Succinobucol (AGI-1067)
(Synonyms: AGI-1067; Probucol monosuccinate) 目录号 : GC31709
A probucol derivative with diverse biological activities
Cas No.:216167-82-7
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
Cell experiment: | The cytotoxicity of Succinobucol is determined in the metastatic 4T1 breast cancer cells. Cells are added to 96-well plates at 6×103 cells/well and cultured overnight. Then, Succinobucol, SCB and the PCD polymer (equivalent concentration to SCB) are respectively added to each well with SCB concentrations ranging from 4 ng/mL to 40 μg/mL. Cells without any treatment are performed as negative control. Thereafter, cells are incubated for further 48 h, and the cell viability is measured by MTT assay method. |
Animal experiment: | Mice are injected with 2×105 4T1-luc cells per mouse to generate the lung metastatic breast cancer model. After the inoculation, mice are divided into three groups (n=4), and respectively treated with saline, SCB solution and Succinobucol (40 mg/kg) by tail injection every three days. At day 12, the formation of lung metastasis is determined by in vivo bioluminescence measurements. Then, mice are autopsied and the lung tissues are removed. In each lung tissue, the visually detected metastatic nodules are counted. The inhibition of lung metastasis is calculated as the average metastatic nodules in Succinobucol or SCB group compared to that in saline group. Moreover, the histological examination is performed by H&E staining to detect the metastatic foci in the lungs. |
References: [1]. Houston SA, et al. An investigation of the antiplatelet effects of succinobucol (AGI-1067). Platelets. 2017 May;28(3):295-300. | |
Succinobucol is a metabolically stable derivative of probucol with diverse biological activities.1,2,3 It inhibits hydrogen peroxide-induced oxidation of the redox-sensitive dye H2DCF in human pulmonary artery endothelial cells (HPAECs) and U937 cells when used at concentrations of 5 and 10 ?M.1 Succinobucol (0.3-10 ?M) reduces LPS-induced production of IL-6, IL-1β, and TNF-α in peripheral blood mononuclear cells (PBMCs). It suppresses TNF-α-induced vascular cell adhesion molecule 1 (VCAM-1) promoter reporter gene expression in human aortic endothelial cells.2 Succinobucol (50 and 100 mg/kg) lowers plasma LDL levels and increases HDL levels in hypercholesterolemic cynomolgus monkeys.3 It also inhibits the formation of aortic atherosclerotic plaques in ApoE-/- or Ldlr-/- mice.
1.Kunsch, C., Luchoomun, J., Grey, J.Y., et al.Selective inhibition of endothelial and monocyte redox-sensitive genes by AGI-1067: a novel antioxidant and anti-inflammatory agentJ. Pharmacol. Exp. Ther.308(3)820-829(2004) 2.Wasserman, M.A., Sundell, C.L., Kunsch, C., et al.Chemistry and pharmacology of vascular protectants: a novel approach to the treatment of atherosclerosis and coronary artery diseaseAm. J. Cardiol.91(3A)34A-40A(2003) 3.Sundell, C.L., Somers, P.K., Meng, C.Q., et al.AGI-1067: a multifunctional phenolic antioxidant, lipid modulator, anti-inflammatory and antiatherosclerotic agentJ. Pharmacol. Exp. Ther.305(3)1116-1123(2003)
| Cas No. | 216167-82-7 | SDF | |
| 别名 | AGI-1067; Probucol monosuccinate | ||
| Canonical SMILES | CC(C)(C)C1=CC(SC(C)(C)SC2=CC(C(C)(C)C)=C(OC(CCC(O)=O)=O)C(C(C)(C)C)=C2)=CC(C(C)(C)C)=C1O | ||
| 分子式 | C35H52O5S2 | 分子量 | 616.91 |
| 溶解度 | DMSO : ≥ 100 mg/mL (162.10 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 | 1.621 mL | 8.1049 mL | 16.2098 mL |
| 5 mM | 0.3242 mL | 1.621 mL | 3.242 mL |
| 10 mM | 0.1621 mL | 0.8105 mL | 1.621 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。
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An investigation of the antiplatelet effects of succinobucol (AGI-1067)
