CORM-401
目录号 : GC34893
CORM-401 含有锰 (Mn) 作为金属中心，CORM-401 可以释放 CO。
Cas No.:1001015-18-4
Sample solution is provided at 25 µL, 10mM.
Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Quantification of CO release using a myoglobin assay [1]: | |
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Preparation method |
1 mL horse heart myoglobin solution prepared in phosphate buffered saline at the desired final concentration was transferred to a cuvette and converted to deoxymyoglobin (deoxyMb) by addition of granular sodium dithionite. A deoxyMb spectrum (500 600 nm) was recorded and then a 2-fold excess of CORM-3 was added to the cuvette to obtain a maximum carbonmonoxy-myoglobin (MbCO) spectrum (saturated MbCO). In a separate cuvette, the release of CO from CORM-401 was then measured by adding the compound to the deoxyMb solution overlaid with olive oil to prevent loss of CO or diffusion of atmospheric oxygen back into the solution. Samples were scanned immediately after addition of the compounds and at consecutive time-points to monitor the formation of MbCO. Experiments were conducted either by: (1) using CORM-401 at a final concentration of 10 μM and varying the concentration of myoglobin (25, 50 and 100 μM) or (2) testing the release of CORM-401 at 5, 10 or 20 μM after addition to a fixed concentration of myoglobin (100 μM). |
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Applications |
CO released by CORM-401 increases with the amount of Mb used in the assay. |
| Cell experiment [1]: | |
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Cell lines |
EA.hy926 endothelial cells |
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Preparation Method |
To assess the amount of CO delivered by CO-RMs intracellularly, EA.hy926 endothelial cells in DPBS (+Ca2+, +Mg2+) were treated with 20 μM CORM-401 or iCORM-401, CORM-3 or CORM-A1 for 15 min at 37 °C followed by 30 min incubation with 1 μM COP-1. The intracellular fluorescence, indicative of CO accumulation in cells, was quantified using a CyAn ADP LX7 Analyzer. |
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Reaction Conditions |
20 μM CORM-401 for 15 min at 37 °C |
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Applications |
COP-1 loaded EA.hy926 endothelial cells displayed increased levels of intracellular CO after exposure to 20 μM CORM-401. |
| Animal experiment [2]: | |
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Animal models |
Eight-week-old male C57BL6 mice weighing approximately 25 g |
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Preparation Method |
Determined the levels of blood carbonmonoxy hemoglobin (COHb) in mice receiving CORM-401 at 2 different doses after oral gavage. |
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Dosage form |
CORM-401 15 mg/kg and 30 mg/kg, given orally 3 times a week. |
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Applications |
Oral administration of CORM-401 reduces body weight gain and improves insulin resistance in HFD-induced obesity in mice. |
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References: [1]. Fayad-Kobeissi S, Ratovonantenaina J, et,al. Vascular and angiogenic activities of CORM-401, an oxidant-sensitive CO-releasing molecule. Biochem Pharmacol. 2016 Feb 15;102:64-77. doi: 10.1016/j.bcp.2015.12.014. Epub 2015 Dec 22. PMID: 26721585. [2]. Braud L, Pini M, et,al. Carbon monoxide-induced metabolic switch in adipocytes improves insulin resistance in obese mice. JCI Insight. 2018 Nov 15;3(22):e123485. doi: 10.1172/jci.insight.123485. PMID: 30429365; PMCID: PMC6302946. |
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CORM-401 contains manganese (Mn) as a metal center, CORM-401 can release CO[1].
When 20 μM CORM-401 was added to a PBS solution containing 100 μM Mb, the formation of MbCO can be detected. By calculating the concentration of MbCO over time and by performing curve fitting, it was established that the half-lives of CO release were 14.1, 13.4 and 11.9 min for 5, 10 and 20 μM CORM-401, respectively. The amount of CO released from the compound diminishes as the ratio of CORM-401/Mb increases[2].
