Fagomine

Fagomine is a good inhibitor of various Glycosidases, including rat intestinal surcase and bovine α-Fucosidase with IC50 of 90μM and 140 μM, respectively. [1]
Fagomine has been shown to have some activity against mammalian gut R -glucosidase and β-galactosidase, Moreover, fagomine was also found to have a potent antihyperglycemic effect in streptozocin-induced diabetic mice and to potentiate markedly immunoreactive insulin release. [2]
Fagomine inhibitory activity was tested against different enzymes with IC50 of 90μM and 140 μM for rat intestinal surcase and bovine α-Fucosidase, respectively. Furthermore, the IC50 values for α-glucosidase in rice and yeast, along with rat intestinal maltase and isomaltase were also determined and the results were 320 880 820 and 460μM, respectively. The activities of rice R -glucosidase and rat digestive glycosidases were determined using the appropriate disaccharides as substrates at the optimum pH of each enzyme. The released D-glucose was determined colorimetrically using the glucose B-test. Other glycosidase activities were determined using an appropriate p-nitrophenyl glycoside as a substrate at the optimum pH of each enzyme. [1]
D-Fagomine lowered postprandial glycaemia in SD rats after the intake of sucrose and starch. D-Fagomine effectively regulated postprandial glycaemia in a dose-dependent manner, which led to a reduction in AUC at 120 min between 17 % and 43 % after the intake of 1 g sucrose/kg body weight. D-Fagomine effectively modulates the glucose level in blood in a dose-dependent manner after the ingestion of sucrose or starch, probably by delaying saccharide hydrolysis by brush-border glycosidases. [3]
References:
[1]. Goujon J Y, Gueyrard D, Compain P, et al. General synthesis and biological evaluation of α-1-C-substituted derivatives of fagomine (2-deoxynojirimycin-α-C-glycosides)[J]. Bioorganic & medicinal chemistry, 2005, 13(6): 2313-2324.
[2]. Kato A, Asano N, Kizu H, et al. Fagomine isomers and glycosides from Xanthocercis zambesiaca[J]. Journal of natural products, 1997, 60(3): 312-314.
[3]. Gómez L, Molinar-Toribio E, Calvo-Torras M Á, et al. d-Fagomine lowers postprandial blood glucose and modulates bacterial adhesion[J]. British Journal of Nutrition, 2011, 1(1): 1-8.

D-Fagomine attenuates metabolic alterations induced by a high-energy-dense diet in rats.[Pubmed:26130374]

Food Funct. 2015 Aug;6(8):2614-9.

d-Fagomine is a natural iminosugar that counteracts the short-term effects of a high-energy-dense diet on body weight, fasting blood glucose levels and the proportion of gut Enterobacteriales. This suggests that supplementation with d-Fagomine for longer periods may delay the onset of other factors related to metabolic syndrome. Here we evaluate the effects of d-Fagomine dietary supplementation on relevant metabolic hormones and lipid peroxidation. Adult Sprague-Dawley rats were fed a high-fat high-sucrose diet supplemented or not with d-Fagomine (0.065% w/w) for 9 weeks. Weight gain, plasma triglycerides, glucose, insulin, glucagon, ghrelin, leptin, and urine F2-isoprostanes were evaluated. d-Fagomine attenuated the changes induced by the high-energy-dense diet in triglycerides and all the hormones tested. These results suggest that d-Fagomine may help to avert the complications associated with unhealthy eating by counteracting the effects of high-energy-dense diets during the early stages of the development of metabolic disorders.

Inhibitor versus chaperone behaviour of d-fagomine, DAB and LAB sp(2)-iminosugar conjugates against glycosidases: A structure-activity relationship study in Gaucher fibroblasts.[Pubmed:26361824]

Eur J Med Chem. 2016 Oct 4;121:880-891.

A library of sp(2)-iminosugar conjugates derived from the piperidine iminosugar d-Fagomine and the enantiomeric pyrrolidine iminosugars DAB and LAB has been generated in only two steps involving direct coupling of the fully unprotected polyhydroxylated heterocycles with isothiocyanates, to give monocyclic thiourea adducts, and further intramolecular nucleophilic displacement of the delta-located primary hydroxyl group by the thiocarbonyl sulphur atom, affording bicyclic isothioureas. These transformations led to a dramatic shift in the inhibitory selectivity from alpha- to beta-glucosidases, with inhibition potencies that depended strongly on the nature of the aglycone-type moiety in the conjugates. Some of the new derivatives behaved as potent inhibitors of human beta-glucocerebrosidase (GCase), the lysosomal enzyme whose dysfunction is responsible for Gaucher disease. Moreover, GCase inhibition was 10-fold weaker at pH 5 as compared to pH 7, which is generally considered as a good property for pharmacological chaperones. Surprisingly, most of the compounds strongly inhibited GCase in wild type fibroblasts at rather low concentrations, showing an unfavourable chaperone/inhibitor balance on disease-associated GCase mutants in cellulo. A structure-activity relationship analysis points to the need for keeping a contiguous triol system in the glycone moiety of the conjugates to elicit a chaperone effect. In any case, the results reported here represent a proof of concept of the utmost importance of implementing diversity-oriented strategies for the identification and optimization of potent and specific glycosidase inhibitors and chaperones.

Synthesis and evaluation of N-alkylated analogues of aza-galacto-fagomine - potential pharmacological chaperones for Krabbe disease.[Pubmed:27545315]

Org Biomol Chem. 2016 Sep 28;14(36):8545-56.

Seven novel alkylated or acylated analogues of hexahydropyridazine aza-galacto-Fagomine (AGF) was prepared and studied as glycosidase inhibitors with the aim of increasing inhibitory potency and selectivity. The enzyme galactocerebrosidase, implicated in Krabbe disease, was found to be potently inhibited by n-butyl N2-alkylated AGF.

Asymmetric syntheses of (-)-3-epi-Fagomine, (2R,3S,4R)-dihydroxypipecolic acid, and several polyhydroxylated homopipecolic acids.[Pubmed:25337869]

J Org Chem. 2014 Nov 21;79(22):10932-44.

A range of enantiopure polyhydroxylated piperidines, including (2R,3S,4R)-dihydroxypipecolic acid, (-)-3-epi-Fagomine, (2S,3S,4R)-dihydroxyhomopipecolic acid, (2S,3R,4R)-dihydroxyhomopipecolic acid, and two trihydroxy-substituted homopipecolic acids, have been prepared using diastereoselective olefinic oxidations of a range of enantiopure tetrahydropyridines as the key step. The requisite substrates were readily prepared from tert-butyl sorbate using our diastereoselective hydroamination or aminohydroxylation protocols followed by ring-closing metathesis. After diastereoselective olefinic oxidation of the resultant enantiopure tetrahydropyridines and deprotection, enantiopure polyhydroxylated piperidines were isolated as single diastereoisomers (>99:1 dr) in good overall yield.

Fagomine is a mild glycosidase inhibitor. The Ki of the iminosugar Fagomine is 4.8 μM, 39 μM, and 70 μM for Amyloglucosidase (A.niger), β-Glucosidase (bovine), and Isomaltase (yeast), respectively.

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