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

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. 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. Results Compounds C4 and G4 showed superior inhibitory activity against EGFR (IC 50 : 0.9 and 0.5 µM, respectively) and displayed good COX-2 inhibition (IC 50 : 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 50 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. 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.

New Insights Into the Anticancer Effects of p-Coumaric Acid: Focus on Colorectal Cancer

“…43,[45][46][47] COX-2 is an enzyme that plays an important role in inflammatory responses through PGE2 synthesis from arachidonic acid, and it is selectively overexpressed in colon tumors. 43,48,49 Hence, COX-2 selective pharmacological inhibition may reduce the incidence of CRC. According to the American Cancer Society, there is a high prevalence of CRC in IBD patients, and p-CouA alleviates DSS-induced intestinal inflammation by suppressing the expression of COX-2.…”

EGFR and COX-2 Dual Inhibitor: The Design, Synthesis, and Biological Evaluation of Novel Chalcones

“…As previously reported, the standard kinase screening protocol was used (Table 2). Further details are explained in the Supplementary Materials [34,35].…”

Screening for EGFR and AKT dual-target inhibitors

“…Abou-Zied HA et al designed a novel xanthine derivative carrying the chalcone component to investigate potential EGFR inhibitors, and obtained the compound 11 against the target enzyme with IC 50 = 0.3 µM [21]. Abdelgawad et al designed novel phenolic compounds as potential inhibitors of EGFR and COX-2, and obtained the compounds C4 and G4 with IC 50 of 0.9 and 0.5 µM, respectively [22]. N Nerdy et al found that sesquiterpene lactones from veronica amygdaline de le had anticarcinogenic potential by inhibiting the EGFR expression [23].…”