After exposure to 20 μM CORM-401 loaded EA.hy926 endothelial cells displayed increased levels of intracellular CO[2]. Upon CORM-401 exposure EROD activity of recombinant Cytochrome P450-dependent monooxygenases (CYP) decreased concentration dependently. Treatment with CORM-401 decreased EROD activity in HepG2 cells at concentrations higher than 50 μM CORM-401 [4]. CORM-401 partially reduced TNF-α/CHX-induced total cellular ROS,and reduced the effect of antimycin-A[5]. CORM-401 (10-100μM) induced a persistent increase in the oxygen consumption rate (OCR) that was accompanied by inhibition of glycolysis (extracellular acidification rate, ECAR) and a decrease in ATP-turnover. Furthermore, CORM-401 increased proton leak, diminished mitochondrial reserve capacity and enhanced non-mitochondrial respiration[6]. CORM-401 caused an apparent suppression of NO production through inhibition of iNOS at both the mRNA and protein levels in RAW264.7 cells stimulated with P. intermedia LPS. CORM-401 upregulated the expression of both the HO-1 gene and its protein in LPS-activated cells, and treatment with the HO-1 inhibitor significantly reversed the attenuating influence of CORM-401 against LPS-induced generation of NO[7].
Oral administration of CORM-401 reduces body weight gain and improves insulin resistance in HFD-induced obesity in mice.The transient uncoupling activity of CO elicited by repetitive administration of CORM-401 is associated with lower weight gain and increased insulin sensitivity during HFD[3].
References:
[1]. Crook SH, Mann BE, et,al. [Mn(CO)4{S2CNMe(CH2CO2H)}], a new water-soluble CO-releasing molecule. Dalton Trans. 2011 Apr 28;40(16):4230-5. doi: 10.1039/c1dt10125k. Epub 2011 Mar 14. PMID: 21403944.
[2]. Fayad-Kobeissi S, Ratovonantenaina J, et,al.Vascular and angiogenic activities of CORM-401, an oxidant-sensitive CO-releasing molecule. Biochem Pharmacol. 2016 Feb 15;102:64-77. doi: 10.1016/j.bcp.2015.12.014. Epub 2015 Dec 22. PMID: 26721585.
[3]. Braud L, Pini M, et,al.Carbon monoxide-induced metabolic switch in adipocytes improves insulin resistance in obese mice. JCI Insight. 2018 Nov 15;3(22):e123485. doi: 10.1172/jci.insight.123485. PMID: 30429365; PMCID: PMC6302946.
[4]. Walter M, Stahl W, et,al. Carbon monoxide releasing molecule 401 (CORM-401) modulates phase I metabolism of xenobiotics. Toxicol In Vitro. 2019 Sep;59:215-220. doi: 10.1016/j.tiv.2019.04.018. Epub 2019 Apr 17. PMID: 31004742.
[5]. Babu D, Leclercq G, et,al.Differential Effects of CORM-2 and CORM-401 in Murine Intestinal Epithelial MODE-K Cells under Oxidative Stress. Front Pharmacol. 2017 Feb 8;8:31. doi: 10.3389/fphar.2017.00031. PMID: 28228725; PMCID: PMC5296622.
[6]. Kaczara P, Motterlini R, et,al.Carbon monoxide released by CORM-401 uncouples mitochondrial respiration and inhibits glycolysis in endothelial cells: A role for mitoBKCa channels. Biochim Biophys Acta. 2015 Oct;1847(10):1297-309. doi: 10.1016/j.bbabio.2015.07.004. Epub 2015 Jul 14. PMID: 26185029.
[7]. Choi EY, Lee JE, et,al. Carbon monoxide-releasing molecule-401, a water-soluble manganese-based metal carbonyl, suppresses Prevotella intermedia lipopolysaccharide-induced production of nitric oxide in murine macrophages. Immunopharmacol Immunotoxicol. 2022 Sep 8:1-8. doi: 10.1080/08923973.2022.2119998. Epub ahead of print. PMID: 36053007.
