Enantiomeric α, β-diaminoethylphosphonic acids as potent inhibitors of aminopeptidases—stereoselective synthesis and biological activity. Issue 43 (26th October 2016)

• Record Type: Journal Article
• Authors: Węglarz-Tomczak, Ewelina; Staszewska, Katarzyna; Talma, Michał; Mucha, Artur
• Is Part Of: Tetrahedron letters. Volume 57:Issue 43(2016)
• Page Start: 4812
• Page End: 4814
• Publication Date: 2016-10-26
• Subjects: M01 aminopeptidases -- Phosphonic amino acid analogues -- Enantiomeric inhibitors -- SAR studies; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tetlet.2016.09.051
• Languages: English
• ISSNs: 0040-4039

Abstract

Graphical abstract: Highlights: Individual enantiomers of selected α, β-diaminoethylphosphonic acids were separated. Thel -enantiomers were better recognized by APNs and ERAP2 than thed -enantiomers. α, β-Diaminoethylphosphonic acids are readily available in optically pure form. Abstract: α, β-Diaminoethylphosphonic acids are efficient transition-state analogue inhibitors of alanyl aminopeptidase and endoplasmic reticulum aminopeptidase 2, biomedically important members of the M01 family of proteases. In this work, the individual enantiomers of selected inhibitors were separated and their inhibitory potency verified. The synthesis involved the use of a chiral α-methylbenzylamine to obtain diastereomeric aziridinephosphonates as key intermediates of the multistep process. The diastereomeric aziridines were resolved chromatographically, and the heterocyclic ring opened with the appropriate amines. The inhibition study revealed an interesting correlation between the absolute configuration and inhibitory activity. Certain enantiomeric phosphonic amino acid analogues exhibited inhibition constants in the nanomolar range.