Synthesis and enzyme inhibition study of unnatural saturated and unsaturated C-alkyl pyrrolidine iminosugars from d-mannose derived nitrone

Das, Pintu; Kundooru, Somireddy; Pandole, Ravikant; Sharma, Sandeep; Singh, B. N.; Shaw, Arun K.

doi:10.1016/j.tetasy.2015.12.003

Cited by 8 publications

(1 citation statement)

References 62 publications

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“…The C-2-extended, hydroxymethyl, and aminomethyl derivatives were also obtained from 6 via diastereoselective nucleophilic addition of Grignard reagents (Scheme a). − C-2-extended molecules were prepared from 6 via its allylation, followed by reduction of the hydroxylamine, and t -butyl carbamate formation to give alkene 9 . Hydroboration/oxidation of alkene 9 gave hydroxypropyl pyrrolidine 10 after acidic deprotection.…”

Section: Resultsmentioning

confidence: 99%

Mechanistic Insights into Dibasic Iminosugars as pH-Selective Pharmacological Chaperones to Stabilize Human α-Galactosidase

Li,

Lin,

Chang

et al. 2024

JACS Au

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The use of pharmacological chaperones (PCs) to stabilize specific enzymes and impart a therapeutic benefit is an emerging strategy in drug discovery. However, designing molecules that can bind optimally to their targets at physiological pH remains a major challenge. Our previous study found that dibasic polyhydroxylated pyrrolidine 5 exhibited superior pH-selective inhibitory activity and chaperoning activity for human α-galactosidase A (α-Gal A) compared with its monobasic parent molecule, 4. To further investigate the role of different C-2 moieties on the pH-selectivity and protecting effects of these compounds, we designed and synthesized a library of monobasic and dibasic iminosugars, screened them for α-Gal A-stabilizing activity using thermal shift and heatinduced denaturation assays, and characterized the mechanistic basis for this stabilization using X-ray crystallography and binding assays. We noted that the dibasic iminosugars 5 and 20 protect α-Gal A from denaturation and inactivation at lower concentrations than monobasic or other N-substituted derivatives; a finding attributed to the nitrogen on the C-2 methylene of 5 and 20, which forms the bifurcated salt bridges (BSBs) with two carboxyl residues, E203 and D231. Additionally, the formation of BSBs at pH 7.0 and the electrostatic repulsion between the vicinal ammonium cations of dibasic iminosugars at pH 4.5 are responsible for their pH-selective binding to α-Gal A. Moreover, compounds 5 and 20 demonstrated promising results in improving enzyme replacement therapy and exhibited significant chaperoning effects in Fabry cells. These findings suggest amino-iminosugars 5 and 20 as useful models to demonstrate how an additional exocyclic amino group can improve their pH-selectivity and protecting effects, providing new insights for the design of pH-selective PCs.

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Section: Resultsmentioning

confidence: 99%

Mechanistic Insights into Dibasic Iminosugars as pH-Selective Pharmacological Chaperones to Stabilize Human α-Galactosidase

Li,

Lin,

Chang

et al. 2024

JACS Au

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Reversal of Stereoselectivity in Cycloadditions of Five‐Membered Cyclic Nitrones Derived from Hexoses

et al. 2017

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Two five‐membered cyclic nitrones derived from hexoses, a newly synthesized d‐allo‐configured nitrone and an already known d‐talo‐configured nitrone, have been examined in 1,3‐dipolar cycloaddition reactions with vinyl acetate, allyl benzoate, methyl acrylate, acrylonitrile, and vinylene carbonate. The reactions of the d‐allo‐configured nitrone proceeded preferentially through the expected exo‐anti transition state, but all the cycloadditions of the d‐talo‐configured nitrone surprisingly showed high exo‐syn selectivity. This reversal of stereoselectivity has been explained by 3D analysis of the preferred conformations of the nitrones, obtained from X‐ray data. The structures were further inspected using CONFLEX, PM5, and DFT calculations. All these methods revealed that the dioxolane substituents attached to C‐5 of both nitrones had opposite spatial locations.

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Synthesis and glycosidase inhibition potency of all- trans substituted 1- C -perfluoroalkyl iminosugars

Massicot

Plantier‐Royon

Vasse

et al. 2018

Carbohydrate Research

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Synthesis and enzyme inhibition study of unnatural saturated and unsaturated C-alkyl pyrrolidine iminosugars from d-mannose derived nitrone

Cited by 8 publications

References 62 publications

Mechanistic Insights into Dibasic Iminosugars as pH-Selective Pharmacological Chaperones to Stabilize Human α-Galactosidase

Mechanistic Insights into Dibasic Iminosugars as pH-Selective Pharmacological Chaperones to Stabilize Human α-Galactosidase

Reversal of Stereoselectivity in Cycloadditions of Five‐Membered Cyclic Nitrones Derived from Hexoses

Synthesis and glycosidase inhibition potency of all- trans substituted 1- C -perfluoroalkyl iminosugars

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