CORM-401含有锰(Mn)作为金属中心，CORM-401可以释放CO[1]。
当将 20 μM CORM-401 添加到含有 100 μM Mb 的 PBS 溶液中时，可以检测到 MbCO 的形成。通过计算随时间变化的 MbCO 浓度并进行曲线拟合，确定 5、10 和 20 μM CORM-401 的 CO 释放半衰期分别为 14.1、13.4 和 11.9 分钟。随着 CORM-401/Mb 比例的增加，化合物释放的 CO 量减少[2]。
暴露于 20 μM CORM-401 负载的 EA.hy926 内皮细胞后，细胞内 CO 水平升高[2]。在 CORM-401 暴露后，重组细胞色素 P450 依赖性单加氧酶 (CYP) 的 EROD 活性浓度依赖性降低。在浓度高于 50 μM CORM-401 时，用 CORM-401 处理可降低 HepG2 细胞中的 EROD 活性[4] 。 CORM-401部分降低了TNF-α/CHX诱导的总细胞ROS，降低了antimycin-A的作用[5]。 CORM-401 (10-100μM) 诱导耗氧率 (OCR) 持续增加，同时抑制糖酵解（细胞外酸化率，ECAR）和 ATP 周转率降低。此外，CORM-401 增加了质子泄漏，降低了线粒体储备能力并增强了非线粒体呼吸[6]。在用 P. intermedia LPS 刺激的 RAW264.7 细胞中，CORM-401 通过抑制 iNOS 在 mRNA 和蛋白质水平上明显抑制 NO 的产生。 CORM-401 上调 LPS 激活细胞中 HO-1 基因及其蛋白的表达，用 HO-1 抑制剂处理可显着逆转 CORM-401 对 LPS 诱导的 NO 生成的减弱作用[ 7].
口服 CORM-401 可减少体重增加并改善 HFD 诱导的肥胖小鼠的胰岛素抵抗。重复给予 CORM-401 引起的 CO 瞬时解偶联活性与体重增加减少和胰岛素敏感性增加有关高频头[3].
| Cas No. | 1001015-18-4 | SDF | |
| Canonical SMILES | O#C[Mn+]1(C#O)(C#O)([SH-]C(N(C)CC([O-])=O)=S1)C#O.[H+] | ||
| 分子式 | C8H6MnNO6S2 | 分子量 | 331.20 |
| 溶解度 | DMSO : 25 mg/mL (Need ultrasonic) | 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 | 3.0193 mL | 15.0966 mL | 30.1932 mL |
| 5 mM | 0.6039 mL | 3.0193 mL | 6.0386 mL |
| 10 mM | 0.3019 mL | 1.5097 mL | 3.0193 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。
CORM-401, an orally active carbon monoxide-releasing molecule, increases body temperature by activating non-shivering thermogenesis in rats
Temperature (Austin) 2022 Apr 26;9(4):310-317.PMID:PMC9629103DOI:10.1080/23328940.2022.2061270.
Thermoregulation is critical in health and disease and is tightly controlled to maintain body temperature homeostasis. Carbon monoxide (CO), an endogenous gasotransmitter produced during heme degradation by heme oxygenases, has been suggested to play a role in body core temperature (Tb) regulation. However, a direct involvement of CO in thermoregulation has not been confirmed and its mechanism(s) of action remain largely unknown. In the present study we characterized the effects of systemic delivery of CO by administration of an orally active CO-releasing molecule (CORM-401) on Tb regulation in conscious freely moving rats. Specifically, we evaluated the main thermo effectors in rats treated with CORM-401 by assessing: (i) non-shivering thermogenesis, i.e. the increased metabolism of brown fat measured through oxygen consumption and (ii) the rate of heat loss from the tail through calculations of heat loss index. We found that oral administration of CORM-401 (30 mg/kg) resulted in augmented CO delivery into the blood circulation as evidenced a by significant increase in carbon monoxy hemoglobin levels(COHb). In addition, treatment with CORM-401 increased Tb, which was caused by an elevated non-shivering thermogenesis indicated by increased oxygen consumption without significant changes in the tail heat loss. On the other hand, CORM-401 did not affect blood pressure, but significantly decreased heart rate. In summary, the findings of the present study reveal that increased circulating CO levels lead to a rise in Tb, which could have important implications in the emerging role of CO in the modulation of energetic metabolism.
