Structural Diversity and Role of Phytochemicals against P38-α Mitogen-activated Protein Kinase and Epidermal Growth Factor Receptor Kinase Domain: A Privileged Computational Approach

Computational databases and tools in recent times have been proved to provide an essential aid for anticancer studies in the field of oncology. Molecular docking studies facilitate the structural diversity of plant-derived phytomolecules having anticancer properties against receptor proteins involved in cancer signaling pathways. The current study involves the investigation of phytocompounds-agasthisflavone, anacardic acid, zoapatanolide A, a purified product of the plant extract Amarogopinois546 were subjected to docking studies on p38-α MAPK and EGFR Kinase domain. The effectiveness of this study was evaluated by comparing the docking interactions of a standard drug, doxorubicin against the receptor molecules. The docking study is analyzed by compound estimated with lowest binding energy is considered to have the highest affinity towards the active site of the receptor proteins. The isolated plant compound Amarogopinois546 displayed the least binding score with a large number of hydrogen bonds and hydrophobic interactions towards the P38α MAP kinase receptor in comparison with the EGFR kinase domain. This preliminary result can strongly be supported for carrying out experimental evaluation in near future.

A novel derivative of picolinic acid induces endoplasmic reticulum stress-mediated apoptosis in human non-small cell lung cancer cells: synthesis, docking study, and anticancer activity

Thirteen new derivatives of picolinic acid (4–7) were designed and synthesized from the starting parent molecule, picolinic acid. The new compounds were characterized by ATR-FTIR, 1HNMR, and CHNS analysis. A molecular docking study was performed to evaluate the binding affinity of the synthesized compounds toward EGFR kinase domain that indicated occupation of the critical site of EGFR kinase pocket and excellent positioning of the compounds in the pocket. The cytotoxic activity of the compounds against two human cancer cell lines (A549 and MCF-7), the non-tumorigenic MCF10A cell line, and white blood cells (WBC) was evaluated using the MTT assay. Compound 5 showed anticancer activity against A549 lung cancer cells (IC50 = 99.93 µM) but not against MCF-7 breast cancer cells or normal cells. Compound 5 mediated cytotoxicity in A549 lung cancer cells by inducing apoptotic cell death, as suggested by fragmented nuclei after DAPI staining, and agarose gel electrophoresis. Moreover, compound 5 triggered the activation of caspases 3, 4 and 9. However, compound 5 treatment did not affect the release of cytochrome c from the mitochondria to the cytosol, as compared to the vehicle-treated control cells. Nevertheless, compound 5-treated cells reported greater release of smac/DIABLO to the cytosol. In the same context, both compound 5 and thapsigargin (specific inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA)) enhanced eIF2 phosphorylation, reflecting the activation of the atypical ER stress pathway and the potential applicability of compound 5 in lung cancer treatment.

Efficient Synthesis and Biological Evaluation of 6-Trifluoroethoxy Functionalized Pteridine Derivatives as EGFR Inhibitors

Background: Pteridine-based scaffolds have been widely prevalent in pharmaceuticals, such as kinase inhibitors targeting EGFR, FLT3 and PI3K/mTOR, which are attractive targets for anticancer therapy. Objective: This work aimed to design and synthesize 6-2,2,2-trifluoroethoxy functionalized pteridine-based derivatives for investigation of their anti-cancer activities as EGFR inhibitor. Method: Pteridine-based derivatives were synthesized in 6 steps involving amination, bromination, cyclization, alkoxylation, chlorination and coupling reactions. Cellular anti-proliferative activities and inhibition activities on EGFR signaling of these pteridine derivatives in vitro were determined by the MTT assay and western blot analysis, respectively. Molecular docking simulation studies were carried out by the crystallographic structure of the erlotinib/EGFR kinase domain [Protein Data Bank (PDB) code: 1M17]. Results: The compound 7m, with IC50 values of 27.40 μM on A549 cell line, exhibited comparable anti-proliferative activity relative to the positive control. Besides western blots showed its obvious down-regulation of p-EGFR and p-ERK expression at 0.8 μM. Molecular docking model displayed a hydrogen bond between Met-769 amide nitrogen and N-1 in pteridine motif of 7m which lay at the ATP binding site of EGFR kinase domain. Conclusion: The inhibition of 7m on cellular growth was comparable to that of the positive control. The inhibitory activities of 7m on EGFR phosphorylation and ERK phosphorylation in A549 cell line were relatively superior to that of the positive control. Both results suggested that the anti-proliferative activity of 7m against A549 cell line was caused by inhibition of EGFR signaling pathway, providing a new perspective for modification on pteridine-based derivatives as EGFR inhibitor.