Study On The Structure And Synthesis Of Caspase Inhibitor

Apoptosis, also known as programmed cell death, apoptosis is critical to the health of many organisms, needed to sculpt the nervous system during development and to maintain the normal functioning of the immune system.Activation of proteolytic enzymes called caspases is a key step in the apoptotic program. All members of this protease family are characterized by their unique requirement for an aspartic acid at the P1 position of the substrate cleavage site.Insufficient caspase activity promotes cell accumulation implicated in cancer and autoimmune diseases, while excessive caspase activity could lead to accelerated cell death, believed to result in neurodegenerative disorders such as Huntington's and Alzheimer's diseases. The Caspase protease family has play a pivotal role in the process of apotosis, and is consequently potential target for drug discovery.Based on the composition of a typical caspase inhibitor peptide, in accordance with the synthetic peptide inhibitor, at first synthesized the structure of the pro-peptide and then junctured the peptide.Benzyl-β-hydroxyethyl ether, synthesized from ethanediol, was oxidized to an aldehyde. Nucleophilic addition reaction with t-butyl-3-nitropropionate, hydrogenation, acylation with BOC-L- Phe-OH, yielded the target compound.Each step in a specific way synthesizes condition is:a) The CH3ONa concentration 15%, HOCH2CH2OH:CH3ONa(3.5:1),80℃,1hrs,62%.b) Oxidized by the DMP, CH2Cl2, r.t, 1hrs, 51%.c) H2SO4, 30℃, 72hrs, 69%.d) r.t., 3hrs, 53%.e) Raney-Nickel, C2H5OH, H2, 30℃, 18hrs, 58%.f) Boc-L-Phe-OH, EDCl, HOBT, DMAP, CH2Cl2, 18hrs, 41%, white solid. The reaction conditions: temperature, time, activator, oxidant, solvent, etc, were studied. And these products were characterized by GC-Ms, IR and 1HNMR. These optimizations are stability foundation to gain higher yield and the design of future industrial production.Further experiment about inhibitor of Caspase activity is under way. Of course, many problems still exist in synthesis. For example, the route is longer, lower yields, higher costs synthesis. In follow-up work, we are committed to enhancing and improving the yield and production processes. Want to enhance the value and application of synthetic drugs.