphenyl-Based Derivatives as Dual EGFR/HDAC Hybrid Inhibitors
description	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.
format	article
author	Tarek S. Ibrahim Azizah M. Malebari Mamdouh F. A. Mohamed
author_facet	Tarek S. Ibrahim Azizah M. Malebari Mamdouh F. A. Mohamed
author_sort	Tarek S. Ibrahim
title	Design, Synthesis, In Vitro Anticancer Evaluation and Molecular Modelling Studies of 3,4,5-Trimethoxyphenyl-Based Derivatives as Dual EGFR/HDAC Hybrid Inhibitors
title_short	Design, Synthesis, In Vitro Anticancer Evaluation and Molecular Modelling Studies of 3,4,5-Trimethoxyphenyl-Based Derivatives as Dual EGFR/HDAC Hybrid Inhibitors
title_full	Design, Synthesis, In Vitro Anticancer Evaluation and Molecular Modelling Studies of 3,4,5-Trimethoxyphenyl-Based Derivatives as Dual EGFR/HDAC Hybrid Inhibitors
title_fullStr	Design, Synthesis, In Vitro Anticancer Evaluation and Molecular Modelling Studies of 3,4,5-Trimethoxyphenyl-Based Derivatives as Dual EGFR/HDAC Hybrid Inhibitors
title_full_unstemmed	Design, Synthesis, In Vitro Anticancer Evaluation and Molecular Modelling Studies of 3,4,5-Trimethoxyphenyl-Based Derivatives as Dual EGFR/HDAC Hybrid Inhibitors
title_sort	design, synthesis, in vitro anticancer evaluation and molecular modelling studies of 3,4,5-trimethoxyphenyl-based derivatives as dual egfr/hdac hybrid inhibitors
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/6b1935634bf64310b98e1acf2ad5f1f6
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Design, Synthesis, In Vitro Anticancer Evaluation and Molecular Modelling Studies of 3,4,5-Trimethoxyphenyl-Based Derivatives as Dual EGFR/HDAC Hybrid Inhibitors

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