PE859
目录号 : GC30801
PE859是tau和Aβ积累的有效抑制剂，IC50值分别为0.66和1.2μM。
Cas No.:1402727-29-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Kinase experiment: | Tau aggregation is monitored using thioflavin T. The test compound (PE859), 10 μM 3RMBD and 10 μM heparin are dissolved in 50 mM Tris-HCl (pH7.6), and incubated at 37°C up to 144 hours. At each point of incubation time, 135 μL of the solutions are removed and mixed with 15 μL of 100 μM ThT solution (final concentration: 10 μM) and the fluorescence intensity with excitation at 440 nm and emission at 486 nm is measured[2]. |
Animal experiment: | Mice: PE859 is dissolved in 80% PEG400 and 20% water solution at 5 mg/mL, and orally-administered at a dose of 40 mg/kg/day for 6 months (from 9 to 15 months of age). The body weights of the mice are measured once a week during PE859 treatment[2]. |
References: [1]. Okuda M, et al. Design and synthesis of curcumin derivatives as tau and amyloid β dual aggregation inhibitors. Bioorg Med Chem Lett. 2016 Oct 15;26(20):5024-5028. | |
PE859 is a potent inhibitor of both tau and Aβ aggregation with IC50 values of 0.66 and 1.2 μM, respectively.
PE859 inhibits the heparin-induced aggregation of both 3RMBD and full length tau in a concentration-dependent manner. In each assay, the IC50 values calculated at the last measurement periods are 0.81 μM, and 2.23 μM, respectively. PE859 inhibits tau aggregation through formation of beta-sheet structure[2].
PE859 could cross the blood-brain barrier and that PE859 could be distributed into the tissues of the central nervous system. The maximum concentration of PE859 is 2.005 μg/mL in the blood at 3 h and 1.428 μg/g in the brain at 6 h. PE859 delays onset and progression of the motor dysfunction in JNPL3 mice. PE859 delays progression of the motor dysfunction through the inhibition of accumulation of sarkosyl-insoluble tau. [2]
[1]. Okuda M, et al. Design and synthesis of curcumin derivatives as tau and amyloid β dual aggregation inhibitors. Bioorg Med Chem Lett. 2016 Oct 15;26(20):5024-5028. [2]. Okuda M, et al. PE859, a novel tau aggregation inhibitor, reduces aggregated tau and prevents onset and progression of neural dysfunction in vivo. PLoS One. 2015 Feb 6;10(2):e0117511.
| Cas No. | 1402727-29-0 | SDF | |
| Canonical SMILES | COC1=CC(OCC2=NC=CC=C2)=CC=C1/C=C/C3=CC(/C=C/C4=CC5=C(C=C4)C=CN5)=NN3 | ||
| 分子式 | C28H24N4O2 | 分子量 | 448.52 |
| 溶解度 | DMSO : 50 mg/mL (111.48 mM);Water : < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.2296 mL | 11.1478 mL | 22.2955 mL |
| 5 mM | 0.4459 mL | 2.2296 mL | 4.4591 mL |
| 10 mM | 0.223 mL | 1.1148 mL | 2.2296 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
PE859, A Novel Curcumin Derivative, Inhibits Amyloid-β and Tau Aggregation, and Ameliorates Cognitive Dysfunction in Senescence-Accelerated Mouse Prone 8
Aggregation of amyloid-β (Aβ) and tau plays a crucial role in the onset and progression of Alzheimer's disease (AD). Therefore, the inhibition of Aβ and tau aggregation may represent a potential therapeutic target for AD. Herein, we designed and synthesized both Aβ and tau dual aggregation inhibitors based on the structure of curcumin and developed the novel curcumin derivative PE859. In this study, we investigated the inhibitory activity of PE859 on Aβ aggregationin vitro and the therapeutic effects of PE859 on cognitive dysfunction via dual inhibition of Aβ and tau aggregation in vivo. PE859 inhibited Aβ aggregation in vitro and protected cultured cells from Aβ-induced cytotoxicity. Furthermore, PE859 ameliorated cognitive dysfunction and reduced the amount of aggregated Aβ and tau in brains of senescence-accelerated mouse prone 8 (SAMP8). These results warrant consideration of PE859 as a candidate drug for AD.
PE859, a novel tau aggregation inhibitor, reduces aggregated tau and prevents onset and progression of neural dysfunction in vivo
In tauopathies, a neural microtubule-associated protein tau (MAPT) is abnormally aggregated and forms neurofibrillary tangle. Therefore, inhibition of the tau aggregation is one of the key approaches for the treatment of these diseases. Here, we have identified a novel tau aggregation inhibitor, PE859. An oral administration of PE859 resulted in the significant reduction of sarkosyl-insoluble aggregated tau along with the prevention of onset and progression of the motor dysfunction in JNPL3 P301L-mutated human tau transgenic mice. These results suggest that PE859 is useful for the treatment of tauopathies.
Curcumin Derivative GT863 Inhibits Amyloid-Beta Production via Inhibition of Protein N-Glycosylation
Amyloid-β (Aβ) peptides play a crucial role in the pathogenesis of Alzheimer's disease (AD). Aβ production, aggregation, and clearance are thought to be important therapeutic targets for AD. Curcumin has been known to have an anti-amyloidogenic effect on AD. In the present study, we performed screening analysis using a curcumin derivative library with the aim of finding derivatives effective in suppressing Aβ production with improved bioavailability of curcumin using CHO cells that stably express human amyloid-β precursor protein and using human neuroblastoma SH-SY5Y cells. We found that the curcumin derivative GT863/PE859, which has been shown to have an inhibitory effect on Aβ and tau aggregation in vivo, was more effective than curcumin itself in reducing Aβ secretion. We further found that GT863 inhibited neither β- nor γ-secretase activity, but did suppress γ-secretase-mediated cleavage in a substrate-dependent manner. We further found that GT863 suppressed N-linked glycosylation, including that of the γ-secretase subunit nicastrin. We also found that mannosidase inhibitors that block the mannose trimming step of N-glycosylation suppressed Aβ production in a similar fashion, as was observed as a result of treatment with GT863. Collectively, these results suggest that GT863 downregulates N-glycosylation, resulting in suppression of Aβ production without affecting secretase activity.
Design and synthesis of curcumin derivatives as tau and amyloid β dual aggregation inhibitors
Alzheimer's disease (AD) is the most common form of dementia. In an AD patient's brain, senile plaques and neurofibrillary tangles, the abnormal aggregates of amyloid β (Aβ) peptide and tau protein, are observed as the two major hallmarks of this disease. To develop a new drug for treatment of AD, we have designed and synthesized a series of curcumin derivatives and evaluated their inhibitory activities against both tau and Aβ aggregation. In this study, we describe the development of the more potent aggregation inhibitor 3-[(1E)-2-(1H-indol-6-yl)ethenyl]-5-[(1E)-2-[2-methoxy-4-(2-pyridylmethoxy) phenyl] ethenyl]-1H-pyrazole (compound 4, PE859). This compound has a better pharmacokinetic profile and pharmacological efficacy in vivo than curcumin, making it suitable as a drug for AD.