L6H21
目录号 : GC49560
An inhibitor of the MD-2 and TLR4 interaction
Cas No.:24533-47-9
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
L6H21 is an inhibitor of myeloid differentiation 2 (MD-2), also known as lymphocyte antigen 96 (LY96).1 It binds to MD-2 (Kd = 33.3 µM in a cell-free assay) and inhibits the protein-protein interaction between MD-2 and toll-like receptor 4 (TLR4) in LPS-stimulated ECV304 cells. L6H21 (10 µM) decreases the migration of LPS-stimulated HCT116 colon cancer cells.2 It inhibits LPS-induced increases in the production of TNF-α and IL-6 in mouse primary macrophages (IC50s = 6.17 and 7.72 µM, respectively), as well as increases survival in a mouse model of LPS-induced sepsis.1 L6H21 (40 mg/kg) increases cardiac levels of glutathione peroxidase 4 (GPX4) and decreases cardiac mitochondrial reactive oxygen species (ROS) in rats fed a high-fat diet.3
1.Wang, Y., Shan, X., Chen, G., et al.MD-2 as the target of a novel small molecule, L6H21, in the attenuation of LPS-induced inflammatory response and sepsisBr. J. Pharmacol.172(17)4391-4405(2015) 2.Rajamanickam, V., Yan, T., Xu, S., et al.Selective targeting of the TLR4 co-receptor, MD2, prevents colon cancer growth and lung metastasisInt. J. Biol. Sci.16(8)1288-1302(2020) 3.Sumneang, N., Oo, T.T., Singhanat, K., et al.Inhibition of myeloid differentiation factor 2 attenuates cardiometabolic impairments via reducing cardiac mitochondrial dysfunction, inflammation, apoptosis and ferroptosis in prediabetic ratsBiochem. Biophys. Acta Mol. Basis Dis1868(2)166301(2021)
| Cas No. | 24533-47-9 | SDF | Download SDF |
| Canonical SMILES | COC1=C(C=CC=C1OC)/C=C/C(C2=CC=C(C=C2)OC)=O | ||
| 分子式 | C18H18O4 | 分子量 | 298.3 |
| 溶解度 | DMF: 20 mg/ml,DMF:PBS (pH 7.2) (1:4): 0.20 mg/ml,DMSO: 5 mg/ml | 储存条件 | -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 | 3.3523 mL | 16.7616 mL | 33.5233 mL |
| 5 mM | 0.6705 mL | 3.3523 mL | 6.7047 mL |
| 10 mM | 0.3352 mL | 1.6762 mL | 3.3523 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。
L6H21 protects against cognitive impairment and brain pathologies via toll-like receptor 4-myeloid differentiation factor 2 signalling in prediabetic rats
Br J Pharmacol 2022 Mar;179(6):1220-1236.PMID:34796473DOI:10.1111/bph.15741.
Background and purpose: Chronic high-fat diet (HFD) intake instigates prediabetes and brain pathologies, which include cognitive decline and neuroinflammation. The myeloid differentiation factor 2 (MD-2)/toll-like receptor 4 (TLR4) complex plays a pivotal role in neuroinflammation. The MD-2 inhibitor (L6H21) reduces systemic inflammation and metabolic disturbances in HFD-induced prediabetes. However, the potential role of L6H21, and its comparison with metformin, on brain pathologies in HFD-induced prediabetes has never been investigated. Experimental approach: Male Wistar rats were given either a normal diet (ND) (n = 8) or a HFD (n = 104) for 16 weeks. At the 13th week, ND-fed rats were given a vehicle, whereas HFD-fed rats were randomly divided into 13 subgroups. Each subgroup was given vehicle, L6H21 (three doses) or metformin (300-mg·kg-1 ·day-1 ) for 1, 2 or 4 weeks. Metabolic parameters, cognitive function, brain mitochondrial function, brain TLR4-MD-2 signalling, microglial morphology, brain oxidative stress, brain cell death and dendritic spine density were investigated. Key results: HFD-fed rats developed prediabetes, neuroinflammation, brain pathologies and cognitive impairment. All doses of L6H21 and metformin given to HFD-fed rats at 2 and 4 weeks attenuated metabolic disturbance. Conclusion and implications: In rats, L6H21 and metformin restored cognition and attenuated brain pathologies dose and time-dependently. These results indicate a neuroprotective role of MD-2 inhibitor in a model of prediabetes.
