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Novel Phenolic Compounds as Potential Dual EGFR and COX-2 Inhibitors: Design, Semisynthesis, in vitro Biological Evaluation and in silico Insights.
- Source :
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Drug design, development and therapy [Drug Des Devel Ther] 2021 May 31; Vol. 15, pp. 2325-2337. Date of Electronic Publication: 2021 May 31 (Print Publication: 2021). - Publication Year :
- 2021
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Abstract
- Introduction: Epidermal growth factor receptor (EGFR) inhibition is an imperative therapeutic approach targeting various types of cancer including colorectal, lung, breast, and pancreatic cancer types. Moreover, cyclooxygenase-2 (COX-2) is frequently overexpressed in different types of cancers and has a role in the promotion of malignancy, apoptosis inhibition, and metastasis of tumor cells. Combination therapy has been emerged to improve the therapeutic benefit against cancer and curb intrinsic and acquired resistance.<br />Methods: Three semi-synthetic series of compounds ( C1-4 , P1-4 , and G1-4 ) were prepared and evaluated biologically as potential dual epidermal growth factor receptor (EGFR) and COX-2 inhibitors. The main phenolic constituents of Amaranthus spinosus L. ( p -coumaric, caffeic and gallic) acids have been isolated and subsequently subjected to diazo coupling with various amines to get novel three chemical scaffolds with potential anticancer activities.<br />Results: Compounds C4 and G4 showed superior inhibitory activity against EGFR (IC <subscript>50</subscript> : 0.9 and 0.5 µM, respectively) and displayed good COX-2 inhibition (IC <subscript>50</subscript> : 4.35 and 2.47 µM, respectively). Moreover, the final compounds were further evaluated for their cytotoxic activity against human colon cancer (HT-29), pancreatic cancer (PaCa-2), human malignant melanoma (A375), lung cancer (H-460), and pancreatic ductal cancer (Panc-1) cell lines. Interestingly, compounds C4 and G4 exhibited the highest cytotoxic activity with average IC <subscript>50</subscript> values of 1.5 µM and 2.8 µM against H-460 and Panc-1, respectively. The virtual docking study was conducted to gain proper understandings of the plausible-binding modes of target compounds within EGFR and COX-2 binding sites.<br />Discussion: The NMR of prepared compounds showed characteristic peaks that confirmed the structure of the target compounds. The synthesized benzoxazolyl scaffold containing compounds showed inhibitory activities for both COXs and EGFR which are consistent with the virtual docking study.<br />Competing Interests: The authors reported no conflicts of interest for this work.<br /> (© 2021 Abdelgawad et al.)
- Subjects :
- Amaranthaceae chemistry
Cyclooxygenase 2 metabolism
Cyclooxygenase 2 Inhibitors chemical synthesis
Cyclooxygenase 2 Inhibitors chemistry
ErbB Receptors antagonists & inhibitors
ErbB Receptors metabolism
Humans
Molecular Docking Simulation
Molecular Structure
Phenols chemical synthesis
Phenols chemistry
Plant Extracts chemical synthesis
Plant Extracts chemistry
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors chemistry
Cyclooxygenase 2 Inhibitors pharmacology
Drug Design
Phenols pharmacology
Plant Extracts pharmacology
Protein Kinase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1177-8881
- Volume :
- 15
- Database :
- MEDLINE
- Journal :
- Drug design, development and therapy
- Publication Type :
- Academic Journal
- Accession number :
- 34103896
- Full Text :
- https://doi.org/10.2147/DDDT.S310820