CDDO-Im (RTA-403)
(Synonyms: RTA-403; TP-235; CDDO-Imidazolide) 目录号 : GC32723
An activator of Nrf2 signaling
Cas No.:443104-02-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | CDDO-Im is dissolved in DMSO. SUM159 and MDA-MB-231 cells are seeded into each well of 96-well plates (1,000 cell/well) and treated the next day with vehicle control or CDDO-Im (1, 10, 50, 100 and 200 nM) for given incubation time. The absorbance is measured with a spectrophotometer to determine cell proliferation rate[3]. |
Animal experiment: | Mice: Mice are injected i.p. with thioglycollate, and the resulting resident peritoneal macrophages are activated 3 days later with an i.p. injection of IFN-γ. CDDO and CDDO-Im are injected i.p. 30 min after IFN-γ. Macrophages are harvested 10 h later, cultured for 12 h, and then assayed for expression of iNOS protein and production of nitric oxide (NO)[1]. |
References: [1]. Place AE, et al. The novel synthetic triterpenoid, CDDO-imidazolide, inhibits inflammatory response and tumor growth in vivo. Clin Cancer Res. 2003 Jul;9(7):2798-806. | |
CDDO-Im is a synthetic triterpenoid and an activator of Nrf2 signaling.1,2 It binds to Keap1, inhibiting the degradation of Nrf2 and leading to increased Nrf2 protein levels.2 CDDO-Im (100 nM) increases the expression of Nrf2 target genes and activates heme oxygenase-1 (HO-1) in a reporter assay using CV-1 cells.1 It also binds to PPARγ and PPARα (Kis = 344 and 232 nM, respectively) and induces PPARγ transactivation in SW480 cells.3,4 It inhibits the production of nitric oxide synthase (NOS) in isolated mouse macrophages (IC50 = 0.014 nM).5 CDDO-Im (300 nM) inhibits proliferation of U937 and MCF-7 cells and reduces fatty acid synthesis in LiSa-2 human liposarcoma cells when used at a concentration of 100 nM.3,6 It reduces tumor growth in a B16 murine melanoma model when administered at a dose of 50 ?g/animal twice per day.3
1.Liby, K., Hock, T., Yore, M.M., et al.The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signalingCancer Res.65(11)4789-4798(2005) 2.Meng, X., Waddington, J.C., Tailor, A., et al.CDDO-imidazolide targets multiple amino acid residues on the Nrf2 adaptor, Keap1J. Med. Chem.63(17)9965-9976(2020) 3.Place, A.E., Suh, N., Williams, C.R., et al.The novel synthetic triterpenoid, CDDO-imidazolide, inhibits inflammatory response and tumor growth in vivoClin. Cancer Res.9(7)2798-2806(2003) 4.Chintharlapalli, S., Papineni, S., Konopleva, M., et al.2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid and related compounds inhibit growth of colon cancer cells through peroxisome proliferator-activated receptor γ-dependent and -independent pathwaysMol. Pharmacol.68(1)119-128(2005) 5.Honda, T., Honda, Y., Favaloro, F.G., Jr., et al.A novel dicyanotriterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile, active at picomolar concentrations for inhibition of nitric oxide productionBioorg. Med. Chem. Lett.12(7)1027-1030(2002) 6.Hughes, D.T., Martel, P.M., Knlaw, W.B., et al.The synthetic triterpenoid CDDO-Im inhibits fatty acid synthase expression and has antiproliferative and proapoptotic effects in human liposarcoma cellsCancer Invest.26(2)118-127(2009)
| Cas No. | 443104-02-7 | SDF | |
| 别名 | RTA-403; TP-235; CDDO-Imidazolide | ||
| Canonical SMILES | CC(C)([C@]1([H])CC[C@@]([C@@]2(CC[C@]3(CCC(C)(C[C@@]3([H])[C@]24[H])C)C(N5C=CN=C5)=O)C)6C)C(C(C#N)=C[C@]1(C)C6=CC4=O)=O | ||
| 分子式 | C34H43N3O3 | 分子量 | 541.72 |
| 溶解度 | DMSO : 50 mg/mL (92.30 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 | 1.846 mL | 9.2299 mL | 18.4597 mL |
| 5 mM | 0.3692 mL | 1.846 mL | 3.6919 mL |
| 10 mM | 0.1846 mL | 0.923 mL | 1.846 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。
CDDO-Im ameliorates osteoarthritis and inhibits chondrocyte apoptosis in mice via enhancing Nrf2-dependent autophagy
Acta Pharmacol Sin 2022 Jul;43(7):1793-1802.PMID:PMC9253092DOI:10.1038/s41401-021-00782-6.
