3,5-Diaryl-1H-pyrazole as a molecular scaffold for the synthesis of apoptosis-inducing agents

The scaffold of 3,5-diaryl-1H-pyrazole was selected as a molecular template to synthesize novel growth-inhibitory agents in the present study. Our findings suggested that analogs bearing electron-withdrawing groups on one ring while electron-donating groups on another reveal significant activities. In particular, 26 bearing a 1,1′-biphenyl moiety displayed the most potent activity against OVCA, SW620, H460 and AGS cells with GI50 values of 0.67, 0.89, 0.73 and 0.79 μM, respectively. The mechanistic study revealed that 26-mediated apoptosis-inducing effect on OVCA cells was, in part, attributed to the inhibition of protein kinase B/Akt activity, accompanied by the mitochondrial apoptotic pathway through the activation of caspase-9, caspase-3, as well as the cleavage of protein poly(ADP-ribose) polymerase (PARP) and DNA fragmentation. Further structure–activity relationship study employed by Comparative Molecular Field Analysis (CoMFA) was carried out with q2 and R2 values of 0.671 and 0.846, respectively.

A series of 3,5-diaryl-1H-pyrazoles were synthesized and evaluated for their growth-inhibitory activity, apoptosis-inducing effect and structure–activity relationship study.Figure optionsDownload as PowerPoint slide