Stereoisomers and analogues of bestatin, [(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]-L-leucine, were synthesized and tested for aminopeptidase B and leucine aminopeptidase inhibiting activity. Among the eight stereoisomers, the 2S stereoisomers exhibited strong activity. In a series of compounds in which the L-leucine residue of bestatin was substituted with other amino acids, only the one containing isoleucine showed more activity than bestatin. Norleucine, norvaline, methionine, valine, serine, glutamine, phenylalanine, glutamic acid, proline, and lysine analogues gave, in that order, decreasing activity. Alkyl and phenyl sub stitution for the benzyl group of bestatin decreased the activity markedly. p-Methyl-, p-chloro-, and p-nitrobestatins showed greater activity than bestatin.

The inhibition of pepsin, cathepsin D and renin by pepstatins, pepstanone A and their partial peptides is described. A new method using a nonapeptide containing 3H-Val as the substrate was devised for determination of renin activity.The pepstatin partial peptides valyl-valyl-4-amino-3-hydroxy-6-methylheptanoic acid (Val-Val-AHMHA), isovaleryl-valyl-valyl-4-amino-3-hydroxy-6-methylheptanoic acid (IVA-Val-Val-AHMHA) and carbobenzoxyvalyl-valyl-4-amino-3-hydroxy-6-methylheptanoic acid (Z-Val-Val-AHMHA) weakly inhibited proteolysis by pepsin and did not inhibit renin. Pepstatins B,C,E and G were as active as pepstatin A against pepsin and were slightly more active against renin than pepstatin A. Pepstanone A was as active as pepstatin A against pepsin but slightly less active against renin.

Stable spergualin analogues were synthesized by substitutions of the or-hydroxyglycine residue of spergualin with various a-or -guanidino-fatty acid amide and a hydrate of glyoxyloylspermidine in an aqueous solution as shown in Scheme 1.In this paper, the syntheses and structure activity of stable spergualin analogues are reported in which the a-hydroxyglycine residue corresponding to 10~12 position of deoxyspergualin is substituted with various a-or w-aminoacids. Scheme1. Degradation of spergualins in an aqueous solution.

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Detailed conditions for handling simple peptide-derivatives with anhydrous hydrogen fluoride (HF) were presented.Since HF has a strong affinity for peptides, the removal of excess HF from the reaction products is rather difficult, but is essential to obtain the product as good crystals. Syntheses of the following peptides were carried out successfully as examples of the HF procedure:The possibility of removing the S-benzyl group by acidolysis was the first indication of the usefulness of anhydrous hydrogen fluoride (HF) for peptide synthesis;1) this was confirmed by the formation of oxytocin from the fully-protected nonapeptide. The general properties of HF as a reagent for the removal of various protective groups have been discussed in our preceding papers.2,3) In this study, detailed conditions for the synthesis of simple peptides were investigated to demonstrate how the HF-procedure can be applied in general peptide synthesis. The HF reaction was carried out in the apparatuses described in the preceding papers.2,3)Although completely dry HF is desirable for accelerating the cleaving reaction, a further drying procedure was unnecessary for the synthesis of simple peptides when HF of more than 99% purity was used under mild conditions. Generally, the HF molecule has a strong affinity for peptides through the hydrogen bonds, and it takes a very long time to remove the excess HF from peptides, even in vacuo. The results shown in Fig. 1 demonstrate that 0.19, 1.57, and 1.81 equivalents of HF were still attached to acetyl-Lleucine, L-leucylglycine and L-leucylglycylglycine respectively, even when their HF-solution had been kept under a vacuum (2-3mmHg) for 20hr at room temperature.These results indicate that about 1.4 equivalents of HF are bound to an amino group and that about 0.2 equivalent of HF is attached to one peptide-bond under these conditions. Therefore, the difficulty in removing HF from peptides increases with the number of the peptide-bonds.Nevertheless, the complete removal