BI-6C9
目录号 : GC41252An inhibitor of tBid-mediated apoptosis
Cas No.:791835-21-7
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
BH3-interacting domain (Bid) is cleaved by caspase-8 to produce the truncated protein tBid, which facilitates cytochrome c release from mitochondria and drives apoptosis. BI-6C9 is an inhibitor of tBid (Kd = 20 µM), blocking the release of both cytochrome c and second mitochondria-derived activator of caspase from mitochondria. It prevents apoptosis in neurons treated with glutamate or oxygen-glucose deprivation. BI-6C9 (10 µM) also inhibits the nuclear translocation of apoptosis-inducing factor AIF, preventing the death of ovarian OVCAR-3 cancer cells induced by IFN-α2a.
| Cas No. | 791835-21-7 | SDF | |
| 化学名 | N-[4-[(4-aminophenyl)thio]phenyl]-4-[[(4-methoxyphenyl)sulfonyl]amino]-butanamide | ||
| Canonical SMILES | NC1=CC=C(SC2=CC=C(NC(CCCNS(C3=CC=C(OC)C=C3)(=O)=O)=O)C=C2)C=C1 | ||
| 分子式 | C23H25N3O4S2 | 分子量 | 471.6 |
| 溶解度 | 0.5mg/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 | 2.1204 mL | 10.6022 mL | 21.2044 mL |
| 5 mM | 0.4241 mL | 2.1204 mL | 4.2409 mL |
| 10 mM | 0.212 mL | 1.0602 mL | 2.1204 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。
Mitochondrial rescue prevents glutathione peroxidase-dependent ferroptosis
Free Radic Biol Med 2018 Mar;117:45-57.PMID:29378335DOI:10.1016/j.freeradbiomed.2018.01.019.
Research into oxidative cell death is producing exciting new mechanisms, such as ferroptosis, in the neuropathologies of cerebral ischemia and hemorrhagic brain insults. Ferroptosis is an oxidative form of regulated necrotic cell death featuring glutathione (GSH) depletion, disrupted glutathione peroxidase-4 (GPX4) redox defense and detrimental lipid reactive oxygen species (ROS) formation. Further, our recent findings identified mitochondrial damage in models of oxidative glutamate toxicity, glutathione peroxidase depletion, and ferroptosis. Despite knowledge on the signaling pathways of ferroptosis increasing, the particular role of mitochondrial damage requires more in depth investigation in order to achieve effective treatment options targeting mitochondria. In the present study, we applied RSL3 to induce ferroptosis in neuronal HT22 cells and mouse embryonic fibroblasts. In both cell types, RSL3 mediated concentration-dependent inhibition of GPX4, lipid peroxidation, enhanced mitochondrial fragmentation, loss of mitochondrial membrane potential, and reduced mitochondrial respiration. Ferroptosis inhibitors, such as deferoxamine, ferrostatin-1 and liproxstatin-1, but also CRISPR/Cas9 Bid knockout and the BID inhibitor BI-6C9 protected against RSL3 toxicity. We found compelling new information that the mitochondria-targeted ROS scavenger mitoquinone (MitoQ) preserved mitochondrial integrity and function, and cell viability despite significant loss of GPX4 expression and associated increases in general lipid peroxidation after exposure to RSL3. Our data demonstrate that rescuing mitochondrial integrity and function through the inhibition of BID or by the mitochondria-targeted ROS scavenger MitoQ serves as a most effective strategy in the prevention of ferroptosis in different cell types. These findings expose mitochondria as promising targets for novel therapeutic intervention strategies in oxidative cell death.
BID links ferroptosis to mitochondrial cell death pathways
Redox Biol 2017 Aug;12:558-570.PMID:28384611DOI:10.1016/j.redox.2017.03.007.
Ferroptosis has been defined as an oxidative and iron-dependent pathway of regulated cell death that is distinct from caspase-dependent apoptosis and established pathways of death receptor-mediated regulated necrosis. While emerging evidence linked features of ferroptosis induced e.g. by erastin-mediated inhibition of the Xc- system or inhibition of glutathione peroxidase 4 (Gpx4) to an increasing number of oxidative cell death paradigms in cancer cells, neurons or kidney cells, the biochemical pathways of oxidative cell death remained largely unclear. In particular, the role of mitochondrial damage in paradigms of ferroptosis needs further investigation. In the present study, we find that erastin-induced ferroptosis in neuronal cells was accompanied by BID transactivation to mitochondria, loss of mitochondrial membrane potential, enhanced mitochondrial fragmentation and reduced ATP levels. These hallmarks of mitochondrial demise are also established features of oxytosis, a paradigm of cell death induced by Xc- inhibition by millimolar concentrations of glutamate. Bid knockout using CRISPR/Cas9 approaches preserved mitochondrial integrity and function, and mediated neuroprotective effects against both, ferroptosis and oxytosis. Furthermore, the BID-inhibitor BI-6C9 inhibited erastin-induced ferroptosis, and, in turn, the ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 prevented mitochondrial dysfunction and cell death in the paradigm of oxytosis. These findings show that mitochondrial transactivation of BID links ferroptosis to mitochondrial damage as the final execution step in this paradigm of oxidative cell death.
Characterization of Novel Diphenylamine Compounds as Ferroptosis Inhibitors
J Pharmacol Exp Ther 2021 Aug;378(2):184-196.PMID:34011530DOI:10.1124/jpet.121.000534.
