A new family of five-carbon iminoalditols which are potent glycosidase inhibitors

Bernotas, Ronald C.; Papandreou, George; Urbach, Jonathan M.; Ganem, Bruce

doi:10.1016/s0040-4039(00)97405-7

Cited by 77 publications

(45 citation statements)

References 9 publications

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“…First, by testing 1‐C‐alkyl imino‐L‐arabitols (Fig. , A), the 5‐CH 2 OH group (marked by an asterisk) was shown to be an essential constituent for both α‐gal A and β‐gal inhibition, supporting previous observations (Bernotas et al, ). Second, it was demonstrated that the 1‐C‐alkyl imino‐D‐galactitols (as with DGJ; Fig.…”

Section: Identifying Candidate Chaperones For Kdsupporting

confidence: 84%

New therapeutic approaches for Krabbe disease: The potential of pharmacological chaperones

Spratley

Deane

2016

J of Neuroscience Research

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Missense mutations in the lysosomal hydrolase β‐galactocerebrosidase (GALC) account for at least 40% of known cases of Krabbe disease (KD). Most of these missense mutations are predicted to disrupt the fold of the enzyme, preventing GALC in sufficient amounts from reaching its site of action in the lysosome. The predominant central nervous system (CNS) pathology and the absence of accumulated primary substrate within the lysosome mean that strategies used to treat other lysosomal storage disorders (LSDs) are insufficient in KD, highlighting the still unmet clinical requirement for successful KD therapeutics. Pharmacological chaperone therapy (PCT) is one strategy being explored to overcome defects in GALC caused by missense mutations. In recent studies, several small‐molecule inhibitors have been identified as promising chaperone candidates for GALC. This Review discusses new insights gained from these studies and highlights the importance of characterizing both the chaperone interaction and the underlying mutation to define properly a responsive population and to improve the translation of existing lead molecules into successful KD therapeutics. We also highlight the importance of using multiple complementary methods to monitor PCT effectiveness. Finally, we explore the exciting potential of using combination therapy to ameliorate disease through the use of PCT with existing therapies or with more generalized therapeutics, such as proteasomal inhibition, that have been shown to have synergistic effects in other LSDs. This, alongside advances in CNS delivery of recombinant enzyme and targeted rational drug design, provides a promising outlook for the development of KD therapeutics. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

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Section: Identifying Candidate Chaperones For Kdsupporting

confidence: 84%

New therapeutic approaches for Krabbe disease: The potential of pharmacological chaperones

Spratley

Deane

2016

J of Neuroscience Research

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“…From a structural viewpoint, the cis-vicinal hy- droxy groups adjacent to the amino group should match with the 2-and 3-hydroxy groups of the cation adopting the flap-up conformation, as roughly depicted in Figure 1. Although studies [31] on a moderate α-mannosidase inhibitor, deoxymannonojirimycin, demonstrated that 5-hydroxymethyl branching is not indispensable for inhibitory action, we found the strong inhibitory activity of compounds 36 and 37 to depend on the presence of 4-hydroxymethyl groups, matching the 5-hydroxymethyl group of the mannopyranosyl cation. In the cases of compounds 1 and 14, the methylthio and methoxy groups seem to act as hydroxymethyl equivalents to provide a certain hydrophobic region of space, increasing their potency.…”

Section: Biological Assaycontrasting

confidence: 70%

Chemical Modification of the α‐Mannosidase Inhibitor Mannostain A: Synthesis of a Potent Inhibitor 1L‐(1,2,3,5/4)‐5‐Amino‐4‐O‐methyl‐1,2,3,4‐cyclopentanetetrol

Ogawa¹,

Morikawa²

2005

Eur J Org Chem

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Demethylthio‐, S‐demethyl‐, and S‐ethyl derivatives of the α‐mannosidase inhibitor, mannostasin A, were synthesized and evaluated for their inhibition of Jack bean α‐mannosidase with the prime objective of elucidating the role of the methylthio group. All methylthio derivatives had significantly lowered inhibitory potentials. However, one mannostatin A analogue with a methoxyl instead of the methylthio group exhibited about twofold enhancement of the activity. The structure and inhibitory activity relationships of mannostatin A and related compounds are discussed in light of our results. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

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“…Removal of the Cbz protecting group of 9 Table 2: FSA-catalyzed cross-aldol additions of GA (1) followed by reductive amination led to the 1-deoxyiminosugars 10 a and 10 b, which are of interest as glycosidase inhibitors. [37][38][39] Interestingly, a single aldol addition was observed in all the examples under the reaction conditions employed; this is also of great value for a two-step biocatalytic aldol addition for the stereoselective synthesis of carbohydrates.…”

mentioning

confidence: 99%

Asymmetric Self‐ and Cross‐Aldol Reactions of Glycolaldehyde Catalyzed by D‐Fructose‐6‐phosphate Aldolase

et al. 2009

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A new family of five-carbon iminoalditols which are potent glycosidase inhibitors

Cited by 77 publications

References 9 publications

New therapeutic approaches for Krabbe disease: The potential of pharmacological chaperones

New therapeutic approaches for Krabbe disease: The potential of pharmacological chaperones

Chemical Modification of the α‐Mannosidase Inhibitor Mannostain A: Synthesis of a Potent Inhibitor 1L‐(1,2,3,5/4)‐5‐Amino‐4‐O‐methyl‐1,2,3,4‐cyclopentanetetrol

Asymmetric Self‐ and Cross‐Aldol Reactions of Glycolaldehyde Catalyzed by D‐Fructose‐6‐phosphate Aldolase

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