Design, synthesis and biological evaluation of novel pyrazolochalcones as potential modulators of PI3K/Akt/mTOR pathway and inducers of apoptosis in breast cancer cells

摘要

Abstract Cancer has been established as the “Emperor of all maladies”. In recent years, medicinal chemistry has focused on identifying novel anti-cancer compounds; though discovery of these compounds appears to be a herculean task. In present study, we synthesized forty pyrazolochalcone conjugates and explored their cytotoxic activity against a panel of sixty cancer cell lines. Fifteen conjugates of the series showed excellent growth inhibition ( 13b-e, 13h-j , 14c-d , 15 a , 15 c-d , 16b , 16d and 18f ; GI 50 for MCF-7: 0.4–20?μM). Conjugates 13b , 13c , 13d , 16b and 14d were also evaluated for their cytotoxic activity in human breast cancer cell line (MCF-7). The promising candidates induced cell cycle arrest, mitochondrial membrane depolarization and apoptosis in MCF-7?cells at a 2?μM concentration. Furthermore, inhibition of PI3K/Akt/mTOR pathway-regulators such as PI3K, p-PI3K, p -AKT, and mTOR were observed; as well as upregulation of p -GSK3β and tumor-suppressor protein, PTEN. Our study indicates that pyrazolochalcone conjugates could serve as potential leads in the development of tailored cancer therapeutics. Graphical abstract A set of forty pyrazolochalcone conjugates and explored their cytotoxic activity against a panel of sixty cancer cell lines. Fifteen conjugates of the series showed excellent growth inhibition ( 13b-e, 13h-j , 14c-d , 15 a , 15 c-d , 16b , 16d and 18f ; GI 50 for MCF-7: 0.4–20?μM). 13b , 13c , 13d , 16b and 14d were evaluated for their mechanism in human breast cancer cell line (MCF-7). Display Omitted Highlights ? Novel pyrazolochalcones synthesized and tested cytotoxic activity. Most of them showed excellent growth inhibitory effect. ? 13b , 13c , 13d , 16b and 14d induced cell cycle arrest in G2-M phase at 24?h and the conjugates 13c and 14d also accumulates in G0-G1 phase. ? Induce mitochondrial membrane depolarization and apoptosis in MCF-7?cells. ? Inhibited PI3K/Akt/mTOR pathway-regulators and docked at the ATP binding site of PI3K.