2-Arylquinolines as novel anticancer agents with dual EGFR/FAK kinase inhibitory activity: synthesis, biological evaluation, and molecular modelling insights

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 (IC 50 s = 25.39, 20.15, 22.36, and 24.81 nM, respectively). Meanwhile, quinolines 6f, 6h , 6i , 16d , and 20f exerted the best FAK inhibition (IC 50 s = 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.

Design, Synthesis, Biological Evaluation, and Molecular Docking Studies of Pleuromutilin Derivatives Containing Thiazole

“…The products were subjected to purification through silica gel column chromatography to obtain the end products. 24 All target compounds were structurally confirmed by 1 H NMR, 13 C NMR, and HR-MS.…”

“…Finally, compounds 12 – 35 were synthesized via the reaction of compound 11 with diverse acid chloride derivatives in an alkaline environment. The products were subjected to purification through silica gel column chromatography to obtain the end products . All target compounds were structurally confirmed by 1 H NMR, 13 C NMR, and HR-MS.…”

The Development of FAK Inhibitors: A Five-Year Update

“…Screening against a panel of nine kinases evidenced their EGFR/FAK dual inhibitory activity, with compound 29 ( Figure 7 ) being the most interesting analog (IC 50 values for FAK and EGFR of 14.25 nM and 20.15 nM respectively). Molecular docking and molecular dynamics simulation confirmed that this derivative represented the first quinoline reported as being a dual EGFR/FAK inhibitor [ 63 ].…”

Novel 4-thiophenyl-pyrazole, pyridine, and pyrimidine derivatives as potential antitumor candidates targeting both EGFR and VEGFR-2; design, synthesis, biological evaluations, andin silicostudies

“…Both types require the presence of four pharmacophores which are the hydrophobic head, H-bond donor (for EGFRI) or H-bond donor and acceptor (for VEGFR-2I), spacer at heteroaromatic ring, and hydrophobic tail. 14,24,25 Pyrazole, pyridine, and pyrimidine systems constitute very promising scaffolds for many anticancer agents. They were previously reported as potential EGFRIs, 26,27 VEGFR-2Is, 28,29 and/ or dual EGFR/VEGFR-2 inhibitors.…”

“…Both types require the presence of four pharmacophores which are the hydrophobic head, H-bond donor (for EGFRI) or H-bond donor and acceptor (for VEGFR-2I), spacer flat heteroaromatic ring, and hydrophobic tail. 14,24,25…”