Gem-diamine 1-N-iminosugars as versatile glycomimetics: synthesis, biological activity and therapeutic potential

Nishimura, Yoshio

doi:10.1038/ja.2009.53

Cited by 29 publications

(13 citation statements)

References 90 publications

(112 reference statements)

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“…IFG is an iminosugar that is a member of the class of inhibitors for glycosidases and glycosyltransferases. Iminosugars have therapeutic applications in the diseases associated with the metabolism of glycoconjugates to treat tumor metastasis, influenza virus infection, and lysosomal storage diseases [33], [34]. Single oral dose of 600 mg/kg to the rat achieves IFG concentration of 1.7 µM in the brain [16].…”

Section: Discussionmentioning

confidence: 99%

Isofagomine In Vivo Effects in a Neuronopathic Gaucher Disease Mouse

et al. 2011

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The pharmacological chaperone, isofagomine (IFG), enhances acid β-glucosidase (GCase) function by altering folding, trafficking, and activity in wild-type and Gaucher disease fibroblasts. The in vivo effects of IFG on GCase activity, its substrate levels, and phenotype were evaluated using a neuronopathic Gaucher disease mouse model, 4L;C* (V394L/V394L + saposin C-/-) that has CNS accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) as well as progressive neurological deterioration. IFG administration to 4L;C* mice at 20 or 600 mg/kg/day resulted in life span extensions of 10 or 20 days, respectively, and increases in GCase activity and protein levels in the brain and visceral tissues. Cerebral cortical GC and GS levels showed no significant reductions with IFG treatment. Increases of GC or GS levels were detected in the visceral tissues of IFG treated (600 mg/kg/day) mice. The attenuations of brain proinflammatory responses in the treated mice were evidenced by reductions in astrogliosis and microglial cell activation, and decreased p38 phosphorylation and TNFα levels. Terminally, axonal degeneration was present in the brain and spinal cord from untreated and treated 4L;C* mice. These data demonstrate that IFG exerts in vivo effects by enhancing V394L GCase protein and activity levels, and in mediating suppression of proinflammation, which led to delayed onset of neurological disease and extension of the life span of 4L;C* mice. However, this was not correlated with a reduction in the accumulation of lipid substrates.

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Section: Discussionmentioning

confidence: 99%

Isofagomine In Vivo Effects in a Neuronopathic Gaucher Disease Mouse

et al. 2011

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“…Although these ring alterations render iminosugars metabolically inert, their protonated forms mimic the pyranosyl or furanosyl unit in GH substrates, especially the putative oxocarbenium ion-like transition state (2, Fig. 2) in GH catalysed hydrolysis [21,169]. This in turn facilitates their recognizability by GHs and other carbohydrate-recognizing proteins for corresponding enzyme inhibition.…”

Section: Iminosugarsmentioning

confidence: 99%

“…10b), with promising antitumor potentials are siastatin B derivatives 57, 58 and 59 with IC 50 ¼ 65, 62 and 68 nM respectively [173]. Therefore, this section reviews iminosugars and their analogues as natural productinspired bGLU inhibitors, without undue repetitions of other monographs [4,21,168,169] covering them.…”

Section: Iminosugarsmentioning

confidence: 99%

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

Awolade

Cele

Kerru

et al. 2020

European Journal of Medicinal Chemistry

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BiomarkerEnzyme inhibition Molecular target Structure activity relationship a b s t r a c tThe emergence of disease and dearth of effective pharmacological agents on most therapeutic fronts, constitutes a major threat to global public health and man's existence. Consequently, this has created an exigency in the search for new drugs with improved clinical utility or means of potentiating available ones. To this end, accumulating empirical evidence supports molecular target therapy as a plausible egress and, b-glucuronidase (bGLU) e a lysosomal acid hydrolase responsible for the catalytic deconjugation of b-D-glucuronides has emerged as a viable molecular target for several therapeutic applications. The enzyme's activity level in body fluids is also deemed a potential biomarker for the diagnosis of some pathological conditions. Moreover, due to its role in colon carcinogenesis and certain drug-induced dose-limiting toxicities, the development of potent inhibitors of bGLU in human intestinal microbiota has aroused increased attention over the years. Nevertheless, although our literature survey revealed both natural products and synthetic scaffolds as potential inhibitors of the enzyme, only few of these have found clinical utility, albeit with moderate to poor pharmacokinetic profile. Hence, in this review we present a compendium of exploits in the present millennium directed towards the inhibition of bGLU. The aim is to proffer a platform on which new scaffolds can be modelled for improved bGLU inhibitory potency and the development of new therapeutic agents in consequential.

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“…Amide-protected substrate 5h was subjected to N−O cleavage by the use of stoichiometric amount of Cp 2 TiCl 2 [32], yielding gem-diamine iminosugar 32 in an efficient fashion (Scheme 16a). It should be noted that gem-diamine iminosugars represent an important class of glycomimetic compounds possessing biological activity [41]. In the same study, the formation of In fact, the use of Mo(CO) 6 at 75 • C in a mixture of CH 3 CN/H 2 O furnished the unexpected 4-hydroxytetrahydropyridine 34a and 34b.…”

Section: Elaboration Of Inverse Cycloadductsmentioning

confidence: 87%

Nitroso Diels-Alder Cycloadducts Derived From N-Acyl-1,2-dihydropyridines as a New Platform to Molecular Diversity

2020

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This review focuses upon the use of nitroso Diels–Alder reactions as a structural complexity generating reaction that has been so far a quite scarcely treated topic, despite its potential. In particular, the use of N-acyl-1,2-dihydropyridines as a non-symmetrical diene component in nitroso Diels–Alder reactions encompasses an initial diversification of pathways giving rise to different cycloadducts (direct and inverse). Selective elaborations of these cycloadducts, basically using a reagent-based approach, deliver a discrete number of structurally diverse compounds, including some original heterobicyclic scaffolds and functionalized heterocycles. This forward synthetic planning allowed the individuation of a new biologically active compound based on a novel oxadiaza-bicyclic-[3.3.1]-nonene scaffold which is still under preclinical evaluation.

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Gem-diamine 1-N-iminosugars as versatile glycomimetics: synthesis, biological activity and therapeutic potential

Cited by 29 publications

References 90 publications

Isofagomine In Vivo Effects in a Neuronopathic Gaucher Disease Mouse

Isofagomine In Vivo Effects in a Neuronopathic Gaucher Disease Mouse

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

Nitroso Diels-Alder Cycloadducts Derived From N-Acyl-1,2-dihydropyridines as a New Platform to Molecular Diversity

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