Osteoarthritis (OA) is the most prevalent chronic degenerative joint disease with few treatment options. The pathogenesis of OA is characterized by sustained inflammation, oxidative stress and chondrocyte apoptosis that eventually lead to cartilage degradation and joint dysfunction. In the present study, we identified a synthetic triterpenoid CDDO-Im(1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole) as an activator of Nrf2 (nuclear factor erythroid 2-related factor 2) that displayed strong anti-OA effects. We showed that CDDO-Im (20 nM) significantly alleviated TNF-α-induced apoptosis of primary human chondrocytes and extracellular matrix degradation. In a mouse OA model incurred by DMM (destabilization of medial meniscus), administration of CDDO-Im (2.5 mg/kg, ip, every other day for 8 weeks) effectively reduced knee joint cartilage erosion and serum levels of inflammatory cytokines IL-1β and IL-6. We revealed that CDDO-Im (20 nM) significantly enhanced autophagy activities in chondrocytes, whereas the autophagy inhibition by chloroquine (CQ, 50 μM) or 3-methyladenine (3-MA, 5 mM) abrogated the anti-apoptosis and chondroprotective effects of CDDO-Im in TNF-α-treated chondrocytes. Moreover, we confirmed that CDDO-Im (1-20 nM) dose-dependently activated Nrf2 pathway in TNF-α-treated chondrocytes, and its chondroprotective and autophagy-enhancing effects were significantly diminished when Nrf2 signaling was blocked by Nrf2 inhibitor ML385 (20 μM) or siRNA-mediated Nrf2 knockdown. Together, our results demonstrate that CDDO-Im exhibits prominent chondroprotective and anti-OA activities owing to its Nrf2 activation and autophagy-enhancing properties, which might provide new insights into the strategies of OA clinical prevention and treatment.
Glucoraphanin: a broccoli sprout extract that ameliorates obesity-induced inflammation and insulin resistance
Adipocyte 2018;7(3):218-225.PMID:29898626DOI:10.1080/21623945.2018.1474669.
Obesity is a low-grade sustained inflammatory state that causes oxidative stress in different metabolic tissues, which leads to insulin resistance and nonalcoholic fatty liver disease (NAFLD). Particularly, obesity-induced metabolic endotoxemia plays an important role in the pathogenesis of insulin resistance and inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of antioxidant signaling that serves as a primary cellular defense against the cytotoxic effects of oxidative stress. Pharmacological stimulation of Nrf2 mitigates obesity and insulin resistance in mice; however, Nrf2 activators are not clinically available due to biosafety concerns. A recent study demonstrated that glucoraphanin, a precursor of the Nrf2 activator sulforaphane, ameliorates obesity by enhancing energy expenditure and browning of white adipose tissue, and attenuates obesity-related inflammation and insulin resistance by polarizing M2 macrophages and reducing metabolic endotoxemia. Thus, this review focuses on the efficiency and safety of glucoraphanin in alleviating obesity, insulin resistance, and NAFLD. Abbreviations: ALT, Alanine aminotransferase; AMPK, AMP-activated protein kinase; ATMs, Adipose tissue macrophages; BAT, Brown adipose tissue; CDDO-Im, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid-imidazolide; CDDO-Me, CDDO-methyl ester; DIO, High-fat-diet-induced obese; FFA, Free fatty acid; FGF, Fibroblast growth factor; GTP, Glutamyl transpeptidase; HFD, High-fat diet; IKKβ, Inhibitor of κB-kinase β; IL, Interleukin; JNK, C-Jun N-terminal kinase; KD, Knockdown; Keap1, Kelch-like ECH-associated protein 1; KO, Knockout; LPS, Lipopolysaccharide; NADPH, Nicotinamide adenine dinucleotide phosphate; NAFLD, Non-alcoholic fatty liver disease; NF-κB, Nuclear factor-κB; Nrf2, Nuclear factor E2-related factor 2; ROS, Reactive oxygen species; T2D, Type 2 diabetes; TLR, Toll-like receptor; TNF, tumor necrosis factor; UCP, Uncoupling protein; WAT, White adipose tissue.
CDDO-Im is a stimulator of megakaryocytic differentiation
Leuk Res 2011 Apr;35(4):534-44.PMID:21035854DOI:10.1016/j.leukres.2010.09.013.
