Chymotrypsin inhibitory conformation induced by amino acid side chain–side chain intramolecular CH/π interaction

Design of serine protease inhibitors with conformation restricted by amino acid side-chain-side-chain CH/? interaction

“…0.57 ppm), and ␦CH 3 (0.17-0.22 ppm). 13 Since DLeu-isobutyl proton signals of H-D-Leu-Phe-OH, H-D-Leu-Phe-OCH 3 , H-D-Leu-Phe-NH 2 , and H-DLeu-Phe-NHCH 3 also showed similar upfield shifts, these upfield shifts are certainly attributed to the shielding effect from the Phe-phenyl group, but not to that of the C-terminal amide-or ester-phenyl group. A similar was observed for D-Thr-Phe dipeptides (Table I). 14 These results clearly implied that the Phe-phenyl group is in proximity to D-Leu-isobutyl.…”

“…Acetyl-L-tyrosine ethyl ester (ATEE), a substrate of chymotrypsin, was completely degraded within 20 min. Although H-D-Leu-Phe-OBzl was completely hydrolyzed to H-D-Leu-Phe-OH within 90 min, 12 the benzyl amide H-D-Leu-Phe-NHBzl exhibited no hydrolysis even after 2 h. 13 None of dipeptide amides having the D-L configurational sequence were degraded by chymotrypsin.…”

D-Leu-L-Phe-containing dipeptide inhibitors of α-chymotrypsin – the role of the N- and C-termini in enzyme affinity

“…Intermediate 8 was assayed in order to verify the assay procedure, and to confirm previously reported results. 4 This compound is essentially identical to the reported inhibitor 1, simply existing as a free amine instead of a hydrochloride salt. A K i value of 4 µM was obtained, which compares favourably to the reported value of 3.6 µM for compound 1.…”

“…2-((R)-1-((S)-1-(benzylamino)-1-oxo-3-phenylpropan-2-ylamino)-4-methyl-1-oxo pentan-2-ylamino)-2-oxoethylcarbamate (4) To a solution of 8 (100 mg, 0.27 mmol), Bocglycine (48 mg, 1 eq) and HATU (115 mg, 1.1 eq) in DMF (8 mL) was added DIEA (105 µL, 78 mg, 2.2 eq) and the resulting mixture was stirred for 16 h, then diluted with EtOAc (50 mL), washed with sat. NaHCO 3 (50 mL), brine (50 mL), dried over MgSO 4 N-((S)-1-oxo-3-phenyl-1-(4-((E)-phenyldiazenyl) …”

“…4 This compound inhibits α-chymotrypsin activity with a reported inhibition constant, K i , of 3.6 µM, and exhibits high stability to α-chymotrypsin catalysed hydrolysis. It has been proposed that the activity of 1 results from its preference to adopt an unusual conformation involving hydrophobic-hydrophobic interactions between the D-Leu and L-Phe side chains.…”