1,6-Cyclophellitol Cyclosulfates: A New Class of Irreversible Glycosidase Inhibitor

TY - JOUR

T1 - 1,6-Cyclophellitol Cyclosulfates

T2 - A New Class of Irreversible Glycosidase Inhibitor

AU - Artola, Marta

AU - Wu, Liang

AU - Ferraz, Maria J.

AU - Kuo, Chi Lin

AU - Raich, Lluís

AU - Breen, Imogen Z.

AU - Offen, Wendy A.

AU - Codée, Jeroen D.C.

AU - Van Der Marel, Gijsbert A.

AU - Rovira, Carme

AU - Aerts, Johannes M.F.G.

AU - Davies, Gideon J.

AU - Overkleeft, Herman S.

N1 - © 2017 American Chemical Society. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

PY - 2017/7/26

Y1 - 2017/7/26

N2 - The essential biological roles played by glycosidases, coupled to the diverse therapeutic benefits of pharmacologically targeting these enzymes, provide considerable motivation for the development of new inhibitor classes. Cyclophellitol epoxides and aziridines are recently established covalent glycosidase inactivators. Inspired by the application of cyclic sulfates as electrophilic equivalents of epoxides in organic synthesis, we sought to test whether cyclophellitol cyclosulfates would similarly act as irreversible glycosidase inhibitors. Here we present the synthesis, conformational analysis, and application of novel 1,6-cyclophellitol cyclosulfates. We show that 1,6-epi-cyclophellitol cyclosulfate (α-cyclosulfate) is a rapidly reacting α-glucosidase inhibitor whose 4C1 chair conformation matches that adopted by α-glucosidase Michaelis complexes. The 1,6-cyclophellitol cyclosulfate (β-cyclosulfate) reacts more slowly, likely reflecting its conformational restrictions. Selective glycosidase inhibitors are invaluable as mechanistic probes and therapeutic agents, and we propose cyclophellitol cyclosulfates as a valuable new class of carbohydrate mimetics for application in these directions.

AB - The essential biological roles played by glycosidases, coupled to the diverse therapeutic benefits of pharmacologically targeting these enzymes, provide considerable motivation for the development of new inhibitor classes. Cyclophellitol epoxides and aziridines are recently established covalent glycosidase inactivators. Inspired by the application of cyclic sulfates as electrophilic equivalents of epoxides in organic synthesis, we sought to test whether cyclophellitol cyclosulfates would similarly act as irreversible glycosidase inhibitors. Here we present the synthesis, conformational analysis, and application of novel 1,6-cyclophellitol cyclosulfates. We show that 1,6-epi-cyclophellitol cyclosulfate (α-cyclosulfate) is a rapidly reacting α-glucosidase inhibitor whose 4C1 chair conformation matches that adopted by α-glucosidase Michaelis complexes. The 1,6-cyclophellitol cyclosulfate (β-cyclosulfate) reacts more slowly, likely reflecting its conformational restrictions. Selective glycosidase inhibitors are invaluable as mechanistic probes and therapeutic agents, and we propose cyclophellitol cyclosulfates as a valuable new class of carbohydrate mimetics for application in these directions.

UR - http://www.scopus.com/inward/record.url?scp=85026431453&partnerID=8YFLogxK

U2 - 10.1021/acscentsci.7b00214

DO - 10.1021/acscentsci.7b00214

M3 - Article

AN - SCOPUS:85026431453

SN - 2374-7943

VL - 3

SP - 784

EP - 793

JO - ACS Central Science

JF - ACS Central Science

IS - 7

ER -