2-Arylquinolines as novel anticancer agents with dual EGFR/FAK kinase inhibitory activity: synthesis, biological evaluation, and molecular modelling insights
Year: 2021
Type: article
Abstract: In this study, different assortments of 2-arylquinolines and 2,6-diarylquinolines have been developed. Recently, we have developed a new series of 6,7-dimethoxy-4-alkoxy-2-arylquinolines as Topoisomerase I (TOP1) inhibitors with potent anticancer activity. Utilising the SAR outputs from this study, we tried to enhance anticancer and TOP1 inhibitory activities. Though target quinolines demonstrated potent antiproliferative effect, specifically against colorectal cancer DLD-1 and HCT-116, they showed weak TOP1 inhibition which may be attributable to their non-coplanarity. Thereafter, screening against kinase panel revealed their dual inhibitory activity against EGFR and FAK. Quinolines 6f, 6h, 6i, and 20f were the most potent EGFR inhibitors (IC50s = 25.39, 20.15, 22.36, and 24.81 nM, respectively). Meanwhile, quinolines 6f, 6h, 6i, 16d, and 20f exerted the best FAK inhibition (IC50s = 22.68, 14.25, 18.36, 17.36, and 15.36 nM, respectively). Finally, molecular modelling was employed to justify the promising EGFR/FAK inhibition. The study outcomes afforded the first reported quinolines with potent EGFR/FAK dual inhibition.
Institutions: Hiroshima University, Kafrelsheikh University, Cairo University, University of California San Diego, British University in Egypt, King Saud University, National Institutes of Health, National Cancer Institute, Center for Cancer Research, Almaarefa University, Veterans Health Administration, Moores Cancer Center
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $2,306
OpenAlex ID: W4200355178