Isofagomine, a Potent, New Glycosidase Inhibitor

Jespersen, Tina M.; Dong, Wei; Sierks, Michael R.; Skrydstrup, Troels; Lundt, Inge; Bols, Mikael

doi:10.1002/anie.199417781

Cited by 169 publications

(65 citation statements)

References 24 publications

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“…[6][7][8] Deoxynojirimycin (1; Scheme 1), which is believed to exist as its conjugate acid and thus possess a positive charge at the position equivalent to the endocyclic oxygen, has served as the paradigm for glucosidase inhibition for many years. Bols and colleagues pioneered the synthesis of isofagomine (2), [9] which is also believed to be protonated in complex with enzyme and which introduces positive charge at the "anomeric carbon" position. The protonation state has been unequivocally demonstrated, with atomic resolution X-ray data, for the "cellobio-derived" form of 2 in complex with an endoglucanase.…”

mentioning

confidence: 99%

Dissection of Conformationally Restricted Inhibitors Binding to a β‐Glucosidase

2006

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mentioning

confidence: 99%

Dissection of Conformationally Restricted Inhibitors Binding to a β‐Glucosidase

2006

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“…Perhaps the best described examples are deoxynojirimycin 5 (reviewed in Ref. 20), and isofagomine 6 (synthesized by Bols and colleagues (21) and Ichikawa et al (22)). Tetrahydrooxazine 1, originally synthesized (racemically) in pioneering work by Bach and Bols (23) and later by Stick and co-workers (13), was conceived as a potentially better mimic of the oxocarbenium ion-like transition state as it incorporates the endocyclic oxygen that is absent from isofagomine 6.…”

Section: Resultsmentioning

confidence: 99%

Structural, Thermodynamic, and Kinetic Analyses of Tetrahydrooxazine-derived Inhibitors Bound to β-Glucosidases

Gloster

MacDonald

Tarling

et al. 2004

Journal of Biological Chemistry

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The understanding of transition state mimicry in glycoside hydrolysis is increasingly important both in the quest for novel specific therapeutic agents and for the deduction of enzyme function and mechanism. To aid comprehension, inhibitors can be characterized through kinetic, thermodynamic, and structural dissection to build an "inhibition profile." Here we dissect the binding of a tetrahydrooxazine inhibitor and its derivatives, which display K i values around 500 nM. X-ray structures with both a ␤-glucosidase, at 2 Å resolution, and an endoglucanase at atomic (ϳ1 Å) resolution reveal similar interactions between the tetrahydrooxazine inhibitor and both enzymes. Kinetic analyses reveal the pH dependence of k cat /K m and 1/K i with both enzyme systems, and isothermal titration calorimetry unveils the enthalpic and entropic contributions to ␤-glucosidase inhibition. The pH dependence of enzyme activity mirrored that of 1/K i in both enzymes, unlike the cases of isofagomine and 1-deoxynojirimycin that have been characterized previously. Calorimetric dissection reveals a large favorable enthalpy that is partially offset by an unfavorable entropy upon binding. In terms of the similar profile for the pH dependence of 1/K i and the pH dependence of k cat /K m , the significant enthalpy of binding when compared with other glycosidase inhibitors, and the tight binding at the optimal pH of the enzymes tested, tetrahydrooxazine and its derivatives are a significantly better class of glycosidase inhibitor than previously assumed.

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“…Later, it was verified that its in vivo activity was only moderate and produced side effects. 41 In 1994 isofagomine (27) was reported as a new potent β-glucosidase inhibitor 42 that mimics the transition state of glycoside cleavage in its protonated form. It is noteworthy that 27 has been described to inhibit β-glucosidase, glucoamylase, and isomaltase more strongly than 26.…”

Section: Alternative Sources Of Natural Products: a Hope For The Discmentioning

confidence: 99%

Tropical biodiversity: has it been a potential source of secondary metabolites useful for medicinal chemistry?

Valli¹,

Pivatto²,

Danuello³

et al. 2012

Quím. Nova

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Recebido em 22/5/12; aceito em 19/7/12; publicado na web em 26/10/12The use of natural products has definitely been the most successful strategy in the discovery of novel medicines. Secondary metabolites from terrestrial and marine organisms have found considerable use in the treatment of numerous diseases and have been considered lead molecules both in their natural form and as templates for medicinal chemistry. This paper seeks to show the great value of secondary metabolites and emphasize the rich chemical diversity of Brazilian biodiversity. This natural chemical library remains understudied, but can be a useful source of new secondary metabolites with potential application as templates for drug discovery.

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Isofagomine, a Potent, New Glycosidase Inhibitor

Cited by 169 publications

References 24 publications

Dissection of Conformationally Restricted Inhibitors Binding to a β‐Glucosidase

Dissection of Conformationally Restricted Inhibitors Binding to a β‐Glucosidase

Structural, Thermodynamic, and Kinetic Analyses of Tetrahydrooxazine-derived Inhibitors Bound to β-Glucosidases

Tropical biodiversity: has it been a potential source of secondary metabolites useful for medicinal chemistry?

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