L6H21 prolonged rats survival after limb allotransplantation by inhibiting acute rejection
Eur Rev Med Pharmacol Sci 2017 Apr;21(8):1891-1903.PMID:28485788doi
Objective: Preventing and reducing allograft rejection play a far more important role in limb allotransplantation. We previously found L6H21 could inhibit LPS-induced (lipopolysaccharide LPS) overexpression inflammatory factors in macrophages and specifically targets to MD-2 (myeloid differential protein-2 MD-2) required for TLR4 (Toll-like receptor 4 TLR4) activation and represented an important therapeutic target in inflammatory disorders. Therefore, we evaluated the effect and explored the mechanism of L6H21 in rats' limb allograft model. Materials and methods: The efficacy of L6H21 was evaluated in limb allograft rats and cyclosporine (CY-A) was used as a positive control agent. T-Lymphocyte in blood was analyzed and dendritic cells (DCs) separated from spleens using flow cytometry. ELISA was used to measure serum cytokine levels. Analysis of protein expressions was performed using Western blotting. Results: L6H21 reduced the risk of acute rejection and prolonged survival of limb allograft rats. At 3 d and 5 d post-transplant, the ratio of CD4+/CD8+ was decreased in L6H21 group. L6H21 suppressed the content of IL-1α at 7d, IL-5 and IL-10 at both 3 d and 7 d after transplantation. L6H21 decreased the protein expressions of IRF3, p-IRF3, P38, p-P38 and p-IκBα while increased IκBα expression and decreased the ratio of p-IRF3/ IRF3, p-P38/ P38, p-IκBα/IκBα correspondingly. Conclusions: L6H21 could reduce the risk of acute rejection and prolong the survival of limb allograft rats through inhibiting the ratio of CD4+/CD8+ in blood and serum cytokine levels and suppressing protein expressions of IRF3, p-IRF3, P38, p-P38 and p-IκBα in DCs. So, it may serve as a potential candidate for the treatment of allograft rejection.
Chalcone Derivative L6H21 Reduces EtOH + LPS-Induced Liver Injury Through Inhibition of NLRP3 Inflammasome Activation
Alcohol Clin Exp Res 2019 Aug;43(8):1662-1671.PMID:31162673DOI:10.1111/acer.14120.
Background: Chronic alcohol intake increases circulating endotoxin levels causing excessive inflammation that aggravates the liver injury. (E)-2,3-dimethoxy-4'-methoxychalcone (L6H21), a derivative of chalcone, has been found to inhibit inflammation in cardiac diseases and nonalcoholic fatty liver disease. However, the use of L6H21 in alcoholic liver disease to inhibit exotoxin-associated inflammation has not been explored. In this study, we examined the effects of L6H21 on EtOH + LPS-induced hepatic inflammation, steatosis, and liver injury and investigated the underlying mechanisms. Methods: C57BL6 mice were treated with 5% EtOH for 10 days, and LPS was given to the mice 6 hours before sacrificing. One group of mice was supplemented with L6H21 with EtOH and LPS. RAW264.7 cells were used to analyze the effects of L6H21 on macrophage activation. Results: EtOH + LPS treatment significantly increased hepatic steatosis and serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), which were reduced by L6H21 treatment. EtOH + LPS treatment increased hepatic inflammation, as shown by the increased hepatic protein levels of Toll-like receptor-4, p65, and p-IκB, and increased oxidative stress, as shown by protein carbonyl levels and reactive oxygen species formation, which were reduced by L6H21 treatment. In addition, L6H21 treatment markedly inhibited EtOH + LPS-elevated hepatic protein levels of NLRP3, cleaved caspase-1, cleaved IL-1β, and caspase-1-associated apoptosis. Conclusions: Our results demonstrate that L6H21 treatment inhibits EtOH + LPS-induced liver steatosis and injury through suppression of NLRP3 inflammasome activation. L6H21 may be used as an alternative strategy for ALD prevention/treatment.
