Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562

A novel series of 4-(4-Methoxyphenyl)-2-(methylthio)pyrimidine-5-carbonitrile was developed linked to an aromatic moiety via N-containing bridge and then evaluated for their cytotoxic activity against MCF-7 and K562 cell lines. Seven compounds exhibited the highest activity against both cell lines where compounds 4d and 7f were the most active against K562 cell line. Exploring their molecular mechanisms by enzyme inhibition assay on PI3K delta/gamma and AKT-1 showed that compound 7f was promising more than 4d with IC50 = 6.99 +/- 0.36, 4.01 +/- 0.55, and 3.36 +/- 0.17 uM, respectively. Also, flowcytometric analysis revealed that 7f caused cell cycle arrest at S-phase followed by caspase 3 dependent apoptosis induction. Mechanistically, compound 7f proved to modulate the expression of PI3K, p-PI3K, AKT, p-AKT, Cyclin D1, and NF Kappa beta. Furthermore, in-vivo toxicity study indicated good safety profile for 7f. These findings suggest that the trimethoxy derivative 7f has strong potential as a multi-acting inhibitor on PI3K/AKT axis targeting breast cancer and leukaemia.

Automated summary

A series of novel compounds were developed and evaluated for their cytotoxic activity against breast cancer and leukemia cell lines. Compound 7f exhibited the highest activity and inhibited cell proliferation by modulating the expression of multiple signaling pathways. In vivo experiments showed that 7f had a good safety profile. These findings suggest that 7f has the potential to be a targeted therapeutic drug for breast cancer and leukemia.