Novel pyrazolopyrimidines: Synthesis, in?vitro cytotoxic activity and mechanistic investigation

摘要

Abstract A series of novel pyrazolo[3,4- d ]pyrimidines bearing benzenesulfonamide moiety 5a-f, 6 and 7 were synthesized. Cytotoxic screening was conducted against MCF-7 and HepG2. 6-(4-Methoxyphenyl)-4-oxopyrazolopyrimidine derivative 5e and 4-imino-6-oxopyrazolopyrimidine derivative 6 revealed potent cytotoxic activity with IC 50 1.4?μM (MCF-7) and 0.4?μM (HepG2), respectively compared to that of doxorubicin, (IC 50 ?=?1.02?μM and 0.9?μM, respectively). Compounds 5e and 6 were subjected to cell cycle analysis and apoptosis assay after 24?h and 48?h treatment. Compound 5e arrested cell at G1 phase, while 6 arrested cell at S and G2/M phases, respectively. The apoptotic effect of both compounds were evidenced by pre G1 apoptosis as its percentage increased by time (7.38%, 11.61%) and (13.92%, 16.71%), respectively. Apoptosis induction capability was confirmed by the effect on early and late apoptosis and augmentation of caspase-3 level. Furthermore, compound 6 inhibited CDK2 enzyme with IC 50 ?=?0.19?μM and increased levels of its regulators, P21 and P27 by 10.06% and 8.5%, respectively. Moreover, a molecular docking study of compound 6 on CDK2 enzyme was adopted to explore binding interaction with amino acid residues of its active site. Graphical abstract Display Omitted Highlights ? Novel pyrazolo[3,4- d ]pyrimidin-1-yl)benzenesulfonamide derivatives. ? In?vitro cytotoxic activity on MCF-7 and HepG2 cell lines. ? In?vitro activation of Caspase-3 and cell cycle analysis. ? In?vitro inhibition of CDK-2 and molecular docking.