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Biocatalyzed Synthesis of Antidiabetic Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Focusing on antidiabetic activity, Miglitol (Glyset™, Fig. 11.40, 117) is a commercial drug used for treating non-insulin dependent diabetes; the chemoenzymatic preparation of the carbohydrate core of this compound, 1-deoxynojirimycin 108 was reported in the late 1970s (Kinast and Schedel, 1978a; Kinast and Schedel, 1978b; Kinast and Schedel, 1981; Kinast et al., 1981), via a regioselective oxidation of the hydroxyl group at C-5 of N-CBz-1-amino-1-deoxysorbitol 115 using whole cells from Gluconobacter oxydans. More recently, a very similar procedure using the same microorganism, but starting from N-2-hydroxyethylglucamine 118 has been described (Zhang et al., 2011a). Considering the use of pure enzymes instead of whole cells, investigation of 1-deoxynojirimycin biosynthesis has led to the identification of Bacillus amyloliquefaciens genes gabT1, yktC1, and gutB1 as part of the overall azasugar biosynthetic pathway (Chen et al., 2007; Clark et al., 2011). These three genes, respectively, encode for transaminase, phosphatase and dehydrogenase activity, and based on these studies, very recently Wu et al. (Wu et al., 2014) have cloned zinc-dependent medium-chain NAD-dependent dehydrogenases from Bacillus amyloliquefaciens FZB42, Bacillus atrophaeus 1942, and Paenibacillus polymyxa SC2 and expressed them in BL21(DE3) Escherichia coli, describing the use of purified enzymes for producing nojirimycin and mannojyrimicin through a similar regioselective oxidation. Some chemoenzymatic synthesis of 1-deoxynojirimycin 108 and analogues via regioselective biooxidations.
sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Manuel González-Cuesta, Irene Herrera-González, M. Isabel García-Moreno, Roger A. Ashmus, David J. Vocadlo, José M. García Fernández, Eiji Nanba, Katsumi Higaki, Carmen Ortiz Mellet
We and others have previously shown that replacing the amine-type endocyclic nitrogen atom in iminosugar frameworks by a pseudoamide-type nitrogen (sp2-iminosugars) represents a versatile strategy to achieve highly selective glycosidase ligands for fundamental studies on enzyme mechanisms40–43 and drug discovery, with applications ranging from cancer44–46 and inflammation47 to antiparasitic agents48. sp2-iminosugars are very well adapted to molecular diversity schemes, including modifications in the configurational pattern, the heterocycle framework and the nature of substituents49–53. Their outstanding chemical flexibility is ideally suited for structure-activity relationship studies, which has allowed optimising candidates capable of restoring the correct folding and trafficking of several LSD-causative mutant glycosidases. Current examples include β-glucocerebrosidase (e.g. 5 N,6O-[N’-octyliminomethylidene]nojirimycin; NOI-NJ)54–56, α-galactosidase (e.g. N-[N’-p-flurophenythiocarbamoyl]-1-deoxygalactonojirimycin; pFPhT-DGJ)57,58, β-galactosidase (e.g. 5 N,6S-[N’-butyliminomethylidene]-1-deoxy-6-thiogalactonojirimycin; 6S-NBI-DGJ)59,60, and α-mannosidase (e.g. 6-[tert-butoxycarbonylamino]hexyl 5 N,6O-[oxamethylidene]mannonojirimycin-1-yl amine; BocNHex-N-OMJ)61 in fibroblasts from patients suffering of Gaucher disease, Fabry disease, GM1 gangliosidosis and α-mannosidosis, respectively (Figure 1). Most interestingly, amphiphilic sp2-iminosugars exhibited very favourable chaperoning/inhibitory balances in patient-derived neurons54 and were shown to cross the blood-brain barrier in a murine model60, supporting their potential to prevent or slow neurological decline. Devising sp2-iminosugars with strong affinity and selectivity towards HexA represents, thus, an appealing tactic towards a PC therapy option for TSD62,63 (Figure 2). To probe this hypothesis, we have now synthesised a series of monocyclic and bicyclic GalNAc mimetics belonging to the sp2-iminosugar family bearing varying substituents, determined the inhibitory profile against different glycosidases and evaluated the hexosaminidase-enhancing capabilities in fibroblasts from healthy donors and TSD patients. The results provide a proof of concept of the potential of sp2-iminosugar-based PCs for the treatment of the late-onset form of TSD disease.