Although the triterpene CDDO and its potent derivatives, CDDO-Im and CDDO-Me, are now in phase I/II studies in the treatment of some pathological conditions, their effects on normal hematopoiesis are not known. In the present study we provide evidence that CDDO-Im exerts in vitro a potent inhibitory effect on erythroid cell proliferation and survival and a stimulatory action on megakaryocytic differentiation. The effect of CDDO-Im on erythroid and megakaryocytic differentiation was evaluated both on normal hemopoietic progenitor cells (HPCs) induced to selective erythroid (E) or megakaryocytic (Mk) differentiation and on erythroleukemic cell lines HEL and TF1. The inhibitory effect of CDDO-Im on erythroid cell survival and proliferation is mainly related to a reduced GATA-1 expression. This conclusion is supported by the observation that GATA-1 overexpressing TF1 cells are partially protected from the inhibitory effect of CDDO-Im on cell proliferation and survival. The stimulatory effect of CDDO-Im on normal megakaryopoiesis is seemingly related to upmodulation of GATA2 expression and induction of mitogen-activated protein kinases ERK1/2.
Triterpenoid CDDO-Im protects against lipopolysaccharide-induced inflammatory response and cytotoxicity in macrophages: The involvement of the NF-κB signaling pathway
Exp Biol Med (Maywood) 2022 Apr;247(8):683-690.PMID:35034476DOI:10.1177/15353702211066912.
Lipopolysaccharide (LPS), also known as endotoxin, can trigger septic shock, a severe form of inflammation-mediated sepsis with a very high mortality rate. However, the precise mechanisms underlying this endotoxin remain to be defined and detoxification of LPS is yet to be established. Macrophages, a type of immune cells, initiate a key response responsible for the cascade of events leading to the surge in inflammatory cytokines and immunopathology of septic shock. This study was undertaken to determine whether the LPS-induced inflammation in macrophage cells could be ameliorated via CDDO-Im (2-cyano-3,12 dioxooleana-1,9 dien-28-oyl imidazoline), a novel triterpenoid compound. Data from this study show that gene expression levels of inflammatory cytokine genes such as interleukin-1 beta (IL-1β), interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) were considerably increased by treatment with LPS in macrophages differentiated from ML-1 monocytes. Interestingly, LPS-induced increase in expression of pro-inflammatory cytokine levels is reduced by CDDO-Im. In addition, endogenous upregulation of a series of antioxidant molecules by CDDO-Im provided protection against LPS-induced cytotoxicity in macrophages. LPS-mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) transcriptional activity was also noted to decrease upon treatment with CDDO-Im in macrophages suggesting the involvement of the NF-κB signaling. This study would contribute to improve our understanding of the detoxification of endotoxin LPS by the triterpenoid CDDO-Im.
CDDO-Im exerts antidepressant-like effects via the Nrf2/ARE pathway in a rat model of post-stroke depression
Brain Res Bull 2021 Aug;173:74-81.PMID:33991607DOI:10.1016/j.brainresbull.2021.05.008.
Increasing evidence suggests that oxidative damage and neuroinflammation play a critical role in the pathogenesis of post-stroke depression (PSD). These pathologic processes are tightly regulated by the NF-E2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway. The synthetic triterpenoid, 2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im), is a potent Nrf2 activator. This study investigated whether CDDO-Im exhibited antidepressant-like activity and elucidated its protective mechanisms in a rat model of PSD, which was produced by middle cerebral artery occlusion (MCAO) followed by 28 days of chronic unpredictable mild stress (CUMS) in conjunction with solitary housing. The results demonstrated that CDDO-Im treatment markedly improved the depressive-like behaviors and reduced neuronal cell loss in the hippocampus, through decreasing the malondialdehyde (MDA) content (indicative of lipid peroxidation), superoxide dismutase (SOD), NF-kB activation, interleukin-6 (IL-6) and interleukin-1b (IL-1β) in PSD rats. CDDO-Im treatment alleviated the oxidative stress and inflammatory response in PSD rats by promoting Nrf2 nuclear import and increasing the protein levels of Nrf2 downstream target genes, including heme oxygenase-1(HOMX1) and, quinone oxidoreductase-1(NQO1).These findings suggested that CDDO-Im treatment exhibited antidepressant-like effects and protected PSD rats from oxidative and inflammatory injury via the Nrf2/ARE pathway. Therefore, CDDO-Im treatment is worthy of further study.