Docking and SAR studies of D- and L-isofagomine isomers as human β-glucocerebrosidase inhibitors
Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan.Bioorganic & medicinal chemistry (Impact Factor: 2.79). 06/2011; 19(11):3558–3568. DOI: 10.1016/j.bmc.2011.04.011
We report the structure–activity relationship of a series of D-, and L-isofagomine and fagomine isomers as glycosidase inhibitors. Our study revealed that a positive charge at the anomeric position of d-isofagomines enhanced the potency toward β-glycosidases, while the epimerization at the C3 OH group drastically reduced their inhibitory potency by over three orders of magnitude. Furthermore, D-3,4-di-epi-isofagomine abolished their inhibition activities against all enzymes. L-Isofagomine was also a fairly potent inhibitor of human β-glucocerebrosidase, with an IC50 value of 8.7 μM. A molecular docking study revealed that the positions and orientations of the piperidine ring of D-3-epi-isofagomine in the binding site was similar to that of D-isofagomine, while D-3-epi-isofagomine missed the hydrogen bond interactions between Asp127 and the 3-OH group and between Trp179 and the 3-OH group. Furthermore, the top 10 docking models ranked by IFDscore suggested that D-3,4-di-epi-isofagomine can not bind to β-glucocerebrosidase at a stable interaction mode. These results provide an insight into the structural requirements of isofagomine isomers for developing a new type of pharmacological chaperone for Gaucher disease.
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ABSTRACT: Examining advances in the class of natural and non-natural piperidine azasugars, important therapeutic agents and potent glycosidaseinhibitors, this review looks at syntheses applying olefinmetathesis as a highly efficient key step and gateway strategy for discovery of better iminosugar leads for treatment of widespread affections like viral and metabolic diseases. Amply illustrated is how ring-closing metathesis (RCM and RCEYM), promoted by commercial ruthenium alkylidene catalysts, manage to construct the common tetrahydropyridine core while cross-metathesis (CM), starting from this generic scaffold, provides general access to families of novel azasugars. Special consideration is given to high-profile iminosugardrugs of this class (1-deoxynojirimycin and congeners, adenophorine, fagomine, isofagomine and some of their N- and C-substituted analogues) stressing upon newest trends for enhancing biological activity and modulating previously unexploited targets in multispecific therapies.
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ABSTRACT: The racemic and enantiodivergent syntheses of 1-deoxymannojirimycin (DMJ) and 1,4-dideoxymannojirimycin have been realized through key enamide ester intermediates obtained by converting cis-4,5-dihydroxylated δ-valerolactam derivatives into the corresponding enol phosphates and subjecting them to Pd-catalyzed methoxycarbonylation. Further elaborations of these intermediates included stereocontrolled catalytic hydrogenation, for the synthesis of racemic 1,4-dideoxymannojirimycin, and hydroboration/oxidation, for the synthesis of DMJ. Enantiodivergency was attained by optical resolution before exhaustive functional group deprotection, through the formation of diastereomeric camphanic esters. As the key racemic intermediate esters were easily prepared in a few steps on a large scale, and the final chromatographic separation of the camphanic esters was straightforward, this approach represents a convenient way to obtain both enantiomers of DMJ for medicinal chemistry studies.
Article: Chiral Synthesis of Iminosugars[Show abstract] [Hide abstract]
ABSTRACT: An chiral synthesis of iminosugars such as fagomine, 1-deoxynojirimycine, and isofagomine together with their stereoisomers are described.
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