Identification of Novel Cyanopyridones and Pyrido[2,3-d]Pyrimidines as Anticancer Agents with Dual VEGFR-2/HER-2 Inhibitory Action: Synthesis, Biological Evaluation and Molecular Docking Studies

Abstract

In the current work, we designed and synthesized three families of non-fused and fused compounds based on cyanopyridone: derivatives of 6-amino-1,2-dihydropyridine-3,5-dicarbonitrile (5a-f) and 3,4,7,8-tetrahydro pyrimidine-6-carbonitrile (6a-b and 7a-e). The newly synthesized compounds’ structure were determined using a variety of techniques, including 1H NMR, 13C NMR, mass spectrum, infrared spectroscopy, and elemental analysis. The developed compounds were tested for the ability to inhibit the growth of breast adenocarcinoma (MCF-7) and hepatic adenocarcinoma (HepG2) cell lines using MTT assay. Some of the synthesized compounds were more effective towards the cancer cell lines than the standard treatment taxol. The best antiproliferative activities were demonstrated by non-fused cyanopyridones 5a and 5e against the MCF-7 cell line (IC50 = 1.77 and 1.39 μM, respectively) and by compounds 6b and 5a against the HepG2 cell line (IC50 = 2.68 and 2.71 μM, respectively). We further explored 5a and 5e, the two most potent compounds against the MCF-7 cell line, for their ability to inhibit VEGFR-2 and HER-2. Finally, docking and molecular dynamics simulations were performed as part of the molecular modeling investigation to elucidate the molecular binding modes of the tested compounds, allowing for a more thorough comprehension of the activity of compounds 5a and 5e.

Antimicrobial, Antibiofilm, and Anticancer Activities of Syzygium aromaticum Essential Oil Nanoemulsion

“…When comparing CL-emulsion (0.748 ± 0.016 ng/mL) to CL-nanoemulsion (0.499 ± 0.017 ng/mL), VEGFR-2 levels were found to be much lower in the latter. Overactivation of VEGFR-2 is known to drive angiogenesis that promotes solid tumor development, which corroborated the findings of Falcon et al For many cancers, including breast cancer, blocking the VEGFR-2 pathway has emerged as an essential therapeutic strategy [52][53][54].…”

Nitrogen Containing Heterocycles as Anticancer Agents: A Medicinal Chemistry Perspective

“…The majority of compounds showed potent anticancer activity. Compound 164 demonstrated comparable activity against the MCF-7 and HepG2 cell lines with IC 50 values of 6.22 and 19.58 µM, respectively, while the control Taxol had IC 50 values 8.48 µM and 14.60 µM, respectively [ 275 ].…”

Unleashing naphthopyranopyrimidine's anticancer potential: a deep eutectic solvent (DES) study

“…Based on the outcomes derived from network pharmacology, potential target proteins were identified. Subsequently, we procured X-ray crystal structures of the inactive EGFR tyrosine kinase domain bound to erlotinib (PDB id: 4HJO), 46 human carbonic IX in complex with 5-(1naphthalen-1-yl-1,2,3-triazol-4-yl) thiophene-2-sulphonamide (PDB id: 5FL4), 47 and HER2 kinase domain complexed with TAK-285 48 (PDB id: 3RCD) from the PDB databank. These structures were then subjected to further scrutiny alongside the synthesized compounds, specifically in the context of hepatocellular carcinoma.…”