Design, Synthesis And Evaluation Of Novel Potent Caspase-3In-Hibitors

Apoptosis is also known as programmed cell death. Many diseases are caused due to abnormal cell apoptosis and caspase family of the whole process involved in apoptosis. Caspase-3protease is apoptosis performer and plays a key role during the apoptotic process. A lot of functional disorded diseases that harm to human health are associated with the abnormal activation of caspase-3. Caspase-3is considered as a valuable drug development target and the exploration of caspase-3inhibitors become a research focus.To find small-molecular caspase-3inhibitors with a novel scaffold directed against diseases involving abnormally upregulated apoptosis, our work was initially based on high-throughput screening of a diverse small-molecule library of establish compound libraries. We got two compounds that had a better inhibition activity of caspase-3realitive to others. Among them,1,2-benzisothiazol-3-one is a unreported caspase-3inhibitor scaffold. Main work of this paper is to transform its structure for getting potent inhibitors.1,2-Benzisothiazol-3-one derivatives3and6were prepared to evaluate their potential in terms of modification of the initial compound, to clarify their structure-activity relationships. Some analogues (e.g.6b,6r,6s and6w) were identified as novel and potent caspase inhibitors with IC50of nanomolar. Within the active compounds, the best activity compound6w presented an IC50value of31nM which is expected to be the new caspase-3inhibitor.To get some insight to binding mode of1,2-benzisothiazol-3-one, compounds60and6w were docked into the active site of caspase-3. The docking study of6w showed that the carbonyl of benzoisothiazol-3-one part of6w molecule that could be generating two hydrogen bonds with H121and G122in S1pocket. The carbonyl of urea group also interacted with H121and formed one hydrogen bond in S2pocket. The benzene ring of6w plunges into the hydrophobic S3part that was made of F256, Y204and W206and generates the hydrophobic interactions, but there is no hydro-phobic interactions between6w and S4part. Furthermore, compared with6w, the60molecule is not enough fitted with the active pockets. So we have come to recognize that the activity of the compounds can be improved to extend the distance between the nitrogen atom and an aromatic ring and a better combination of the compound with the protein pocket was obtained. The poor solubility in water of series6can’t satisfy with the basic requirements of the cellular level test.In summary, we have discovered a new class of non-peptide caspase-3inhibitor. Although the1,2-benzisothiazol-3-one inhibitors that we have prepared existed many shortcomings, they provided some important information for the development of a novel type of inhibitors of caspase-3. Our next step will be to change the structure of these inhibitors to further improve their water-soluble and the inhibitory activity of caspase-3.