Discovery of New Pyrazole-Tosylamide Derivatives as Apoptosis Inducers Through BCL-2 Inhibition and Caspase-3 Activation.

In this presented study, a series of new carbonitrile-substituted pyrazole-tosyl amide derivatives were designed and synthesized according to previous studies. The antiproliferative effects of the synthesized compounds on MDA-MB-231, MCF-7, HepG2, PC-3, and A549 cancer cell lines were assessed by MTT assay compared with non-cancerous cells. The results demonstrate that compounds 9d, 9e, and 9f had a higher antiproliferative effect (IC <10 μM) against both breast cancer cells. To investigate the ability of these compounds (9d-f) to induce apoptosis against breast cancer cells, BCL-2 levels and Caspase-3 activities of compound-treated breast cancer cell lines were measured by ELISA. The results revealed that these compounds significantly inhibited the levels of anti-apoptotic protein BCL-2 and increased the activity of apoptotic protein Caspase-3 in MDA-MB-231 and MCF-7 cells. Molecular docking studies confirmed that the selected compounds have high binding affinity towards the active site in the crystal structures of BCL-2 and Caspase-3. Moreover, drug-likeness and pre-ADMET evaluation showed that the compounds had suitable drug properties. This study may be a new milestone in terms of the promising importance of carbonitrile-substituted pyrazole-tosyl amide scaffolds as apoptosis-inducing agents for cancer therapy in the future.