N-Guanidino Derivatives of 1,5-Dideoxy-1,5-imino-d-xylitol are Potent, Selective, and Stable Inhibitors of β-Glucocerebrosidase.
A series of lipidated guanidino and urea derivatives of 1,5-dideoxy-1,5-imino-d-xylitol were prepared from d-xylose using a concise synthetic protocol. Inhibition assays with a panel of glycosidases revealed that the guanidino analogues display potent inhibition against human recombinant β-glucocerebrosidase with IC50values in the low nanomolar range. Related urea analogues of 1,5-dideoxy-1,5-imino-d-xylitol were also synthesized and evaluated in the same fashion and found to be selective for β-galactosidase from bovine liver. No inhibition of human recombinant β-glucocerebrosidase was observed for the urea analogues. Computational studies provided insight into the potent activity of analogues bearing the substituted guanidine moiety in the inhibition of lysosomal glucocerebrosidase (GBA).
Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 3508 TB, 3508, TB, Utrecht, The Netherlands.
Alen
A
Sevšek
Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 3508 TB, 3508, TB, Utrecht, The Netherlands.
Luka
L
Šrot
Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 3508 TB, 3508, TB, Utrecht, The Netherlands.
Jakob
J
Rihter
Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 3508 TB, 3508, TB, Utrecht, The Netherlands.
Maša
M
Čelan
Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 3508 TB, 3508, TB, Utrecht, The Netherlands.
Linda Quarles
LQ
van Ufford
Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 3508 TB, 3508, TB, Utrecht, The Netherlands.
Ed E
EE
Moret
Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 3508 TB, 3508, TB, Utrecht, The Netherlands.
Nathaniel I
NI
Martin
Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P.O. Box 3508 TB, 3508, TB, Utrecht, The Netherlands.
Roland J
0000-0003-4723-3584
RJ
Pieters
D000818:Animals; D001665:Binding Sites; D002417:Cattle; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019791:Guanidine / Q000737:chemistry*; D006801:Humans; D008099:Liver / Q000201:enzymology; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D013329:Structure-Activity Relationship; D014993:Xylitol / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D001616:beta-Galactosidase; D005962:Glucosylceramidase; D019791:Guanidine; D014993:Xylitol
Gaucher disease; glycosidase inhibitors; guanidinium; iminosugars; pharmacological chaperones; β-glucocerebrosidase