ISSN:
0749-1581
Keywords:
Val-boroPro
;
DP IV
;
CD26
;
NMR
;
pseudo-rotation
;
Chemistry
;
Analytical Chemistry and Spectroscopy
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
L-Val-L-boroPro, a potent DP IV (CD26) inhibitor, and its non-inhibitory diastereomer L-Val-D-boroPro, were studied by 1D 1H and 11H NMR and by 2D 1H NMR methods in aqueous solution. Complete 1D 1H NMR fine structures were computer analyzed to obtain the 1H 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 1H and 11H 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.
Additional Material:
5 Ill.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/mrc.1260331204
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