Glycosidase inhibition by novel guanidinium and urea iminosugar derivatives

Kooij, Raymond; Branderhorst, Hilbert M.; Bonte, Simon; Wieclawska, Sara; Martin, Nathaniel I.; Pieters, Roland J.

doi:10.1039/c2md20343j

Cited by 21 publications

(16 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In doing so both the conformation and charge delocalization of the endocyclic nitrogen atom is altered. These modifications have resulted in interesting specificity changes in comparison with the parent iminosugars . To this end, we recently attempted the synthesis of a series of lipidated DNJ guanidine analogues (compounds I , Scheme ) .…”

Section: Figurementioning

confidence: 99%

“…These modifications have resultedi ni nteresting specificity changes in comparison with the parent iminosugars. [34] To this end, we recently attempted the synthesis of as eries of lipidated DNJ guanidine analogues( compounds I,S cheme1). [35] Interestingly,w ef ound that such N-alkylated guanidine DNJ analogues I spontaneously cyclized to generate the corresponding stable bicyclic isoureas II.G ratifyingly,the isoureas proved to be very potent and specific inhibitors of b-glucocerebrosidase.…”

mentioning

confidence: 99%

See 1 more Smart Citation

N‐Guanidino Derivatives of 1,5‐Dideoxy‐1,5‐imino‐d‐xylitol are Potent, Selective, and Stable Inhibitors of β‐Glucocerebrosidase

et al. 2017

Self Cite

View full text Add to dashboard Cite

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 IC values 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).

show abstract

Section: Figurementioning

confidence: 99%

mentioning

confidence: 99%

N‐Guanidino Derivatives of 1,5‐Dideoxy‐1,5‐imino‐d‐xylitol are Potent, Selective, and Stable Inhibitors of β‐Glucocerebrosidase

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Previously reported glycosidase inhibitors were sugar mimics (azasugars and carbasugars) and their analogs; however, no efforts were made to discover new scaffolds of better pharmacokinetic profiles, chemical stabilities, and higher potencies (Wang et al, 2013;Kooij et al, 2013;Asano et al, 2000;Asano, 2003;Berecibar et al, 1999;Kim et al, 2006;Li et al, 2006;Pandey et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Tryptophan and thiosemicarbazide derivatives: design, synthesis, and biological evaluation as potential β-d-galactosidase and β-d-glucosidase inhibitors

et al. 2014

View full text Add to dashboard Cite

Glycosidases, including b-D-galactosidase and b-D-glucosidase, are involved in a range of metabolic disorders, such as cancer, viral or bacterial infections, and diabetes. Previously, we scanned the pharmacophoric space of these enzymes and had a self-consistent and predictive quantitative structure-activity relationship that was used to identify several b-D-galactosidase and b-D-glucosidase inhibitors via in silico search of structural databases. Guided by the preceding modeling efforts, synthesis of a series of tryptophan and thiosemicarbazide derivatives as b-Dgalactosidase and b-D-glucosidase inhibitors that match the generated pharmacophores followed by in vitro bioassay was carried out. Synthesized compounds 3c (37 % inhibition at 100 lM) and 4d (49 % inhibition at 100 lM) exhibited the best inhibitory bioactivities against b-Dgalactosidase and b-D-glucosidase, respectively. They can serve as a promising lead compounds for the development of potential glycosidase inhibitors.

show abstract

“…62,63 Transmuting the endocyclic sp 3 -amine nitrogen into a sp 2 -hybridized pseudoamide functionality by introduction of amide, urea, thiourea or guanidinium moieties has proven particularly successful in this respect. [64][65][66][67][68] For instance, N-(N'-butylaminocarbamoyl)-1-deoxynojirimycin, the urea analog of the marketed drug Zavesca, was found to be a very selective inhibitor of bovine liver -galactosidase. 67 The sp 2 -hybridized character is also observed in some natural products such as kifunensine, a potent inhibitor of class I α-mannosidase.…”

mentioning

confidence: 99%

“…[64][65][66][67][68] For instance, N-(N'-butylaminocarbamoyl)-1-deoxynojirimycin, the urea analog of the marketed drug Zavesca, was found to be a very selective inhibitor of bovine liver -galactosidase. 67 The sp 2 -hybridized character is also observed in some natural products such as kifunensine, a potent inhibitor of class I α-mannosidase. 69,70 To check this strategy for the particular case of hexosaminidases, we synthesized a series of ureido-DNJNAc derivatives (10).…”

mentioning

confidence: 99%

Stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc) and ureido-DNJNAc derivatives as new hexosaminidase inhibitors

et al. 2015

View full text Add to dashboard Cite

2-Acetamido-1,2-dideoxyiminosugars are selective and potent inhibitors of hexosaminidases and therefore show high therapeutic potential for the treatment of various diseases, including several lysosomal storage disorders. A stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc), the iminosugar analog of N-acetylglucosamine, with high overall yield is here described. This novel procedure further allowed accessing ureidoDNJNAc conjugates through derivatization of the endocyclic amine on a key pivotal intermediate. Remarkably, some of the ureido-DNJNAc representatives behaved as potent and selective inhibitors of β-hexosaminidases, including the human enzyme, being the first examples of neutral sp 2 -iminosugar-type inhibitors reported for these enzymes. Moreover, the amphiphilic character of the new ureido-DNJNAc is expected to confer better drug-like properties.

show abstract

Glycosidase inhibition by novel guanidinium and urea iminosugar derivatives

Cited by 21 publications

References 32 publications

N‐Guanidino Derivatives of 1,5‐Dideoxy‐1,5‐imino‐d‐xylitol are Potent, Selective, and Stable Inhibitors of β‐Glucocerebrosidase

N‐Guanidino Derivatives of 1,5‐Dideoxy‐1,5‐imino‐d‐xylitol are Potent, Selective, and Stable Inhibitors of β‐Glucocerebrosidase

Tryptophan and thiosemicarbazide derivatives: design, synthesis, and biological evaluation as potential β-d-galactosidase and β-d-glucosidase inhibitors

Stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc) and ureido-DNJNAc derivatives as new hexosaminidase inhibitors

Contact Info

Product

Resources

About