Thiamet G

Names

[ Name ]:
Thiamet G

[Synonym ]:
Thiamet G
Thiamet G0nDiscontinued
(3aR,5R,6S,7R,7aR)-2-(Ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol
5H-Pyrano[3,2-d]thiazole-6,7-diol, 2-(ethylamino)-3a,6,7,7a-tetrahydro-5-(hydroxymethyl)-, (3aR,5R,6S,7R,7aR)-

Biological Activity

[Description]:

Thiamet-G is a potent and selective inhibitor of OGA, which acts to remove O-GlcNAc from modified proteins, with Ki of 20 nM for human OGA.

[Related Catalog]:

Signaling Pathways >> Autophagy >> Autophagy

Research Areas >> Cancer

[Target]

Ki: 20 nM (Human OGA)[1]

[In Vitro]

Thiamet G (1 μM) induces a clear increase in the accumulation of O-GlcNAcylated proteins of ATDC5 cells. O-GlcNAc accumulation induced by Thiamet G also evokes a clear increase in the activity of these MMPs. Thiamet G (1 μM) induces the phosphorylation of JNK, ERK, and p38 but not phosphorylation of Akt[2]. Thiamet G (0.1-10 μM) does not significantly affect the cell viability. Thiamet G decreases phosphorylation of tau and alters the microtubule dynamics[3].

[In Vivo]

Thiamet G (500 mg/kg/d) increases global and tau O-GlcNAc and reduces neurodegeneration. Thiamet G-treated group has 1.4-fold more motor neurons and hinders tau-driven neurodegeneration within this transgenic model. Thiamet G treatment therefore has no detectable effect on mice lacking the P301L transgene, indicating that prevention of neurodegeneration and weight loss is mediated by Thiamet G treatment only in the context of the P301L transgene. In Thiamet G-treated mice, the O-GlcNAc increases in the brain and spinal cord tissues[1]. Thiamet G (20 mg/kg, i.p.) increases O-GlcNAc levels in brain, liver, and knee of the C57BL/6 mice in a dose-dependent manner[2].

[Kinase Assay]

All enzymatic assays are performed in triplicate at 37°C using 4-methylumbelliferyl N-acetyl-β-d-glucosaminide dehydrate as substrate. 1 nM of purified OGA is incubated with the compounds for 5 min, and then 0.2 mM of the substrate is added. The liberation of 4-methylumbellifery is monitored by kinetic reading at excitation/emission 355/460 nm using a Tecan M200 plate in a mode of 60 s/cycle and 15 cycles in total.

[Cell Assay]

Jurkat cells are seeded at 6000 cells/well in a 96-well plate, and 12 h later, cells are treated with compounds for the indicated time. Cell viability is determined by XTT assay.

[Animal admin]

For the Thiamet G dose dependence study, six 23-day-old male C57BL/6 mice receive single intraperitoneal injections of either 0, 10, 20, 100, 200, or 500 mg/kg of Thiamet G dissolved in phosphate-buffered saline (PBS) and then are euthanized 8 h later to evaluate the O-GlcNAc levels in different tissues (brain, liver, muscle, and knee). The time of sacrifice is chosen on the basis of previously published data on Thiamet G in rodents, which demonstrates that the peak level of O-GlcNAc proteins following administration of the drug is achieved after 8-10 h. Tissues are collected immediately after sacrifice, flash-frozen in liquid nitrogen, and stored at −80°C until required for use.

[References]

[1]. Yuzwa SA, et al. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol. 2012 Feb 26;8(4):393-9.

[2]. Andrés-Bergós J, et al. The increase in O-linked N-acetylglucosamine protein modification stimulates chondrogenic differentiation both in vitro and in vivo. J Biol Chem. 2012 Sep 28;287(40):33615-28.

[3]. Ding N, et al. Thiamet-G-mediated inhibition of O-GlcNAcase sensitizes human leukemia cells to microtubule-stabilizing agent paclitaxel. Biochem Biophys Res Commun. 2014 Oct 24;453(3):392-7.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.8±0.1 g/cm3

[ Boiling Point ]:
483.2±55.0 °C at 760 mmHg

[ Molecular Formula ]:
C₉H₁₆N₂O₄S

[ Molecular Weight ]:
248.299

[ Flash Point ]:
246.0±31.5 °C

[ Exact Mass ]:
248.083084

[ PSA ]:
119.61000

[ LogP ]:
-0.09

[ Vapour Pressure ]:
0.0±2.8 mmHg at 25°C

[ Index of Refraction ]:
1.729

[ Storage condition ]:
-20℃

MSDS

Click to get detail MSDS

Safety Information

[ Symbol ]:

GHS07

[ Signal Word ]:
Warning

[ Hazard Statements ]:
H317

[ RIDADR ]:
NONH for all modes of transport

Articles

Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice.

Molecular Neurodegeneration 9 , 42, (2014)

Amyloid plaques and neurofibrillary tangles (NFTs) are the defining pathological hallmarks of Alzheimer's disease (AD). Increasing the quantity of the O-linked N-acetylglucosamine (O-GlcNAc) post-tran...

Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation.

Nat. Chem. Biol. 8(4) , 393-9, (2012)

Oligomerization of tau is a key process contributing to the progressive death of neurons in Alzheimer's disease. Tau is modified by O-linked N-acetylglucosamine (O-GlcNAc), and O-GlcNAc can influence ...

A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo.

.PubMed ID

Pathological hyperphosphorylation of the microtubule-associated protein tau is characteristic of Alzheimer's disease (AD) and the associated tauopathies. The reciprocal relationship between phosphoryl...

Related Compounds

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