Design, Synthesis And Evaluation Of Caspase-3 Inhibitors

Apoptosis, or programmed cell death, is an essential physiological process of tissue development and homeostasis. Dysregulation of apoptosis is involved in a wide variety of diseases, such as Alzheimer’s, Parkinson’s and Huntington’s diseases. Therefore, key apoptosis factors are attractive molecular targets for designing specific drugs for the treatment of apoptosis diseases. Caspases play critical roles in initiation and execution stages of apoptosism, especially, caspase-3 has been found to get involved in nearly every model of apoptosis and several different signaling pathways. Therefore, caspase-3 is a potential target for the treatment of diseases caused by dysregulated apoptosis.Recently,1,2-benzisothiazol-3-one was identified as lead compound of caspase-3 inhibitor by high throughput screening. And one of its analogs exhibited very goodp otency against caspase-3(IC50=31nmol/L). The docking studies of this molecule indic atedit fitted the pocket of S1, S2, S3, but there is no hydrophobic interactions betw een this compound and S4 part. However, it has been the reported that based on th eco-crystallized structure analysis, the S4 pocket is very important. Hence, we thoug ht that the inhibitory activity of the compounds could be improved by extending the length of the molecule. A series of novel 1,2-benzisothiazol-3-one derivatives were synthesized and their biological activities were evaluated for the inhibition of caspa se-3 and -7. Some of them showed low nanomolar potency against caspase-3. Amon g the tested compounds, compound 5j exhibited the most potent caspase-3 inhibitory activity (IC50= 1.15 nmol/L). Additionally, compound 5t also demonstrated a cellul ar levelof protection activity to human Jurkat T cells.To clerity the potency of the synthesized compounds and guide further structure-activity relationships (SARs) studies, compounds 5j and 13a were docked into the active site of caspase-3.The docking results revealed that the presence of a rigid cyclic amide and the adjacent carbonyl group outside the benzisothiazol ring are very important for the binding affinity. This result was consistent with our expectation. In addition, compound 5a-5f,5t,9,13 have much improved the solubility, comparing to that of previously reported caspase-3 inhibitors. That will be helpful to further animal test of those compounds.