Sudmeier_1994_Biochemistry_33_12427

Synthesis of the boronic acid analog of the dipeptide Pro-Pro yields a mixture of diastereomers Pro-L-boroPro and Pro-D-boroPro, one of which is a potent inhibitor [Ki = 16 pM; Gutheil, W. G., & Bachovchin, W. W. (1993) Biochemistry 32, 8723-8731] of dipeptidyl amino peptidase type IV (DP IV), also known as CD26. The structures of both diasteremers are determined here in aqueous solution by means of 1D and 2D NMR of 1H, 13C, and 11B, and force-field calculations, and the inhibitor is proven to have the L-L configuration. At low pH values (approximately 2), both diastereomers are trans with respect to the peptide bond. Populations of proline ring conformers are determined by pseudorotation analysis, using vicinal proton spin-coupling constants obtained by computer analysis of 1D1H NMR spectral fine structure. At neutral pH values, the Pro-boroPro inhibitor of DP IV undergoes slow, reversible inactivation (Gutheil & Bachovchin, 1993). By structural determination of the decomposition products of both diasteromers, the process is shown here to involve formation of a six-membered ring between the residues by means of trans-cis conversion and formation of a B-N bond, producing chiral nitrogen atoms in both cases having the S configuration. Analogy to cyclic dipeptides suggests the new compounds be named cyclo(Pro-L-boroPro) and cyclo(Pro-D-boroPro).