Succinobucol is a phenolic antioxidant with anti-inflammatory and antiplatelet effects. Given the importance of oxidant stress in modulating platelet-platelet and platelet-vessel wall interactions, the aim of this study was to establish if antioxidant activity was responsible for the antiplatelet activity of succinobucol. Platelet aggregation in response to collagen and adenosine diphosphate (ADP) was studied in rabbit whole blood and platelet-rich plasma using impedance aggregometry. The effect of oxidant stress on aggregation, platelet lipid peroxides, and vascular tone was studied by incubating platelets, washed platelets or preconstricted rabbit iliac artery rings respectively with a combination of xanthine and xanthine oxidase (X/XO). To study the effect of succinobucol in vivo, anaesthetized rats were injected with up to 150 mg/kg succinobucol and aggregation measured in blood removed 15 mins later. Succinobucol (10-5-10-4 M) significantly attenuated platelet aggregation to collagen and ADP in whole blood and platelet-rich plasma. X/XO significantly increased aggregation to collagen and platelet lipid peroxides and this was reversed by succinobucol. Addition of X/XO to denuded rabbit iliac arteries caused a dose-dependent relaxation which was significantly inhibited by succinobucol. In vivo administration up to 150 mg/kg had no effect on heart rate or mean arterial blood pressure but significantly inhibited platelet aggregation to collagen ex vivo. In conclusion, succinobucol displays anti-platelet activity in rabbit and rat blood and reverses the increase in platelet aggregation in response to oxidant stress.
Effects of the antioxidant succinobucol (AGI-1067) on human atherosclerosis in a randomized clinical trial
Background: The antioxidant AGI-1067 was shown to reduce experimental atherosclerosis. The present study originally intended to study restenosis as a primary endpoint but was subsequently modified to primarily investigate the effects of AGI-1067 on coronary atherosclerosis.
Methods and results: This placebo-controlled randomized trial assessed the effects of AGI-1067 280 mg qd started before percutaneous coronary intervention (PCI) and administered for 12 months after PCI on atherosclerosis progression as assessed by coronary intravascular ultrasound (IVUS). Among patients with IVUS examinations considered technically adequate both at baseline and follow-up upon central laboratory assessments (n=232), plaque volume was not significantly modified with placebo (least squares mean change: -0.4mm(3), P=0.85 versus baseline), but was significantly reduced by -4.0mm(3) at end of treatment in the AGI-1067 group (P=0.001 versus baseline, P=0.12 versus placebo). LDL-cholesterol varied by -9% and +4% in the placebo and AGI-1067 groups, respectively (P<0.05 between groups), and HDL-cholesterol was reduced by 1% with placebo and 14% with AGI-1067 (P<0.05 between groups). Plasma myeloperoxidase was reduced by 6% with AGI-1067 (P<0.05) but hs-CRP was not significantly different between groups.
Conclusions: Atherosclerosis regression (-4.0mm(3)) was observed in patients treated with AGI-1067, although this was not significantly different from placebo. The anti-inflammatory effect of AGI-1067 is supported by reduced levels of myeloperoxidase.
Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial
Background: Oxidative stress and inflammation are involved in the pathophysiology of atherosclerosis. Our aim was to assess the effects of the antioxidant succinobucol (AGI-1067) on cardiovascular outcomes in patients with recent acute coronary syndromes already managed with conventional treatments.
Methods: After an acute coronary syndrome occurring 14-365 days before recruitment, 6144 patients were randomly assigned with a computer-generated randomisation list, stratified by study site, to receive succinobucol (n=3078) or placebo (n=3066) in addition to standard of care. Enrolment began in July, 2003; this event-driven trial was stopped in August, 2006, after the prespecified number of primary outcome events had occurred. The composite primary endpoint was time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, unstable angina, or coronary revascularisation. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00066898.
