Chemistry - A European Journal p. 14860 - 14866 (2012)
Update date:2022-08-05
Topics:
Ansiaux, Christophe
N'Go, Inès
Vincent, Stéphane P.
A series of UDP-galactitols were designed as analogues of high-energy intermediates of the UDP-galactopyranose mutase (UGM) catalyzed furanose/pyranose interconversion, an essential step of Mycobacterium tuberculosis cell wall biosynthesis. The final compounds structurally share the UDP and the galactitol substructures that were connected by four distinct electrophilic connections (epoxide, lactone and Michael acceptors). All molecules were synthesized from a common perbenzylated acyclic galactose precursor that was derivatized by alkenylation, alkynylation and cyclopropanation. The inhibition study against UGM could clearly show that slight changes in the relative orientation of the UDP and the galactitol moieties resulted in dramatic variations of binding properties. Compared to known inhibitors, the epoxide derivative displayed a very tight, reversible, inhibition profile. Moreover, a time-dependent inactivation study showed that none of these electrophilic structures could react with UGM, or its FAD cofactor, the catalytic nucleophile of this still intriguing reaction. Shedding inhibitors: UDP-Galactopyranose mutase (UGM) is a validated target for treating tuberculosis. Its mechanism involves formation of a key covalent FAD-substrate intermediate, 1. A series of electrophilic UDP-galactitols were synthesized and assayed as inhibitors or inactivators of UGM. Strong inhibitions were observed, especially with epoxide 2. Interestingly, none of the molecules displayed an irreversible inhibition mode. Copyright
View MoreShanghai Demand Chemical Co., ltd,China
Contact:86-021-55237578/55239122
Address:Room 3H, No.578, Yingkou Road, Yangpu District, Shanghai, China
Wuhan Sunrise Pharmaceutical Technology Co., Ltd
Contact:+86-27-83314682
Address:Room 340, New material Industrial base No.17, Gu Tian Five Lu , Qiaokou District, Wuhan , China
Wuxi Pharma-Trading Import & Export Co.,Ltd.
Contact:+86-510-82304590 82716390
Address:Room 523,Youzu Alliance Building,No.88 Renmin Zhonglu,Wuxi,Jiangsu,China
Nanjing Ruizhi Industry & Technologh Co.,Ltd.
Contact:+86-25-86808110
Address:441-4-A5,NO.12 Longzang Avenue,Yuhuatai District,210039,Nanjing
Contact:+86-717-6370352
Address:168 Chengdong Avenue, Yichang, Hubei 443003, P. R.China
Doi:10.1021/jo302474r
(2013)Doi:10.1039/c9dt01373c
(2019)Doi:10.1021/bc300610f
(2013)Doi:10.1007/s00726-016-2200-9
(2016)Doi:10.1016/j.bmcl.2012.12.008
(2013)Doi:10.1002/chem.201203251
(2013)