Synthesis and Antiproliferative Activity of a New Series of Mono- and Bis(dimethylpyrazolyl)-s-triazine Derivatives Targeting EGFR/ PI3K/AKT/mTOR Cascades

Here, we synthesized a newseries of mono-and bis(dimethylpyrazolyl)-s-triazine derivatives. The synthetic methodology involved the reaction of different mono-and dihydrazinyl-s-triazine derivatives with acetylacetone in the presence of triethylamine to produce the corresponding target products in high yield and purity. The antiproliferative activity of the novel mono-and bis(dimethylpyrazolyl)-s-triazine derivatives was studied against three cancer cell lines, namely, MCF-7, HCT-116, and HepG2. N-(4-Bromophenyl)-4-(3,5-dimethyl-1H-pyrazol-1-yl)-6-morpholino-1,3,5-triazin-2-amine 4f, N-(4-chloro-phenyl)-4,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,3,5-triazin-2-amine 5c, and 4,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-N-(4-methoxyphenyl)-1,3,5-triazin-2-amine 5d showed promising activity against these cancer cells: 4f [(IC50 = 4.53 +/- 0.30 mu M (MCF-7); 0.50 +/- 0.080 mu M (HCT-116); and 3.01 +/- 0.49 mu M (HepG2)]; 5d [(IC50 = 3.66 +/- 0.96 mu M (HCT-116); and 5.42 +/- 0.82 mu M (HepG2)]; and 5c [(IC50 = 2.29 +/- 0.92 mu M (MCF-7)]. Molecular docking studies revealed good binding affinity with the receptor targeting EGFR/PI3K/AKT/ mTOR signaling cascades. Compound 4f exhibited potent EGFR inhibitory activity with an IC50 value of 61 nM compared to that of Tamoxifen (IC50 value of 69 nM), with EGFR inhibition of 83 and 84%, respectively, at a concentration of 10 mu M. Interestingly, 4f showed remarkable PI3K/AKT/mTOR inhibitory activity with 0.18-, 0.27-, and 0.39-fold decrease in their concentration (reduction in controls from 6.64, 45.39, and 86.39 ng/mL to 1.24, 12.35, and 34.36 ng/mL, respectively). Hence, the synthetic 1,3,5-triazine derivative 4f exhibited promising antiproliferative activity in HCT-116 cells through apoptosis induction by targeting the EGFR and its downstream pathway.

Automated summary

In this study, a series of novel 1,3,5-triazine derivatives were synthesized and their inhibitory activity against cancer cells was evaluated through in vitro assays. Among them, compound 4f showed significant antitumor activity and induced apoptosis by targeting EGFR and its downstream pathway.