STUDIES ON PROLINE BORONIC ACID DIPEPTIDE INHIBITORS OF DIPEPTIDYL PEPTIDASE-IV - IDENTIFICATION OF A CYCLIC SPECIES CONTAINING A B-N BOND

The proline boronic acid dipeptides AlaboroPro (14), ProboroPro (15), and ValboroPro (16) are very potent inhibitors of the enzyme dipeptidy l peptidase IV (DPP IV or CD26), found on the surface of T-cells, and are a new class of immunosuppressants. The efficient synthesis of the free boronic acids as single enantiomers is described, and the absolut e configuration determined. These compounds are known to lose DPP IV i nhibitory activity in solution: this is shown to be due to the reversi ble formation of a cyclic species analogous to a diketopiperazine, con taining a B-N bond. The cyclic compounds, both as the free boronic aci ds (17-19) and as the pinanediol esters (11-13), have been isolated an d characterized by H-1 and B-11 NMR, and in one case by X-ray crystall ography. The cyclization is pH dependent, with the open form favored a t low pH, while the cyclic form predominates at neutral pH. Both the r ate and extent of cyclization depend on the N-terminal amino acid. The rates of cyclization have been measured by H-1 NMR and shown to corre late with the decrease in DPP IV inhibitory activity. ValboroPro cycli zes more slowly, and to a lesser extent than AlaboroPro or ProboroPro, which is predicted to lead to greater immunosuppressive potency in vi vo.