Ferroptosis is a form of oxidative cell death that is increasingly recognized as a key mechanism not only in neurodegeneration but also in regulated cell death, causing disease in other tissues. In neurons, major hallmarks of ferroptosis involve the accumulation of lipid reactive oxygen species (ROS) and impairment of mitochondrial morphology and function. Compounds that interfere with ferroptosis could provide novel treatment options for neurodegenerative disorders and other diseases involving ferroptosis. In the present study, we developed new compounds by refining structural elements of the BH3 interacting-domain death agonist inhibitor BI-6C9, which was previously demonstrated to block ferroptosis signaling at the level of mitochondria. Here, we inserted an antioxidative diphenylamine (DPA) structure to the BI-6C9 structure. These DPA compounds were then tested in models of erastin, and Ras-selective lethal small molecule 3 induced ferroptosis in neuronal HT22 cells. The DPA compounds showed an increased protective potency against ferroptotic cell death compared with the scaffold molecule BI-6C9. Moreover, hallmarks of ferroptosis such as lipid, cytosolic, and mitochondrial ROS formation were abrogated in a concentration- and time-dependent manner. Additionally, mitochondrial parameters such as mitochondrial morphology, mitochondrial membrane potential, and mitochondrial respiration were preserved by the DPA compounds, supporting the conclusion that lipid ROS toxicity and mitochondrial impairment are closely related in ferroptosis. Our findings confirm that the DPA compounds are very effective agents in preventing ferroptotic cell death by blocking ROS production and, in particular, via mitochondrial protection. SIGNIFICANCE STATEMENT: Preventing neuronal cells from different forms of oxidative cell death was previously described as a promising strategy for treatment against several neurodegenerative diseases. This study reports novel compounds based on a diphenylamine structure that strongly protects neuronal HT22 cells from ferroptotic cell death upon erastin and Ras-selective lethal small molecule 3 induction by preventing the development of different reactive oxygen species and by protecting mitochondria from ferroptotic impairments.
Detergent Sclerosants Stimulate Leukocyte Apoptosis and Oncosis
Eur J Vasc Endovasc Surg 2016 Jun;51(6):846-56.PMID:27067723DOI:10.1016/j.ejvs.2016.03.008.
Objective/background: The objective was to investigate the effects of the detergent sclerosants sodium tetradecyl sulfate (STS) and polidocanol (POL) on human leukocytes at sublytic concentrations. Methods: Leukocytes were isolated and labelled with antibodies to assess for apoptosis and examined with confocal microscopy and flow cytometry. Isolated leukocyte count and viability was assessed using trypan blue, and propidium iodide staining. Phosphatidylserine (PS) exposure, a universal hallmark to measure cell apoptosis, was identified by flow cytometry using lactadherin. Caspases 3, 8, and 9, and Bax activation, as well as inhibitory assays with pan-caspase (Z-VAD-FMK) and Bax (BI-6C9) were assessed to determine apoptotic pathways. Porimin activation was used to assess cell permeability. Results: Up to 40% of leukocytes maintained membrane integrity at sublytic concentrations (≤0.15%) of sclerosants. The remaining 60% did not maintain membrane integrity but were not completely lysed. PS exposure was increased with both STS and POL exhibiting a dose- and time-dependant trend. While activation of caspases 3, 8, and 9, as well as Bax activation, were increased in leukocytes stimulated with low concentrations of STS, only caspases 3 and 9 and Bax were increased with POL. Inhibitory assays demonstrated caspases 3, 8, and 9, and Bax inhibition at low concentrations with both STS and POL. Both agents increased the leukocyte activation of porimin at all concentrations. On confocal microscopy, stains for caspases 3, 8, and 9, and Bax were increased for both STS and POL. Porimin stain was markedly positive for both STS and POL. Conclusion: Both sclerosants induced leukocyte apoptosis at sublytic concentrations. STS activated both extrinsic and intrinsic pathways of apoptosis, while POL stimulated the intrinsic pathway of apoptosis only. Both agents induced oncosis. Based on these results, STS appears to have a greater effect than POL.
Apoptosis-inducing factor (AIF) is targeted in IFN-α2a-induced Bid-mediated apoptosis through Bak activation in ovarian cancer cells
Biochim Biophys Acta 2012 Aug;1823(8):1378-88.PMID:22683989DOI:10.1016/j.bbamcr.2012.05.031.
Previously we have shown that interferon (IFN)-α induced apoptosis is predominantly mediated by the upregulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) via the caspase-8 pathway. It was also shown that recruitment of mitochondria in IFN-α induced apoptosis involves the cleavage of BH3 interacting domain death agonist (Bid) to truncated Bid (tBid). In the present study, we demonstrate that tBid induced by IFN-α2a activates mitochondrial Bak to trigger the loss of mitochondrial membrane integrity, consequently causing release of apoptosis-inducing factor (AIF) in ovarian cancer cells, OVCAR3. AIF translocates from the mitochondria to the nucleus and induces nuclear fragmentation and cell death. Both a small molecule Bid inhibitor (BI-6C9) or Bid-RNA interference (RNAi) preserved mitochondrial membrane potential, prevented nuclear translocation of AIF, and abrogated IFN-α2a-induced cell death. Cell death induced by tBid was inhibited by AIF-RNAi, indicating that caspase-independent AIF signaling is the main pathway through which Bid mediates cell death. This was further supported by experiments showing that BI-6C9 did not prevent the release of cytochrome c from mitochondria to cytosol, while the release of AIF was prevented. In conclusion, IFN-α2a-induced apoptosis is mediated via the mitochondria-associated pathway involving the cleavage of Bid followed by AIF release that involves Bak activation and translocation of AIF from the mitochondria to the nucleus in OVCAR3 cells.