Inflachromene
(Synonyms: 炎性色素,ICM) 目录号 : GC40924An anti-inflammatory HMGB inhibitor
Cas No.:908568-01-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >95.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Inflachromene is an anti-inflammatory agent that directly binds high mobility group protein 1 (HMGB1) and HMGB2 and reduces their cytoplasmic accumulation in microglial cells.[1] It is functional in vivo, downregulating proinflammatory functions of HMGB proteins and reducing neuronal damage. Inflachromene also ameliorates inflammatory pathogenesis in a mouse model of sepsis.[2]
Reference:
[1]. Lee, S., Nam, Y., Koo, J.Y., et al. A small molecule binding HMGB1 and HMGB2 inhibits microglia-mediated neuroinflammation. Nat. Chem. Biol. 10(12), 1055-1060 (2014).
[2]. Cho, W., Koo, J.Y., Park, Y., et al. Treatment of sepsis pathogenesis with high mobility group box protein 1-regulating anti-inflammatory agents. J. Med. Chem. 60(1), 170-179 (2017).
| Cas No. | 908568-01-4 | SDF | |
| 别名 | 炎性色素,ICM | ||
| 化学名 | 5,12b-dihydro-10-hydroxy-7,7-dimethyl-2-phenyl-1H,7H-[1]benzopyrano[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione | ||
| Canonical SMILES | OC1=CC(OC(C)(C)C2=CCN(C(N(C3=CC=CC=C3)C4=O)=O)N4C25)=C5C=C1 | ||
| 分子式 | C21H19N3O4 | 分子量 | 377.4 |
| 溶解度 | 2.5mg/mL in ethanol, 30mg/mL in DMSO, or in DMF | 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 | 2.6497 mL | 13.2485 mL | 26.4971 mL |
| 5 mM | 0.5299 mL | 2.6497 mL | 5.2994 mL |
| 10 mM | 0.265 mL | 1.3249 mL | 2.6497 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。
FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome
Nat Cell Biol 2020 Jun;22(6):728-739.PMID:32367049DOI:10.1038/s41556-020-0511-2.
The crosstalk between deregulated hepatocyte metabolism and cells within the tumour microenvironment, as well as the consequent effects on liver tumorigenesis, are not completely understood. We show here that hepatocyte-specific loss of the gluconeogenic enzyme fructose 1,6-bisphosphatase 1 (FBP1) disrupts liver metabolic homeostasis and promotes tumour progression. FBP1 is universally silenced in both human and murine liver tumours. Hepatocyte-specific Fbp1 deletion results in steatosis, concomitant with activation and senescence of hepatic stellate cells (HSCs), exhibiting a senescence-associated secretory phenotype. Depleting senescent HSCs by 'senolytic' treatment with dasatinib/quercetin or ABT-263 inhibits tumour progression. We further demonstrate that FBP1-deficient hepatocytes promote HSC activation by releasing HMGB1; blocking its release with the small molecule Inflachromene limits FBP1-dependent HSC activation, the subsequent development of the senescence-associated secretory phenotype and tumour progression. Collectively, these findings provide genetic evidence for FBP1 as a metabolic tumour suppressor in liver cancer and establish a critical crosstalk between hepatocyte metabolism and HSC senescence that promotes tumour growth.
Inflachromene inhibits autophagy through modulation of Beclin 1 activity
J Cell Sci 2018 Feb 20;131(4):jcs211201.PMID:29361549DOI:10.1242/jcs.211201.
Autophagy is a central intracellular catabolic mechanism that mediates the degradation of cytoplasmic proteins and organelles, and regulation of autophagy is essential for homeostasis. HMGB1 is an important sepsis mediator when secreted and also functions as an inducer of autophagy by binding to Beclin 1. In this study, we studied the effect of Inflachromene (ICM), a novel HMGB1 secretion inhibitor, on autophagy. ICM inhibited autophagy by inhibiting nucleocytoplasmic translocation of HMGB1 and by increasing Beclin 1 ubiquitylation for degradation by enhancing the interaction between Beclin 1 and E3 ubiquitin ligase RNF216. These data suggest that ICM could be used as a potential autophagy suppressor.
Inflachromene inhibits intimal hyperplasia through the HMGB1/2- regulated TLR4-NF-κB pathway
Int Immunopharmacol 2023 Apr 21;119:110198.PMID:37087872DOI:10.1016/j.intimp.2023.110198.
