POTENTIALLY MACROCYCLIC PEPTIDYL BORONIC ACIDS AS CHYMOTRYPSIN INHIBITORS

The possibility of forming a peptide boronate adduct in a serine prote ase active site that mimics the first tetrahedral intermediate in the peptide hydrolysis mechanism was explored with the complex boronic aci d analogs 7, 8-OH, and 8-NH2. In these structures, the P-1 and P-2 res idues 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 ad ducts via macrocyclization. These inhibitors were assembled from suita bly protected derivatives of 2,4-diaminobutanoic acid or 2,4-diaminope ntanoic acid (11), borophenylalanine (12), aspartic acid, malic acid o r the substituted malic acid analog 13, and Leu-Arg dipeptide. Stereos elective syntheses were developed for the (S,S)-2,4-diaminopentanoate 11 and for the (S,S)-beta-isobutylmalate 13 derivatives. The complex p eptidyl boronates 7 (K-i = 26 nM) and 8-OH (68 nM) are potent inhibito rs of alpha-chymotrypsin; however, the affinity of 7 is neither time- nor pH-dependent, and it is only moderately greater than that found fo r comparison compounds like 8-H (114 nM), 9 (356 nM), and 10 (219 nM) that cannot cyclize or form a diester adduct.