Carbon monoxide releasing molecule 401 (CORM-401) modulates phase I metabolism of xenobiotics
Toxicol In Vitro 2019 Sep;59:215-220.PMID:31004742DOI:10.1016/j.tiv.2019.04.018.
Next to its well-studied toxicity, carbon monoxide (CO) is recognized as a signalling molecule in various cellular processes. Thus, CO-releasing molecules (CORMs) are of considerable interest for basic research and drug development. Aim of the present study was to investigate if CO, released from CORMs, inhibits cytochrome P450-dependent monooxygenase (CYP) activity and modulates xenobiotic metabolism. CORM-401 was used as a model CO delivering compound; inactive CORM-401 (iCORM-401), unable to release CO, served as control compound. CO release from CORM-401, but not from iCORM-401, was validated using the cell free myoglobin assay. CO-dependent inhibition of CYP activity was shown by 7-ethoxyresorufin-O-deethylation (EROD) with recombinant CYP and HepG2 cells. Upon CORM-401 exposure EROD activity of recombinant CYP decreased concentration dependently, while iCORM-401 had no effect. Treatment with CORM-401 decreased EROD activity in HepG2 cells at concentrations higher than 50 μM CORM-401, while iCORM-401 showed no effect. At the given concentrations cell viability was not affected. Amitriptyline was selected as a model xenobiotic and formation of its metabolite nortriptyline by recombinant CYP was determined by HPLC. CORM-401 treatment inhibited the formation of nortriptyline whereas iCORM-401 treatment did not. Overall, we demonstrate CO-mediated inhibitory effects on CYP activity when applying CORMs. Since CORMs are currently under drug development, the findings emphasize the importance to take into account that this class of compounds may interfere with xenobiotic metabolism.
CORM-401 induces calcium signalling, NO increase and activation of pentose phosphate pathway in endothelial cells
FEBS J 2018 Apr;285(7):1346-1358.PMID:29464848DOI:10.1111/febs.14411.
Carbon monoxide-releasing molecules (CO-RMs) induce nitric oxide (NO) release (which requires NADPH), and Ca2+ -dependent signalling; however, their contribution in mediating endothelial responses to CO-RMs is not clear. Here, we studied the effects of CO liberated from CORM-401 on NO production, calcium signalling and pentose phosphate pathway (PPP) activity in human endothelial cell line (EA.hy926). CORM-401 induced NO production and two types of calcium signalling: a peak-like calcium signal and a gradual increase in cytosolic calcium. CORM-401-induced peak-like calcium signal, originating from endoplasmic reticulum, was reduced by thapsigargin, a SERCA inhibitor, and by dantrolene, a ryanodine receptors (RyR) inhibitor. In contrast, the phospholipase C inhibitor U73122 did not significantly affect peak-like calcium signalling, but a slow and progressive CORM-401-induced increase in cytosolic calcium was dependent on store-operated calcium entrance. CORM-401 augmented coupling of endoplasmic reticulum and plasmalemmal store-operated calcium channels. Interestingly, in the presence of NO synthase inhibitor (l-NAME) CORM-401-induced increases in NO and cytosolic calcium were both abrogated. CORM-401-induced calcium signalling was also inhibited by superoxide dismutase (poly(ethylene glycol)-SOD). Furthermore, CORM-401 accelerated PPP, increased NADPH concentration and decreased the ratio of reduced to oxidized glutathione (GSH/GSSG). Importantly, CORM-401-induced NO increase was inhibited by the PPP inhibitor 6-aminonicotinamide (6-AN), but neither by dantrolene nor by an inhibitor of large-conductance calcium-regulated potassium ion channel (paxilline). The results identify the primary role of CO-induced NO increase in the regulation of endothelial calcium signalling, that may have important consequences in controlling endothelial function.