The contractile-syntheticphenotypicconversion of vascular smooth muscle cells (VSMCs) plays a key role in atherosclerosis, vascular restenosis, and hypertension. Our previous study explored the correlation between high mobility group box protein (HMGB) 1 and HMGB2 and neointimal hyperplasia after vascular injury. In the present study, we explore whether Inflachromene (ICM), a novel inhibitor of the expression of both HMGB1 and HMGB2, modulates phenotypic changes in VSMCs and the mechanisms involved. Mice treated with ICM after carotid artery wire injury showed a decrease in excessive neointimal hyperplasia compared with that in the vehicle groups. In cultured VSMCs, pretreatment with ICM suppressed the angiotensin II (Ang II)-induced phenotypic conversion, proliferation, and migration. We discovered that ICM reduced the Ang II-induced upregulation of the expression of HMGB1 and HMGB2 and inhibited their shuttling between the nucleus and the cytosol. Mechanistically, Ang II-treated VSMCs exhibited higher levels of Toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) phosphorylation, which were attenuated by ICM. In addition, the NF-κB inhibitor Bay-117082 abolished the recombinant HMGB1-mediated VSMC phenotypic conversion, proliferation, and migration. Furthermore, ICM ameliorated the Ang II-induced increases in NAD[P]H oxidase expression, thereby attenuating the Ang II-induced proliferation and migration. These results reveal that ICM pretreatment attenuates Ang II-induced VSMC dedifferentiation, proliferation, and migration may by regulating the TLR4-NF-kB pathway. Thus, ICM is a potential therapy and preventive treatment for vascular proliferative diseases.
Inflachromene attenuates seizure severity in mouse epilepsy models via inhibiting HMGB1 translocation
Acta Pharmacol Sin 2023 Apr 19.PMID:37076634DOI:10.1038/s41401-023-01087-6.
Epilepsy is not well controlled by current anti-seizure drugs (ASDs). High mobility group box 1 (HMGB1) is a DNA-binding protein in the nucleus regulating transcriptional activity and maintaining chromatin structure and DNA repair. In epileptic brains, HMGB1 is released by activated glia and neurons, interacting with various receptors like Toll-like receptor 4 (TLR4) and downstream glutamatergic NMDA receptor, thus enhancing neural excitability. But there is a lack of small-molecule drugs targeting the HMGB1-related pathways. In this study we evaluated the therapeutic potential of Inflachromene (ICM), an HMGB-targeting small-molecule inhibitor, in mouse epilepsy models. Pentylenetetrazol-, kainic acid- and kindling-induced epilepsy models were established in mice. The mice were pre-treated with ICM (3, 10 mg/kg, i.p.). We showed that ICM pretreatment significantly reduced the severity of epileptic seizures in all the three epilepsy models. ICM (10 mg/kg) exerted the most apparent anti-seizure effect in kainic acid-induced epileptic status (SE) model. By immunohistochemical analysis of brain sections from kainic acid-induced SE mice, we found that kainic acid greatly enhanced HMGB1 translocation in the hippocampus, which was attenuated by ICM pretreatment in subregion- and cell type-dependent manners. Notably, in CA1 region, the seizure focus, ICM pretreatment mainly inhibited HMGB1 translocation in microglia. Furthermore, the anti-seizure effect of ICM was related to HMGB1 targeting, as pre-injection of anti-HMGB1 monoclonal antibody (5 mg/kg, i.p.) blocked the seizure-suppressing effect of ICM in kainic acid-induced SE model. In addition, ICM pretreatment significantly alleviated pyramidal neuronal loss and granule cell dispersion in kainic acid-induced SE model. These results demonstrate that ICM is an HMGB-targeting small molecule with anti-seizure potential, which may help develop a potential drug for treating epilepsy.
A validated UPLC-MS/MS method for pharmacokinetic study of Inflachromene, a novel microglia inhibitor
J Pharm Biomed Anal 2019 Mar 20;166:183-188.PMID:30654206DOI:10.1016/j.jpba.2019.01.013.
Inflachromene (ICM), a novel microglia inhibitor, is under development to treat neuroinflammatory disorders. For the pharmacokinetic evaluation of ICM, we developed quantitative ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method in rat plasma. Protein precipitation method with acetonitrile (ACN) was used for plasma sample preparation. The analyte and carbamazepine (the internal standard) were separated by the chromatography on an ACQUITY UPLC™ BEH C18 column running gradient mobile phase system made up of 0.1% [v/v] formic acid in water and 0.1% [v/v] formic acid in acetonitrile. For the quantification of ICM, the ion transitions, m/z 378.2→187.1 (ICM) and m/z 237.1→194.1 (IS) were monitored in multiple reaction monitoring (MRM) mode. Standard calibration curve showed excellent linearity with the correlation coefficient (R2) of 0.99 within the concentration range of 0.05-10 μg/mL. The precision and accuracy were within acceptable limits (all < 20%). ICM was degraded time and temperature dependently in rat plasma. The analytical method was successfully utilized in a pharmacokinetic study following intravenous and oral administration of ICM in rats.