Journal of the Chemical Society. Perkin transactions I p. 2479 - 2485 (1996)
Update date:2022-08-03
Topics:
Shimohigashi, Yasuyuki
Maeda, Iori
Nose, Takeru
Ikesue, Koichi
Sakamoto, Hiroshi
Ogawa, Tomohisa
Ide, Yuzuru
Kawahara, Megumi
Nezu, Takashi
Terada, Yoshihiro
Kawano, Keiichi
Ohno, Motonori
Dipeptide amides H-D-Leu-Phe-NH-R have been found to assume a conformation induced by the CH/π interaction and to inhibit chymotrypsin strongly. A series of benzyl amide derivatives H-D-Leu-Phe-NH-[CH2]n-C6H5 (n = 0-4) have been assayed for chymotrypsin. They inhibit the enzyme in a competitive manner and the highest inhibition is achieved by the amide of n = 1 (Ki = 3.6 × 10-6 M). The activity enhancement is dependent upon the length of methylene chain, not upon the increase in molecular hydrophobicity, indicating the presence of an optimal distance between dipeptide backbone and C-terminal phenyl group for chymotrypsin inhibition. The C-terminal phenyl group has been found to interact with chymotrypsin stereospecifically. The R-isomer of H-D-Leu-Phe-NH-CH(CH3)-C6H5 is as active as the benzyl amide, while the S-isomer is about twenty-fold less active. When the fluorine atom is introduced at a para-position of the C-terminal phenyl group, the resulting dipeptide H-D-Leu-Phe-NH-CH2-C6H4F-p exhibits about six-times increased inhibitory activity (Ki = 6.1 × 107 M; this dipeptide is one of the most potent chymotrypsin inhibitors to date). 1H NMR conformational analyses of these dipeptide amide derivatives show the CH/π interaction between D-Leu-isobutyl and Phe-phenyl as a key structural element for chymotrypsin inhibition. These structural examinations strongly suggest that in the inhibitory conformation the C-terminal phenyl group fits the chymotrypsin S1 site, while the hydrophobic core constructed by D-Leu-Phe CH/π interaction fits the chymotrypsin S2 or S1′ site.
View MoreChina Synchem Technology Co.,Ltd
website:http://www.cnsynchem.com
Contact:+86-0552-4929311
Address:No.217 Daqing Road
Contact:+86-371-67759225
Address:No.32, Jinsuo Road, High-tech Zone
Chengdu Boon Stream Chemical Industry Co.,Ltd.
Contact:+86-28-83156758
Address:No.859,Dongzikou Road,Jinniu District,Chengdu,Sichuan,P.R.China
Contact:+86-0512-69209969
Address:Room 317,Lushan Road,Suzhou New District,Jiangsu Province,China.
Hefei Lifeon Pharmaceutical Co., Ltd.
Contact:+86-551-65328450
Address:No522 Wangjiang West Road
Doi:10.1016/S0277-5387(01)00698-2
(2001)Doi:10.1016/S0031-9422(00)81114-0
(1985)Doi:10.1021/om010075r
(2001)Doi:10.1080/00304940409458678
(2004)Doi:10.1055/s-1989-27314
(1989)Doi:10.1016/S0960-894X(01)00168-8
(2001)
