Triple targeting of mutant EGFR ^L858R/T790M , COX-2, and 15-LOX: design and synthesis of novel quinazolinone tethered phenyl urea derivatives for anti-inflammatory and anticancer evaluation

Abstract

We designed and synthesised novel quinazolinone tethered phenyl urea derivatives ( 6a–p ) that triple target the double mutant EGFR L858R/T790M , COX-2, and 15-LOX. Compounds ( 6e , 6d , 6j , 6m , and 6n ) not only had low micromolar IC50 inhibitory activities against the three targets, but they also showed good selectivity for COX-2 over COX-1 and for EGFR L858R/T790M over wild-type EGFR. Except for 6e and 6n , all of the tested compounds inhibited the NO production significantly more potently than celecoxib, diclofenac, and indomethacin. Compounds 6i and 6k reduced ROS levels more effectively than celecoxib and diclofenac. In terms of inhibiting TNF-α production, 6o- treated cells showed TNF-α level, which is ∼10 times lower than celecoxib. Furthermore, 6e and 6j had the highest anticancer activity against the breast cancer cell line BT-459 with growth inhibition percentages of 67.14 and 70.07%, respectively. Docking studies confirm their favoured binding affinity. The proposed compounds could be promising multi-targeted leads.

Design, Synthesis, Biological Evaluation, and Molecular Docking Study of 4,6-Dimethyl-5-aryl/alkyl-2-[2-hydroxy-3-(4-substituted-1-piperazinyl)propyl]pyrrolo[3,4-c]pyrrole-1,3(2H,5H)-diones as Anti-Inflammatory Agents with Dual Inhibition of COX and LOX

“…Dual inhibition of COX-2 and LOX (mainly 5-LOX and 15-LOX) has become a research “hotspot” for the treatment of inflammatory diseases, and compounds with such properties are characterized by increased efficacy, reduced side effects, and a broader anti-inflammatory spectrum in comparison with classic NSAIDs [ 4 , 81 , 82 ]. Dual COX-2/LOX inhibitors showed better anti-cancer activity than their counterparts, which are inhibitors of one pathway [ 6 ]. At the same time, selective inhibition of both COX-2 and 15-LOX may provide a good strategy for alleviating inflammation while minimizing side effects during potential use in asthma [ 26 ].…”

“…It is responsible for the synthesis of prostaglandins, which protec the gastric mucosa and regulate platelet aggregation and renal blood flow. COX-2 i induced during inflammation, pain, and oncogenesis and can be found in many cell types such as the brain, kidney, and endothelial cells, as well as reproductive tissues, inflamed tissues, and tumor cells [4][5][6]. It also plays an important role in cancer progression and resistance radiotherapy and chemotherapy, as indicated by the overexpression of COXin various types of cancer, including human prostate, breast, colorectal, and melanoma Moreover, COX-2 inhibitors have shown both chemopreventive and anti-cancer effect through synergistic or additive effects with anti-cancer agents and can restore norma apoptosis in many types of cancer cells or inhibit angiogenesis [7].…”

Lipoxygenases at the Intersection of Infection and Carcinogenesis

“…In enzalutamideresistant prostate cancer cells, the inhibition of ALOX5 interferes with c-Myc signaling, killing cells by enhancing caspase-mediated apoptosis [230]. Triple targeting of ALOX5, COX-2 and double mutant EGFR by novel quinazolinone tethered phenyl urea derivatives demonstrate anti-inflammatory and anti-cancer activities in numerous cancer cell lines, not limited to BT-459 breast cancer cell line [231]. The invasive and metastatic role of ALOX5 in the progression of pancreatic cancer have been demonstrated both in vitro and in vivo using an approved ALOX5 inhibitor, Zileuton.…”

Recruitment of hexahydroquinoline as anticancer scaffold targeting inhibition of wild and mutants EGFR (EGFR WT , EGFR T790M , and EGFR L858R )

“…Despite massive attempts to develop novel anticancer agents, cancer remains one of the worst diseases in the world 1 . The development of resistance to several highly successful anticancer agents is a significant hurdle in the treatment of cancer 2 .…”