Potentially Macrocyclic Peptidyl Boronic Acids as Chymotrypsin Inhibitors.
The possibility of forming a peptide boronate adduct in a serine protease active site that mimics the first tetrahedral intermediate in the peptide hydrolysis mechanism was explored with the complex boronic acid analogs 7, 8-OH, and 8-NH(2)(). In these structures, the P(1) and P(2) residues and the P(1)'-P(3)' residues are connected through the P(2) and P(1)' side chains, to encourage formation of the diester or amide-ester adducts via macrocyclization. These inhibitors were assembled from suitably protected derivatives of 2,4-diaminobutanoic acid or 2,4-diaminopentanoic acid (11), borophenylalanine (12), aspartic acid, malic acid or the substituted malic acid analog 13, and Leu-Arg dipeptide. Stereoselective syntheses were developed for the (S,S)-2,4-diaminopentanoate 11 and for the (S,S)-beta-isobutylmalate 13 derivatives. The complex peptidyl boronates 7 (K(i) = 26 nM) and 8-OH (68 nM) are potent inhibitors of alpha-chymotrypsin; however, the affinity of 7 is neither time- nor pH-dependent, and it is only moderately greater than that found for comparison compounds like 8-H (114 nM), 9 (356 nM), and 10 (219 nM) that cannot cyclize or form a diester adduct.
Tian
Zong-Qiang
ZQ
Department of Chemistry, University of California, Berkeley, California 94720-1460.
Brown
Bradley B.
BB
Mack
David P.
DP
Hutton
Craig A.
CA
Bartlett
Paul A.
PA