EGFR inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and docking studies of novel xanthine derivatives carrying chalcone moiety as hybrid molecules

Hesham A Abou-Zied; Bahaa G M Youssif; Mamdouh F A Mohamed; Alaa M Hayallah; Mohamed Abdel-Aziz

doi:10.1016/j.bioorg.2019.102997

EGFR inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and docking studies of novel xanthine derivatives carrying chalcone moiety as hybrid molecules

Bioorg Chem. 2019 Aug:89:102997. doi: 10.1016/j.bioorg.2019.102997. Epub 2019 May 22.

Authors

Hesham A Abou-Zied¹, Bahaa G M Youssif², Mamdouh F A Mohamed³, Alaa M Hayallah⁴, Mohamed Abdel-Aziz⁵

Affiliations

¹ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Deraya University, Minia, Egypt.
² Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Aljouf, Sakaka 2014, Saudi Arabia. Electronic address: bgyoussif@ju.edu.sa.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, 82524 Sohag, Egypt.
⁴ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Deraya University, Minia, Egypt; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. Electronic address: alaa_hayalah@yahoo.com.
⁵ Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt.

PMID: 31136902
DOI: 10.1016/j.bioorg.2019.102997

Abstract

One of the helpful ways to improve the effectiveness of anticancer agents and weaken drug resistance is to use hybrid molecules. therefore, the current study intended to introduce 20 novel xanthine/chalcone hybrids 9-28 of promising anticancer activity. Compounds 10, 11, 13, 14, 16, 20 and 23 exhibited potent inhibition of cancer cells growth with IC₅₀ ranging from 1.0 ± 0.1 to 3.5 ± 0.4 μM compared to doxorubicin with IC₅₀ ranging from 0.90 ± 0.62 to 1.41 ± 0.58 μM and that compounds 11 and 16 were the best. To verify the mechanism of their anticancer activity, compounds 10, 11, 13, 14, 16, 20 and 23 were evaluated for their EGFR inhibitory effect. The study results revealed that compound 11 showed IC₅₀ = 0.3 µM on the target enzyme which is more potent than staurosporine reference drug (IC₅₀ = 0.4 µM). Accordingly, the apoptotic effect of the most potent compounds 11 was extensively investigated and showed a marked increase in Bax level up to 29 folds, and down-regulation in Bcl2 to 0.28 fold, in comparison to the control. Furthermore, the effect of compound 11 on Caspases 3 and 8 was evaluated and was found to increase their levels by 8 and 14 folds, respectively. Also, the effect of compound 11 on the cell cycle and its cytotoxic effect were examined. Moreover, a molecular docking study was adopted to confirm mechanism of action.

Keywords: Anti-proliferative; Apoptotic assay; Chalcone; EGFR; Hybrids; Xanthine.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Cell Proliferation / drug effects
Chalcone / chemistry
Chalcone / pharmacology*
Dose-Response Relationship, Drug
Drug Design
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism
Hep G2 Cells
Humans
MCF-7 Cells
Molecular Docking Simulation*
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Xanthine / chemical synthesis
Xanthine / chemistry
Xanthine / pharmacology*

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Xanthine
Chalcone
EGFR protein, human
ErbB Receptors