Synthesis of enantiomerically enriched non-protein α-amino acids and their study as aldose reductase inhibitors

Ni(II) complexes of the Schiff base of the chiral auxiliary (S)-2-N-(N′-benzylprolyl)aminobenzophenone (BPB) and α-substituted propargylglycines as the initial complexes in the Glaser reaction were investigated. Three new bis-derivatives of propargylglycine were obtained with high chemical yields. To study the patterns of biological activity of the structure of bis-derivatives of propargylglycine, mono analogs of these amino acids were obtained. Bis-derivative of propargylglycine selectively inhibited ALR2 while did not inhibit ALR1. Thus, (2S,9S)-2,9-diamino-2,9-bis(2-chlorobenzyl)deca-4,6-diynedioic selectively inhibited ALR2 with IC50 = 0.335 mM, while (S)-2-(2-chlorobenzyl)-2-aminopent-4-ynoic and (2S,9S)-2,9-diamino-2,9-bis(3-fluorobenzyl)deca-4,6-diynedioic acids showed inhibitory effect on ALR1 with IC50 = 0.49mM and IC50 = 0.289 mM, respectively. The results of docking analysis indicated that both amino acids demonstrated the ability to form bonds with different functional groups of the enzyme. We assume that some amino acids of nonfunctional groups, such as Trp20 of ALR2, can play a key role in inhibitor–enzyme interactions.