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 (IC50 <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.