Findings: All randomised patients were included in the efficacy analyses. Succinobucol had no effect on the primary endpoint (530 events in succinobucol group vs 529 in placebo group; hazard ratio 1.00, 95% CI 0.89-1.13, p=0.96). The composite secondary endpoint of cardiovascular death, cardiac arrest, myocardial infarction, or stroke occurred in fewer patients in the succinobucol group than in the placebo group (207 vs 252 events; 0.81, 0.68-0.98, p=0.029). The tertiary endpoint of new-onset diabetes developed in fewer patients without diabetes at baseline in the succinobucol group than in such patients in the placebo group (30 of 1923 vs 82 of 1950 patients; 0.37, 0.24-0.56, p<0.0001). New-onset atrial fibrillation occurred more often in the succinobucol group than in the placebo group (107 of 2818 vs 55 of 2787 patients; 1.87, 1.67-2.09, p=0.0002). Although the number of patients who reported any treatment emergent adverse event was much the same in the two groups, more patients in the succinobucol group than in the placebo group reported bleeding episodes or anaemia (32 vs 18 and 37 vs ten, respectively) as serious adverse events. Relative to treatment with placebo, succinobucol increased LDL cholesterol and systolic blood pressure, and decreased HDL cholesterol and glycated haemoglobin (p<0.0001 for all).
Interpretation: Although succinobucol had no effect on the primary endpoint, changes in the rates of other clinical outcomes-both beneficial and harmful-will need to be further assessed before succinobucol is used in patients with atherosclerosis or as an antidiabetic agent.
AGI-1067, a novel antioxidant and anti-inflammatory agent, enhances insulin release and protects mouse islets
The antioxidant and anti-inflammatory compound AGI-1067 (succinobucol) has potential as an oral anti-diabetic agent. AGI-1067 reduces H(b)A1c, improves fasting plasma glucose, and reduces new-onset diabetes. We investigated AGI-1067 for possible effects on mouse pancreatic islets in vitro. Pretreatment with 10 microM AGI-1067 increased glucose-stimulated insulin secretion (11 mM) without affecting secretion in basal (3 mM) glucose. AGI-1067 enhanced the intracellular calcium response to glucose stimulation in 7 mM and 11 mM glucose, but had no effect in 28 mM or basal glucose. AGI-1067-pretreated islets also showed enhanced calcium responses to methyl pyruvate and alpha-ketoisocaproate at low doses, but not high doses. The AGI-1067-mediated effects on glucose-stimulated calcium were maintained during continuous diazoxide exposure, suggesting effects on the K(ATP)-channel-independent pathway. AGI-1067 also reduced cytokine-induced islet cell death and expression of iNOS, a key component in cytokine signaling. This is the first report of direct stimulatory and protective effects of a first-in-class potential anti-diabetic agent on pancreatic islets.
AGI-1067, a novel vascular protectant, anti-inflammatory drug and mild antiplatelet agent for treatment of atherosclerosis
Oxidation-sensitive signals play an important role in platelet activation. AGI-1067 is a novel, phenolic, intra- and extracellular antioxidant that inhibits the expression of a number of proinflammatory genes involved in atherosclerosis. AGI-1067 is the metabolically stable monosuccinic acid ester of probucol, and a potent phenolic antioxidant representing a novel class of orally bioavailable compounds termed vascular protectants. AGI-1067 exhibits antioxidant activity equipotent to probucol. In addition, animal studies have demonstrated dual pharmacological activities of AGI-1067: the ability to block the expression of oxidation-sensitive inflammatory genes including genes that code for vascular cell adhesion molecule-1 and monocyte chemotactic protein-1. Importantly, AGI-1067 also exhibits mild antiplatelet properties inhibiting surface expression of various key platelet receptors, the formation of platelet monocyte microparticles and PAR-1 thrombin receptors. AGI-1067 is currently being tested in the late trials, and if proven to improve clinical outcomes (ARISE trial), the drug will ultimately be used in patients with different manifestations of atherosclerosis and atherothrombosis.