The Synthesis Of Cyclic Amino Acids And Bioactive Peptides

Based on the development of LHRH antagonists, it was suggested that there was a Type- IIβ-turn in the peptide backbone around the residues 5-8 or 3-6, which would be favourable for the binding affinity of antagonists to the receptor, and the activities of the angonists in vivo and in vitro. As it is known that the introduction of cyclic amino acids could cause significant changes in peptide conformation ensistance chemical and biological properties in peptides would be affected. When introduced cyclic amino acids into LHRH antagonists, through significant conformational restrictions in the amino acid residues. It would be favourable for binding the pocket of hydrophobicity receptor to formβ-turn or helical structure. We assumed that the introduction of D L amino acid in LHRH antagonists at position 7, forced the peptide chain intoβ-turn to bind the receptor. These D L amino acids would be increase resistance to proteolytic degradation and prolong the active time in vivo.Based on this hypothesis, 10 protected unnatural amino acids have been synthesized, the end products have passed optical rotation test, all of them have achieved optical requirement in peptide synthesis, and synthesizing cyclic amino acids have been investigated by using cyclic ketones as starting materials reacting with sodium cyanide, parts of the products have been characterized by ~1H NMR or MS. We used solid-phase peptide synthesis, MBHA resin, Boc synthesis strategy, DCC/HOBt or BOP/DIEA kondensational method. Theα-amino were protected by Boc, the side chain aminos were protected by steady in 4M HCl/Diox, and could be eliminated by 25% piperidine/DMF or anhydride HF. 8 decapeptides were designed and synthesized by using an effective LHRH antagonist as a leading compound, replacing or modifying at position 5 6 7 10. 1 -Amino-cyclo-pentanecarboxylic acid (Acc~5) and 1-amino-cyclohexanecarboxylic acid (Acc~6) were introduced onto position 7 of leading compound successfully and the modification of Acc was reported for the firsr time. The designed peptides have been purified by flash column, and the purity was analyzed by HPLC. The bio-activity assay of new peptides is going.