Synthesis of the C8’-epimeric thymine pyranosyl amino acid core of amipurimycin

The C8’-epimeric pyranosyl amino acid core 2 of amipurimycin was synthesized from D-glucose derived alcohol 3 in 13 steps and 14% overall yield. Thus, the Sharpless asymmetric epoxidation of allyl alcohol 7 followed by trimethyl borate mediated regio-selective oxirane ring opening with azide, afforded azido diol 10. The acid-catalyzed 1,2-acetonide ring opening in 10 concomitantly led to the formation of the pyranose ring skeleton to give 2,7-dioxabicyclo[3.2.1]octane 12. Functional group manipulation in 12 gave 21 that on stereoselective β-glycosylation afforded the pyranosyl thymine nucleoside 2 – a core of amipurimycin

γ-Hydroxyethyl piperidine iminosugar and N-alkylated derivatives: A study of their activity as glycosidase inhibitors and as immunosuppressive agents

An efficient and practical strategy for the synthesis of (3R,4s,5S)-4-(2-hydroxyethyl) piperidine-3,4,5-triol and its N-alkyl derivatives 8a-f, starting from the d-glucose, is reported. The chiral pool methodology involves preparation of the C-3-allyl-α-d-ribofuranodialdose 10, which was converted to the C-5-amino derivative 11 by reductive amination. The presence of C-3-allyl group gives an easy access to the requisite hydroxyethyl substituted compound 13. Intramolecular reductive aminocyclization of C-5 amino group with C-1 aldehyde provided the γ-hydroxyethyl substituted piperidine iminosugar 8a that was N-alkylated to get N-alkyl derivatives 8b-f. Iminosugars 8a-f were screened against glycosidase enzymes. Amongst synthetic N-alkylated iminosugars, 8b and 8c were found to be α-galactosidase inhibitors while 8d and 8e were selective and moderate α-mannosidase inhibitors. In addition, immunomodulatory activity of compounds 8a-f was examined. These results were substantiated by molecular docking studies using AUTODOCK 4.2 programme.publisher: Elsevier articletitle: γ-Hydroxyethyl piperidine iminosugar and N-alkylated derivatives: A study of their activity as glycosidase inhibitors and as immunosuppressive agents journaltitle: Bioorganic & Medicinal Chemistry articlelink: http://dx.doi.org/10.1016/j.bmc.2014.09.034 content_type: article copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.status: publishe

Diosgenin from <i>Dioscorea bulbifera</i>: Novel Hit for Treatment of Type II Diabetes Mellitus with Inhibitory Activity against α-Amylase and α-Glucosidase

<div><p>Diabetes mellitus is a multifactorial metabolic disease characterized by post-prandial hyperglycemia (PPHG). α-amylase and α-glucosidase inhibitors aim to explore novel therapeutic agents. Herein we report the promises of <i>Dioscorea bulbifera</i> and its bioactive principle, diosgenin as novel α-amylase and α-glucosidase inhibitor. Among petroleum ether, ethyl acetate, methanol and 70% ethanol (v/v) extracts of bulbs of <i>D. bulbifera</i>, ethyl acetate extract showed highest inhibition upto 72.06 ± 0.51% and 82.64 ± 2.32% against α-amylase and α-glucosidase respectively. GC-TOF-MS analysis of ethyl acetate extract indicated presence of high diosgenin content. Diosgenin was isolated and identified by FTIR, ¹H NMR and ¹³C NMR and confirmed by HPLC which showed an α-amylase and α-glucosidase inhibition upto 70.94 ± 1.24% and 81.71 ± 3.39%, respectively. Kinetic studies confirmed the uncompetitive mode of binding of diosgenin to α-amylase indicated by lowering of both Km and Vm. Interaction studies revealed the quenching of intrinsic fluorescence of α-amylase in presence of diosgenin. Similarly, circular dichroism spectrometry showed diminished negative humped peaks at 208 nm and 222 nm. Molecular docking indicated hydrogen bonding between carboxyl group of Asp300, while hydrophobic interactions between Tyr62, Trp58, Trp59, Val163, His305 and Gln63 residues of α-amylase. Diosgenin interacted with two catalytic residues (Asp352 and Glu411) from α-glucosidase. This is the first report of its kind that provides an intense scientific rationale for use of diosgenin as novel drug candidate for type II diabetes mellitus.</p></div

Percent crude murine pancreatic amylase inhibition by plant extracts and isolated compound D.

<p>Acarbose is taken as standard inhibitor. The data is indicated as the mean SEM; [<i>n</i>  =  3].</p

Synthesis of 1,5-Dideoxy-1,5-iminoribitol <i>C</i>‑Glycosides through a Nitrone–Olefin Cycloaddition Domino Strategy: Identification of Pharmacological Chaperones of Mutant Human Lysosomal β‑Galactosidase

We report herein a newly developed domino reaction that facilitates the synthesis of new 1,5-dideoxy-1,5-iminoribitol iminosugar <i>C</i>-glycosides <b>7a</b>–<b>e</b> and <b>8</b>. The key intermediate in this approach is a six-membered cyclic sugar nitrone that is generated in situ and trapped by an alkene dipolarophile via a [2 + 3] cycloaddition reaction to give the corresponding isooxazolidines <b>10a</b>–<b>e</b> in a “one-pot” protocol. The iminoribitol <i>C</i>-glycosides <b>7a</b>–<b>e</b> and <b>8</b> were found to be modest β-galactosidase (bGal) inhibitors. However, compounds <b>7c</b> and <b>7e</b> showed “pharmacological chaperone” activity for mutant lysosomal bGal activity and facilitated its recovery in GM1 gangliosidosis patient fibroblasts by 2–6-fold

Percent <i>α</i>-amylase inhibition by plant extracts and isolated compound D.

<p>Acarbose is taken as standard inhibitor. The data is indicated as the mean SEM; [<i>n</i>  =  3].</p

Kinetic analysis of porcine pancreatic α-amylase inhibition by isolated compound D by Lineweaver–Burk plot with starch as substrate.

<p>Kinetic analysis of porcine pancreatic α-amylase inhibition by isolated compound D by Lineweaver–Burk plot with starch as substrate.</p

Quenching of intrinsic fluorescence of porcine pancreatic α-amylase bound to isolated compound D.

<p>Quenching of intrinsic fluorescence of porcine pancreatic α-amylase bound to isolated compound D.</p

CD spectra of porcine pancreatic α-amylase bound with isolated compound D.

<p>CD spectra of porcine pancreatic α-amylase bound with isolated compound D.</p

Binding of diosgenin to α-glucosidase active pocket.

<p>(a) Depicts docked conformation of diosgenin with yeast alpha glucosidase (3AXI.pdb), (b) hydrogen bonding and hydrophobic interactions from alpha glucosidase-diosgenin inhibitor complex.</p