The Design And Synthesis Of Cyclic Tetrapeptide Histone Deacetylase Inhibitors

Histones can be in one of the two antagonist forms, acetylated or deacetylated, equilibrium regulates by the corresponding enzymes, histone acetyltransferase (HAT) and histone deacetylases (HDAC). Inhibition of HDAC represents a new strategy in human cancer therapy since these enzymes play a fundamental role in regulating gene expression and chromatin assembly. They are potent inducers of growth arrest, differentiation and apoptosis of tumor cells. A wide variety of HDAC inhibitors of both natural and synthetic origin have been reported. Cyclic tetrapeptide histone deacetylases inhibitor is one of effective types.In this paper, new type inhibitors of histone deacetylases bearing a sulfhydryl group are designed on the base of the corresponding cyclic tetrapeptide compounds and FK228 in order to get more potent histone deacetylases inhibitor which is a potential anticancer prodrug .(1) Cyclic tetrapeptide histone deacetylases inhibitors containing L-phenylalanine: cyclo(-Ab7-Aib-Phe-D-Pro-);(2) Cyclic tetrapeptide histone deacetylases inhibitors containing L-methylphenylalanine:cyclo(-Ab7-Aib-Phe(X-Me)-D-Pro-);L-methylphenylalanine as one of analogues of L-phenylalanine is very important in the study of medicament synthesis.New cyclic tetrapeptide HDAC inhibitors designed by this paper are also including L-methylphenylalanine .Therefor, L-methylphenylalanine should be prepared at first. By using substituted benzyl bromide and diethyl (Boc-amino)malonate as starting material, Boc-L-2-methylphenylalanine , Boc-L-3-methylphenylalanine and Boc-L-4-methylphenylalanine have been synthesized in this paper. Above three racemic amino acids have been separated into six optical isomers with subtilisin under 37℃, pH7.5 and 0. 25mol·L^-1 substrate. The yield are 42.5% , 47.7% and 64.5%.The chemical structures of the amino acids are characterized by IR ,¹HNMR, MS and optical rotation.The synthesis of cyclo(-Ab7-Aib-Phe-D-Pro-) which uses solid phase peptide synthesis with N-Fmoc protection is faild. So liquid phase peptide synthesis is tried.Finally, cyclo(-Ab7-Aib-Phe(2-Me)-D-Pro-) is successfully prepared by using liquid phase peptide synthesis with Boc protection.The yield is 0.8%.