Synthesis of novel gefitinib‐based derivatives and their anticancer activity

Abstract

Drug latentiation is a process of modifying a drug molecule structurally to improve its binding affinity as well as increasing the drug–receptor interactions and potentiate its therapeutic potential. In the quest for discovering more potent epidermal growth factor receptor (EGFR) inhibitors, gefitinib‐based derivatives were designed by simple structural modification at the secondary amine of gefitinib by N‐alkylation. Three gefitinib derivatives (gefitinib‐NB, ‐NP, and ‐NIP) were synthesized by N‐alkylation and phase transfer catalysis. Structural characterization, physicochemical parameters such as solubility, log P, and p K a were determined. Molecular docking studies were carried out to investigate the binding interactions at the active site. Further drug‐bovine serum albumin (BSA) protein and drug‐calf thymus (CT) DNA interactions were performed to understand the pharmacokinetics of the synthesized derivatives. All the compounds were screened for preliminary in vitro cytotoxic activity against A549, A431 lung, and MDA‐MB‐231 breast cancer cell lines by MTT assay. The gefitinib‐NP and gefitinib‐NB derivatives exhibited strong cytotoxic activity compared with gefitinib. They also showed higher drug‐BSA and drug‐DNA interactions. Molecular docking studies showed the orientation and binding interactions with the EGFR as well as with BSA and CT DNA. The results establish a strong correlation between the experimental and molecular docking studies. EGFR inhibition studies were also carried out for the derivatives and we identified the NP derivative of gefitinib as a potential lead compound. The gefitinib‐based derivatives reported herein are cytotoxic agents and can be tested for further pharmacokinetic profiles and toxicity studies which might be helpful for designing more potent gefitinib‐based derivatives in the future.

Integration of Molecular Docking and In Vitro Studies: A Powerful Approach for Drug Discovery in Breast Cancer

“…Synthesized compounds were further screened in different cancer cell lines, including MDA-MB-231, to evaluate the cytotoxicity of the new compounds. The results demonstrated a similar effect between experimental and molecular docking analyses, suggesting the important role of gefitinib-based derivatives [70]. Indeed, the in vitro cytotoxicity and antiproliferative activity demonstrated that the derivatives are more potent than gefitinib.…”

“…Gefitinib is one of the more effective and specific epidermal growth factor receptor (EGFR) inhibitors, which interacts with the adenosine triphosphate (ATP)-binding site of the EGFR tyrosine kinase enzyme. Sharma et al designed three gefitinib-based derivatives to improve the ligand-receptor interaction [70]. Molecular docking studies were also presented for the study of the interactions of the gefitinib derivatives with EGFR, DNA, and BSA.…”

Cocrystallization of Gefitinib Potentiate Single-Dose Oral Administration for Lung Tumor Eradication via Unbalancing the DNA Damage/Repair

“…Its mechanism of action involves the selective inhibition of EGFR, a growth factor that regulates several critical cellular processes, including cell growth, apoptosis, and angiogenesis [ 18 ]. Upon administration, GEF undergoes extensive hepatic metabolism mediated by cytochrome P450 enzymes, primarily CYP3A4 and, to a lesser extent, CYP3A5 and CYP2D6 enzymes, resulting in the formation of five metabolites [ 19 , 20 ]. Pharmacokinetically, GEF is slowly absorbed after oral treatment, exhibiting a human bioavailability of approximately 60%.…”

Busting the Breast Cancer with AstraZeneca’s Gefitinib

“…Nevertheless, only two therapeutic approaches have been widely used in clinical studies. They are (a) monoclonal antibodies/therapeutic antibodies (MAbs)—etuximab (Erbitux®), trastuzumab (Herceptin®), Osimertinib [ 14 ], Nimotuzumab [ 15 ], panitumumab (Vectibix®) [ 16 ], and Necitumumab [ 17 ]; (b) small-molecule inhibitors of EGFR tyrosine kinase (EGFR-TKI)—first generation: ZD 1839 (Iressa®, Gefitinib), Erlotinib (Tarceva®), and Crizotinib (Xalkori®) [ 6 , 10 ]; second generation: Lapatinib (Tyverb®), Afatinib (Gilotrif®), and Dacomitinib [ 18 ]. Monoclonal antibodies exert their action by blocking the ligand from binding to the extracellular area of the receptor.…”