Design, synthesis, and anti-cancer evaluation of new pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as potential EGFRWT and EGFRT790M inhibitors and apoptosis inducers

Abstract

A new series of pyrido[2,3-d]pyrimidin-4(3H)-one derivatives having the essential pharmacophoric features of EGFR inhibitors has been designed and synthesised. Cell viability screening was performed for these compounds against A-549, PC-3, HCT-116, and MCF-7 cell lines at a dose of 100 μM. The highest active derivatives ( 8a, 8 b, 8d, 9a, and 12b ) were selected for IC 50 screening. Compounds 8a, 8 b, and 9a showed the highest cytotoxic activities and were further investigated for wild EGFR WT and mutant EGFR T790M inhibitory activities. Compound 8a showed the highest inhibitory activities against EGFR WT and EGFR T790M with IC 50 values of 0.099 and 0.123 µM, respectively. In addition, it arrested the cell cycle at pre-G1 phase and induced a significant apoptotic effect in PC-3 cells. Furthermore, compound 8a induced a 5.3-fold increase in the level of caspase-3 in PC-3 cells. Finally, docking studies were carried out to examine the binding mode of the synthesised compounds against both EGFR WT and EGFR T790M .

Discovery of new 5-substituted-indole-2-carboxamides as dual epidermal growth factor receptor (EGFR)/cyclin dependent kinase-2 (CDK2) inhibitors with potent antiproliferative action

“…3-Ethylindole-2-carboxylates 3a–c , 25 carboxylic acids 4a–c , 26 and carboxamides 5a–k and 6a–c 24 were synthesized according to previously reported procedures. See Appendix A (ESI†).…”

“…EGFR inhibitors were found to have a characteristic Y-shaped skeleton. 25 The main pharmacophoric features for EGFR inhibitors can be summarized as: 1) a planar hetero structure can form H-bonds with some key amino acids such as Met769, Thr790, and Thr854 which are crucial to reside in the adenine binding pocket. 2) Additionally, in order to enhance the binding affinity of the inhibitor, two hydrophobic moieties are required as head and tail structures forming hydrophobic interactions within the hydrophobic regions.…”

Anticancer derivative of the natural alkaloid, theobromine, inhibiting EGFR protein: Computer-aided drug discovery approach

“…In this work and as an extension of our previous efforts in the discovery of new anti-EGFR agents [36,[42][43][44], compound V was used as a lead compound to reach a more promising anticancer agent targeting EGFR. Several chemical modifications were carried out at four positions.…”

A New Anticancer Semisynthetic Theobromine Derivative Targeting EGFR Protein: CADDD Study

“…Molecular Docking could analyze that interaction through the identification of binding energies as well as binding modes of the docked molecules inside the active sites of the targeted receptors [ 16 ]. Over the last few years, our team has applied the CADDD in the design and synthesis of several anti-EGFR compounds belonging to pyrimidine [ 17 , 18 , 19 ] and xanthin [ 20 ] derivatives.…”