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

Abstract

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 = 0.49 mM 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.

Graphical Abstract

Keywords:

• Inhibitor
• aldose reductase
• enantiomeric excess
• asymmetric synthesis
• non-protein α-amino acid

Disclosure statement

The authors declare no conflict of interest.

Ethical approval

This article does not contain any studies with animals or humans performed by any of the authors.

Informed consent

All authors are aware of the details of their research work that are published in the current paper and give their consent to their publication.

Additional information

Funding

This work was supported by the RA MES State Committee of Science in the frames of the joint research projects SCS 18T-1D317, ISTC A-2289 and Armenian National Science and Education Fund (ANSEF) based in New York USA (Chemorg-5279).