Differential Effects of CORM-2 and CORM-401 in Murine Intestinal Epithelial MODE-K Cells under Oxidative Stress
Front Pharmacol 2017 Feb 8;8:31.PMID:28228725DOI:10.3389/fphar.2017.00031.
Carbon monoxide (CO)-releasing molecules (CO-RMs) are intensively studied to provide cytoprotective and anti-inflammatory effects of CO in inflammatory conditions including intestinal inflammation. The water-soluble CORM-A1 reduced apoptosis and NADPH oxidase (NOX)-derived reactive oxygen species (ROS) induced by tumor necrosis factor (TNF)-α/cycloheximide (CHX) in mouse MODE-K intestinal epithelial cells (IECs), without influencing TNF-α/CHX-induced mitochondrial superoxide anion ([Formula: see text]). The aim of the present study in the same model was to comparatively investigate the influence of lipid-soluble CORM-2 and water-soluble CORM-401, shown in vitro to release more CO under oxidative conditions. CORM-2 abolished TNF-α/CHX-induced total cellular ROS whereas CORM-401 partially reduced it, both partially reducing TNF-α/CHX-induced cell death. Only CORM-2 increased mitochondrial [Formula: see text] production after 2 h of incubation. CORM-2 reduced TNF-α/CHX-, rotenone- and antimycin-A-induced mitochondrial [Formula: see text] production; CORM-401 only reduced the effect of antimycin-A. Co-treatment with CORM-401 during 1 h exposure to H2O2 reduced H2O2 (7.5 mM)-induced ROS production and cell death, whereas CORM-2 did not. The study illustrates the importance of the chemical characteristics of different CO-RMs. The lipid solubility of CORM-2 might contribute to its interference with TNF-α/CHX-induced mitochondrial ROS signaling, at least in mouse IECs. CORM-401 is more effective than other CO-RMs under H2O2-induced oxidative stress conditions.
CORM-401 Reduces Ischemia Reperfusion Injury in an Ex Vivo Renal Porcine Model of the Donation After Circulatory Death
Transplantation 2018 Jul;102(7):1066-1074.PMID:29677080DOI:10.1097/TP.0000000000002201.
Background: Carbon monoxide (CO) inhalation protects organ by reducing inflammation and cell death during transplantation processes in animal model. However, using CO in clinical transplantation is difficult due to its delivery in a controlled manner. A manganese-containing CO releasing molecules (CORM)-401 has recently been synthesized which can efficiently deliver 3 molar equivalents of CO. We report the ability of this anti-inflammatory CORM-401 to reduce ischemia reperfusion injury associated with prolonged cold storage of renal allografts obtained from donation after circulatory death in a porcine model of transplantation. Methods: To stimulate donation after circulatory death condition, kidneys from large male Landrace pig were retrieved after 1 hour warm ischemia in situ by cross-clamping the renal pedicle. Procured kidneys, after a brief flushing with histidine-tryptophan-ketoglutarate solution were subjected to pulsatile perfusion at 4°C with University of Wisconsin solution for 4 hours and both kidneys were treated with either 200 μM CORM-401 or inactive CORM-401, respectively. Kidneys were then reperfused with normothermic isogeneic porcine blood through oxygenated pulsatile perfusion for 10 hours. Urine was collected, vascular flow was assessed during reperfusion and histopathology was assessed after 10 hours of reperfusion. Results: We have found that CORM-401 administration reduced urinary protein excretion, attenuated kidney damage markers (kidney damage marker-1 and neutrophil gelatinase-associated lipocalin), and reduced ATN and dUTP nick end labeling staining in histopathologic sections. CORM-401 also prevented intrarenal hemorrhage and vascular clotting during reperfusion. Mechanistically, CORM-401 appeared to exert anti-inflammatory actions by suppressing Toll-like receptors 2, 4, and 6. Conclusions: Carbon monoxide releasing molecules-401 provides renal protection after cold storage of kidneys and provides a novel clinically relevant ex vivo organ preservation strategy.