title: Phosphorus amino acid analogues as inhibitors of leucine aminopeptidase.
abstract: A variety of phosphorus amino acid and dipeptide analogues have been synthesized and evaluated as inhibitors of the metalloenzyme leucine aminopeptidase from porcine kidney. Two phosphonate dipeptides were found to be modest inhibitors of the enzyme (8e, Ki = 58 microM; 8h, Ki = 340 microM). The phosphinic acid (17-OH) and phosphinamide (17-NH2) analogues related to bestatin were prepared by condensation of the phosphinate amino acid derivative 11, via a trivalent phosphonite ester 12, with leucine isocyanate derivatives 13. These compounds also proved to be unexceptional in their inhibition of LAP (17-O-, Ki = 56 microM; 17-NH2, Ki = 40 microM). A series of simple (alpha-aminoalkyl)phosphonic acid and -phosphinic acids were also evaluated, and the most potent inhibitors were found to be the phosphonic acid analogues of L-Leu and L-Phe [R)-3e, Ki = 0.23 microM; (R)-3h, Ki = 0.42 microM). Slow-binding behavior was observed for (R)-3e (kon = 400 +/- 55 M-1 s-1) and (R)-3h (kon = 445 +/- 50 M-1 s-1). The phosphinic acid analogues of Leu and Phe are 100-fold less potent than the phosphonate derivatives. The fact that tetrahedral phosphorus analogues are less potent inhibitors of LAP than they are of other zinc peptidases suggests that the mechanism of LAP may be fundamentally different than that of the latter enzymes.
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D004151:Dipeptides / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D007931:Leucyl Aminopeptidase / Q000037:antagonists & inhibitors*; D008433:Mathematics; D010758:Phosphorus; D013552:Swine
chemical_list: D000596:Amino Acids; D004151:Dipeptides; D010758:Phosphorus; D007931:Leucyl Aminopeptidase; D007930:Leucine; C012211:ubenimex