Solution structures of the DP IV (CD26) inhibitor Val-boroPro determined by NMR spectroscopy

✍ Scribed by Ulrich L. Günther; James L. Sudmeier; Simon J. Coutts; Roger J. Snow; Randall W. Barton; William W. Bachovchin

• Book ID: 102952491
• Publisher: John Wiley and Sons
• Year: 1995
• Tongue: English
• Weight: 917 KB
• Volume: 33
• Category: Article
• ISSN: 0749-1581
• DOI: 10.1002/mrc.1260331204

✦ Synopsis

Abstract

L‐Val‐L‐boroPro, a potent DP IV (CD26) inhibitor, and its non‐inhibitory diastereomer L‐Val‐D‐boroPro, were studied by 1D ^1^H and ^11^H NMR and by 2D ^1^H NMR methods in aqueous solution. Complete 1D ^1^H NMR fine structures were computer analyzed to obtain the ^1^H chemical shifts and spin‐coupling constants. Dihedral angles were derived from coupling constants on the basis of the Altona equation (i.e. an improved Karplus equation). The structures and populations of proline ring conformations were determined with the aid of pseudo‐rotation analysis. Good agreement between the distances derived from NOESY data and dihedral angle‐constrained force‐field calculations was obtained. Structural analysis allowed the identification of the absolute stereochemistry of the α‐carbon of the proline residue, and showed that the active inhibitor is the diastereomer which is homochiral with L‐proline. L‐Val‐L‐boroPro exists largely in a single conformer, in contrast to L‐Val‐D‐boroPro, which adopts two proline conformations in a 2:1 ratio. Analysis of ^1^H and ^11^H NMR spectra proves that inactivation of the inhibitor at physiological pH results from a cyclization reaction in which the free N‐terminal nitrogen atom forms a covalent bond with the B atom.