(1S,2S,3R,6R)‐6‐Aminocyclohex‐4‐ene‐1,2,3‐triol (= (−)‐Conduramine B‐1) Is a Selective Inhibitor of α‐Mannosidases. Its Inhibitory Activity Is Enhanced by N‐Benzylation
ABSTRACT (−)- and (+)-Conduramine B-1 ((−)- and (+)-5, resp.) have been derived from (+)- and (−)-7-oxabicyclo[2.2.1]hept-5-en-2-one (‘naked sugars’ of the first generation). Although (−)-5 imitates the structure of β-glucosides, it does not inhibit β-glucosidases but inhibits α-mannosidases selectively. N-Benzylation of (−)-5 improves the potency of conduramine B-1 as α-mannosidase inhibitor and also generates compounds inhibiting β-glucosidases. For instance, (−)-N-benzyl-conduramine B-1 ((−)-19a) is a competitive inhibitor of β-glucosidase from almonds (IC50 = 32 μM, Ki = 10 μM) and a weak inhibitor of α-mannosidases from jack bean (IC50 = 171 μM) and from almonds (IC50 = 225 μM) whereas (−)-N-(4-phenylbenzyl)conduramine B-1 ((−)-19g) is a good inhibitor of α-mannosidase from jack beans (IC50 = 29 μM, Ki = 4.8 μM) and a weaker inhibitor of β-glucosidase from almonds (IC50 = 32 μM, Ki = 7.8 μM) (Table 1).
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ABSTRACT: We synthesized a galactose derivative, N-octyl-4-epi-beta-valienamine (NOEV), for a molecular therapy (chemical chaperone therapy) of a human neurogenetic disease, beta-galactosidosis (GM1-gangliosidosis and Morquio B disease). It is a potent inhibitor of lysosomal beta-galactosidase in vitro. Addition of NOEV in the culture medium restored mutant enzyme activity in cultured human or murine fibroblasts at low intracellular concentrations, resulting in a marked decrease of intracellular substrate storage. Short-term oral administration of NOEV to a model mouse of juvenile GM1-gangliosidosis, expressing a mutant enzyme protein R201C, resulted in significant enhancement of the enzyme activity in the brain and other tissues. Immunohistochemical stain revealed a decrease in the amount of GM1 and GA1 in neuronal cells in the fronto-temporal cerebral cortex and brainstem. However, mass biochemical analysis did not show the substrate reduction observed histochemically in these limited areas in the brain probably because of the brief duration of this investigation. Chemical chaperone therapy may be useful for certain patients with beta-galactosidosis and potentially other lysosomal storage diseases with central nervous system involvement.Proceedings of the National Academy of Sciences 01/2004; 100(26):15912-7. · 9.74 Impact Factor
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ABSTRACT: Swainsonine, an indolizidine alkaloid, was initially used in biomedical research as a tool to investigate the biosynthesis and function of asparagine-linked 'complex' type oligosaccharide moieties of glycoproteins. Recently, swainsonine has generated interest in its potential use as an anticancer agent with reports that it (i) inhibits tumor growth and metastasis, (ii) augments natural killer (NK) and macrophage-mediated tumor cell killing, and (iii) stimulates bone marrow cell proliferation. The antineoplastic activity of swainsonine can be explained at least in part by augmentation of immune effector mechanisms. The potential application of swainsonine as an anticancer agent is discussed.Pharmacology [?] Therapeutics 02/1991; 50(3):285-90. · 7.79 Impact Factor
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ABSTRACT: 1,4-Dideoxy-1,4-imino-D-mannitol (1), synthesised from benzyl α-D-mannopyranoside, is a potent competitive inhibitor of the hydrolysis of p-nitrophenyl α-D-mannopyranoside catalysed by Jack Bean α-mannosidase (Cnavalia ensiformis); this is the first report of the specific inhibition of a glycosidase by a pyrrolidine analogue of a furanose sugar.Journal of the Chemical Society Chemical Communications 01/1984;