MD-2 as the target of a novel small molecule, L6H21, in the attenuation of LPS-induced inflammatory response and sepsis
Br J Pharmacol 2015 Sep;172(17):4391-405.PMID:26076332DOI:10.1111/bph.13221.
Background and purpose: Myeloid differentiation 2 (MD-2) recognizes LPS, which is required for TLR4 activation, and represents an attractive therapeutic target for severe inflammatory disorders. We previously found that a chalcone derivative, L6H21, could inhibit LPS-induced overexpression of TNF-α and IL-6 in macrophages. Here, we performed a series of biochemical experiments to investigate whether L6H21 specifically targets MD-2 and inhibits the interaction and signalling transduction of LPS-TLR4/MD-2. Experimental approach: The binding affinity of L6H21 to MD-2 protein was analysed using computer docking, surface plasmon resonance analysis, elisa, fluorescence measurements and flow cytometric analysis. The effects of L6H21 on MAPK and NF-κB signalling were determined using EMSA, fluorescence staining, Western blotting and immunoprecipitation. The anti-inflammatory effects of L6H21 were confirmed using elisa and RT-qPCR in vitro. The anti-inflammatory effects of L6H21 were also evaluated in septic C57BL/6 mice. Key results: Compound L6H21 inserted into the hydrophobic region of the MD-2 pocket, forming hydrogen bonds with Arg(90) and Tyr(102) in the MD-2 pocket. In vitro, L6H21 subsequently suppressed MAPK phosphorylation, NF-κB activation and cytokine expression in macrophages stimulated by LPS. In vivo, L6H21 pretreatment improved survival, prevented lung injury, decreased serum and hepatic cytokine levels in mice subjected to LPS. In addition, mice with MD-2 gene knockout were universally protected from the effects of LPS-induced septic shock. Conclusions and implications: Overall, this work demonstrated that the new chalcone derivative, L6H21, is a potential candidate for the treatment of sepsis. More importantly, the data confirmed that MD-2 is an important therapeutic target for inflammatory disorders.
An anti-inflammatory chalcone derivative prevents heart and kidney from hyperlipidemia-induced injuries by attenuating inflammation
Toxicol Appl Pharmacol 2018 Jan 1;338:43-53.PMID:29128402DOI:10.1016/j.taap.2017.11.003.
Obesity is a growing pandemic in both developed and developing countries. Lipid overload in obesity generates a chronic, low-grade inflammation state. Increased inflammation in heart and renal tissues has been shown to promote the progression of heart and renal damage in obesity. Previously, we found that a novel chalcone derivative, L6H21, inhibited lipopolysaccharide-induced inflammatory response. In the present study, we investigated the effects of L6H21 on inflammatory responses in culture and in animal models of lipid overload. We utilized palmitic acid (PA) challenging in mouse peritoneal macrophages and apolipoprotein E knockout (ApoE-/-) mice fed a high fat diet (HFD) to study whether L6H21 mitigates the inflammatory response. Our studies show that L6H21 significantly reduced PA-induced expression of inflammatory cytokines in macrophages by inhibiting mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NFκB) signaling pathways. L6H21 also reduced fibrosis in the kidney and heart tissues, and indices of inflammatory response in the ApoE-/- mice fed a HFD. These effects in vivo were also associated with inhibition of MAPK and NFκB signaling by L6H21. These findings strongly suggest that L6H21 may be a potential agent for high fat diet-induced injuries in heart and kidney.