Novel Phenolic Compounds as Potential Dual EGFR and COX-2 Inhibitors: Design, Semisynthesis, in vitro Biological Evaluation and in silico Insights

• Published in: Drug design, development and therapy Vol. 15; pp. 2325 - 2337
• Main Authors: Abdelgawad, Mohamed A, Musa, Arafa, Almalki, Atiah H, Alzarea, Sami I, Mostafa, Ehab M, Hegazy, Mostafa M, Mostafa-Hedeab, Gomaa, Ghoneim, Mohammed M, Parambi, Della G T, Bakr, Rania B, Al-Muaikel, Nayef S, Alanazi, Abdullah S, Alharbi, Metab, Ahmad, Waqas, Bukhari, Syed N A, Al-Sanea, Mohammad M
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01-01-2021; Taylor & Francis Ltd; Dove; Dove Medical Press
• Subjects: Acids; Amaranthaceae - chemistry; Amines; anti-inflammatory; anticancer; Anticancer properties; Apoptosis; Binding sites; braf; Breast cancer; Cancer; Chromatography; Colon; Colon cancer; COX-2 inhibitors; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - chemical synthesis; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - pharmacology; Cyclooxygenase-2; Cytotoxicity; Docking; Drug Design; Drugs; Enzymes; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Growth factors; Health aspects; Humans; Inhibitors; kinase inhibitors; Kinases; Lung cancer; Malignancy; Melanoma; Metastases; Metastasis; Molecular Docking Simulation; Molecular Structure; multitarget agents; NMR; Nuclear magnetic resonance; Original Research; Pancreatic cancer; Phenolic compounds; Phenols; Phenols - chemical synthesis; Phenols - chemistry; Phenols - pharmacology; Phytochemicals; Plant Extracts - chemical synthesis; Plant Extracts - chemistry; Plant Extracts - pharmacology; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Receptors; Scaffolds; Semisynthesis; Tumor cell lines; Tumor cells; Saudi Arabia; anti-inflammatory; BRAF; kinase inhibitors; multitarget agents; anticancer
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S310820

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.
Three semi-synthetic series of compounds (
,
, and
) were prepared and evaluated biologically as potential dual epidermal growth factor receptor (EGFR) and COX-2 inhibitors. The main phenolic constituents of
L. (
-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.
Compounds
and
showed superior inhibitory activity against EGFR (IC
: 0.9 and 0.5 µM, respectively) and displayed good COX-2 inhibition (IC
: 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
and
exhibited the highest cytotoxic activity with average IC
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.
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.