Conduritol B epoxide

An irreversible inhibitor of glucocerebrosidase

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5mg

￥400.00

320.00

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1230.00

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货号: ajci20358
CAS: 6090-95-5
别名: 1,2-脱水肌醇,CBE
分子式: C6H10O5
分子量: 162.1
纯度: >98%
溶解度: ≤25mg/ml in DMSO;10mg/ml in dimethyl formamide
储存: Store at -20°C
库存: 现货

Background

IC50: 9 μM

Conduritol B epoxide is a β-glucosidase inhibitor.

β-glucosidase catalyzes the hydrolysis of the glycosidic bond to terminal non-reducing residues in β-D-glucosides and oligosaccharides, with release of glucose.

In vitro: Conduritol B epoxide was identifies as an active-site-directed inhibitor of some glucosidases. The inactivation of α-glucosidase from Monascus ruber by conduritol B epoxide was found to be irreversible and first-order with respect to time and inhibitor concentration. The inactivation could be prevented in the presence of maltose [1].

In vivo: The time course of the distribution of [3H]conduritol B epoxide was determined in various organs of mice, which had received a single i.p. dose. Results showd that the epoxide was rapidly distributed over all tissues except brain, indicating that the epoxide could pass the blood/brain barrier only with difficulty. A 4-fold enrichment was observed in the kidney. [3H]conduritol B epoxide was excreted with a half-life of about 7 h. A parallel determination of beta-glucosidase activity in the tissues showed greater than 90% inhibition within 1 and 2 h and a beginning recovery between 4 and 12 h. The only exception was brain, where no effects could be found after 1 h and a subsequent decrease to 37% of normal was seen after 12 h [2].

Clinical trial: So far, no clinical study has been conducted.

参考文献:
[1] Yang SJ, Ge SG, Zeng YC, Zhang SZ.? Inactivation of alpha-glucosidase by the active-site-directed inhibitor, conduritol B epoxide. Biochim Biophys Acta. 1985 Apr 29;828(3):236-40.
[2] Stephens MC, Bernatsky A, Singh H, Kanfer JN, Legler G.? Distribution of conduritol B epoxide in the animal model for Gaucher's disease (Gaucher mouse). Biochim Biophys Acta. 1981 Jan 7;672(1):29-32.

Protocol

Kinase experiment:

Cells are homogenized in 1% sodium taurocholate/1% Triton X-100. GCase activity is determined fluorometrically using 4MU-Glucose as the substrate in 0.25% sodium taurocholate, 0.25% Triton X-100 and 0.1M citric-phosphate buffer (pH 5.6). Brain tissues are homogenized in 1X PBS and incubated in 5 μM brain phosphatidylserine and 0.1M citric-phosphate buffer (pH 5.6) for GCase activity assay using 4MU-Glucose as substrate. Protein concentrations are determined by BCA assay using BSA as standard.

Animal experiment:

Gba1 point mutated 4L, 9H and 9V mice or WT mice are intraperitoneally injected with 100 mg/kg/day of Conduritol B epoxide. In short-term experiments, daily injections are initiated at postnatal day 5 and continued for 6 daily doses. The mice are sacrificed on day 12 or 2 months after last injection. In long-term experiments, 4L mice are injected daily beginning at postnatal day 15 for 24 or 36 daily doses and sacrificed the day after last injection. Mice are perfused with PBS and organs are harvested for enzyme activity, lipid and histological analyses.

参考文献:

[1]. Liou B, et al. Modulating ryanodine receptors with dantrolene attenuates neuronopathic phenotype in Gaucher disease mice. Hum Mol Genet. 2016 Sep 20. pii: ddw322. [Epub ahead of print]
[2]. YH Xu, et al. Accumulation and distribution of α-synuclein and ubiquitin in the CNS of Gaucher disease mouse models. Mol Genet Metab. Author manuscript; available in PMC 2012 Apr 1