Synthesis And Characterization Of Caspase Inhibitor

Apoptosis is an evolutionarily conserved process of cell suicide. It requires specialized machinery which involving a family of proteases named caspases. Manipulation of apoptosis through inhibiting or activating caspases has been of great therapeutic interests in the pharmaceutical industry.Using substrate based approach,a systematic investigation of conformationally constrained peptidomimetic inhibitors has led to the discovery of highly selective ones against selected members of the caspase family. It also resulted novel dipeptide inhibitors as useful tools and possible therapeutic agents against diseases caused by excessive apoptotic cell death. This presentation will focus on the synthesis and application of novel caspase inhibitors. This thesis describes the synthesis of Caspase Inhibitor, Construction of the peptide which this thesis want to synthetic is described below.The R1 is preferred to be OtBu ,carbobenzoxy or acetyl; The AA is an aminoacid residue ;R2 is an tBu or 1- benzene ethyl. . Benzyl-β-hydroxyethyl ether, synthesized from ethanediol, was oxidized to an aldehyde. Nucleophilic addition reaction with t-butyl-3-nitropropionate, hydrogenation, acylation with N-Z-ValOH, yielded the target compound.The first step in this thesis is to synthesize an aldehyde by ethanediol, the second one is the oxidation of the aldehyde where the product is prepared to carry out nucleophilic addition reaction with t-butyl-3-nitropropionate in the third step ,than hydrogenation is carry out in the fourth step and in the next step acylation with N-Z-ValOH is needed , the target compound is yielded.The processes described in the table 6－1 are summarised as follows : in the process (a) the purity as high as 85.18%,while the output amount to 42.11% when the concentration of sodium methylate is 15% and the proportion between alcohol and sodium methylate is 3.5:1. Therefore, author think the producte yielded in this condition is useful as the resource in the further research.In the reaction( b): oxidized by the DMSO/( COCI)2 , in the process there is nothing indissolvable ,so after the reaction ,it can proceed directly without separation after oxidizing so that the process is simplised and it is more important that the reaction of the product itself is avoided so that the reaction proceeding can be carry out properly. the reaction is carried out under -78℃ and the oxidation is completed after 1.5h. In the reaction(c) t-butyl-3-nitropropionate is prepared under room temperature catalyzed by concentrated sulfuric acid ,3h. The yield amount to 72.03～75.44%.When the reaction is carried out under temperature of 30 ℃,after 72～96h the yield acquired is about 70% .In the reaction(d),the products of (b),(c) react in CH2Cl2 yielding the product is used directly in the reaction(e) where it is hydrogenated by hydrogen catalyzed by Ra-Ni under 50℃, 2 h. The yield amount to 89.04%.In the reaction(f) ,amidation of the product of reacion (d) is carried out in CH2Cl2 and the reactants are well dissolved. The yield amount to 64.78%.And DMAP acting as catalyzer of great efficiency raises the yield by 20%,shorten the time by 4-5h. In this experiment, the process designed is longer,all the products of each reaction need to be purified. It is not favourable for the improvement of the yield of product.So the field of improvement of the process and the purification ,especially in the field of the process of trade production more work is needed to be done .In addition before the commercial production ,the result of the experiment on animal and human is of great importance to the value of the synthetic medicine.The reaction conditions: temperature , time, activator, oxidant, solvent, etc, were studied. And these products were characterized by GC-Ms, IR and 1HNMR.