Studies On The Synthesis Of Caspases 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 report describes the synthesis of caspase Inhibitors: N-Z-Val-Asp-CH₂OCH₂Ph and N-Z-Ala-Asp-CH₂OCH₂Ph..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 or N-Z-AlaOH, oxidation and acidification, yielded the two target compounds.Each step in a specific way synthesize condition is: a). The CH3ONa concentration 15%, HOCH₂CH₂OH: CH₃ONa 3.5:1,70⁹0℃,1hrs, purity : 85.18%, output amount :41.87%. b). Oxidized by the DMSO/( COCI)₂. CH2Cl₂,NEt₃,-78 ℃, 1.5hrs. c). H₂SO₄,30℃, 72⁹6hrs,70%. d). r.t.,3hrs,75.44%. e).Raney-Nickel,C2H5OH,H2,30 ℃, 18hrs,89.04%. f). Z-Val-OH or Z-Ala-OH,EDCl,HOBT,DMAP,CH2Cl2,18hrs, 64.78%,69.97%, white solid. g). (COCl)2,DMSO,CH2Cl2,Net3,-60 ℃, 1.5hrs, 65.25% ,69.78%, white solid. h). TFA, CH2Cl2,83.58%,86.56%, white solid. The reaction conditions: temperature , time, activator, oxidant, solvent, etc, were studied. And these products were characterized by GC-Ms, IR and 1HNMR.