Halofuginone hydrobromide (RU-19110 (hydrobromide))
(Synonyms: 常山酮溴酸盐; RU-19110 hydrobromide) 目录号 : GC31950
Halofuginone (RU-19110) hydrobromid 是一种Ferifugine 衍生物，是一种竞争性脯氨酰-tRNA 合成酶抑制剂，Ki 为 18.3 nM。
Cas No.:64924-67-0
Sample solution is provided at 25 µL, 10mM.
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Halofuginone hydrobromide (RU-19110 hydrobromide) is a less-toxic form of Febrifugine, which is isolated from the plant Dichroa febrifuga[1]. Halofuginone inhibits prolyl-tRNA synthetase in an ATP-dependent manner with a Ki of 18.3 nM[2]. Halofuginone attenuates osteoarthritis (OA) by inhibition of TGF-β activity[3].
Halofuginone competitively inhibits prolyl-tRNA synthetase by occupying both the prolineand tRNA-binding pockets of prolyl-tRNA synthetase[1]. The IC50s of Halofuginone (1, 10, 100, 1000, 10000 nM; 48 hours) are 114.6 and 58.9 nM in KYSE70 and A549 cells, respectively. The IC50s of Halofuginone (1, 10, 100, 1000 nM; 24 hours) for NRF2 protein are 22.3 and 37.2 nM in KYSE70 and A549 cells, respectively. The IC50 of Halofuginone for global protein synthesis is 22.6 and 45.7 nM in KYSE70 and A549 cells, respectively[1].|| Cell Viability Assay[1]||Cell Line:|KYSE70 cells from human oesophageal cancer harbouring a mutation in the NRF2 gene and A549 cells harbouring theKEAP1 gene mutation|Concentration:|1, 10, 100, 1000, 10000 nM|Incubation Time:|48 hours|Result:|The IC50s were 114.6 and 58.9 nM in KYSE70 and A549 cells, respectively.|| Western Blot Analysis[1]||Cell Line:|KYSE70 cells from human oesophageal cancer harbouring a mutation in the NRF2 gene and A549 cells harbouring theKEAP1 gene mutation.|Concentration:|1, 10, 100, 1000 nM|Incubation Time:|24 hours|Result:|The IC50s for NRF2 protein were 22.3 and 37.2 nM in KYSE70 and A549 cells, respectively.
Halofuginone attenuates progression of OA in anterior cruciate ligament transection (ACLT) mice. The optimal dose (1 mg/kg body weight) is identified using multiple concentrations of HF (0.2, 0.5, 1 or 2.5 mg/kg) injected every other day for 1 month post surgery. Lower concentration (0.2 or 0.5 mg/kg) has minimal effects on subchondral bone and higher concentration (2.5 mg/kg) induces proteoglycan loss in articular cartilage[3]. Halofuginone (0.25-mg/kg, intraperitoneally) decreases NRF2 protein levels in tumors. While the tumor volumes do not change substantially between treatments with the vehicle, Halofuginone(0.25 mg/kg, intraperitoneally injected, every day) or cisplatin alone, combined treatment with Halofuginone and Cisplatin significantly suppresses the tumor volume compared to treatment with Halofuginone or cisplatin alone[1].
[1]. Tsuchida K, et al. Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation. Free Radic Biol Med. 2017 Feb;103:236-247. [2]. Keller TL, et al. Halofuginone and other Febrifugine derivatives inhibit prolyl-tRNA synthetase. Nat Chem Biol. 2012 Feb 12;8(3):311-7. [3]. Cui Z, et al. Halofuginone attenuates osteoarthritis by inhibition of TGF-β activity and H-type vessel formation in subchondral bone. Ann Rheum Dis. 2016 Sep;75(9):1714-21.
| Cas No. | 64924-67-0 | SDF | |
| 别名 | 常山酮溴酸盐; RU-19110 hydrobromide | ||
| Canonical SMILES | O=C1N(CC(C[C@@H]2NCCC[C@H]2O)=O)C=NC3=C1C=C(Cl)C(Br)=C3.Br | ||
| 分子式 | C16H18Br2ClN3O3 | 分子量 | 495.59 |
| 溶解度 | DMSO : 50 mg/mL (100.89 mM) | 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 | 2.0178 mL | 10.089 mL | 20.178 mL |
| 5 mM | 0.4036 mL | 2.0178 mL | 4.0356 mL |
| 10 mM | 0.2018 mL | 1.0089 mL | 2.0178 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 | ||||||||||
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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。
Encapsulating Halofuginone Hydrobromide in TPGS Polymeric Micelles Enhances Efficacy Against Triple-Negative Breast Cancer Cells
Background: Halofuginone hydrobromide (HF) is a synthetic analogue of the naturally occurring quinazolinone alkaloid febrifugine, which has potential therapeutic effects against breast cancer, however, its poor water solubility greatly limits its pharmaceutical application. D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) is a water-soluble derivative of vitamin E, which can self-assemble to form polymeric micelles (PMs) for encapsulating insoluble anti-tumor drugs, thereby effectively enhancing their anti-cancer effects. Methods: HF-loaded TPGS PMs (HTPMs) were manufactured using a thin-film hydration technique, followed by a series of characterizations, including the hydrodynamic diameter (HD), zeta potential (ZP), stability, drug loading (DL), encapsulation efficiency (EE), and in vitro drug release. The anti-cancer effects and potential mechanism of HTPMs were investigated in the breast cell lines MDA-MB-231 and MCF-7, and normal breast epithelial cell line Eph-ev. The breast cancer-bearing BALB/c nude mouse model was successfully established by subcutaneous injection of MDA-MB-231 cells and used to evaluate the in vivo therapeutic effect and safety of the HTPMs. Results: The optimized HTPMs had an HD of 17.8±0.5 nm and ZP of 14.40±0.1 mV. These PMs exhibited DL of 12.94 ± 0.46% and EE of 90.6 ± 0.85%, along with excellent storage stability, dilution tolerance and sustained drug release in pH-dependent manner within 24 h compared to free HF. Additionally, the HTPMs had stronger inhibitory effects than free HF and paclitaxel against MDA-MB-231 triple-negative breast cancer cells, and little toxicity in normal breast epithelial Eph-ev cells. The HTPMs induced cell cycle arrest and apoptosis of MDA-MB-231 by disrupting the mitochondrial membrane potential and enhancing reactive oxygen species formation. Evaluation of in vivo anti-tumor efficacy demonstrated that HTPMs exerted a stronger tumor inhibition rate (68.17%) than free HF, and exhibited excellent biocompatibility. Conclusion: The findings from this study indicate that HTPMs holds great clinical potential for treating triple-negative breast cancer.
A Novel Synthesis of the Efficient Anti-Coccidial Drug Halofuginone Hydrobromide
Background: Halofuginone hydrobromide (1) is recognized as an effective drug against several species of Eimeria (E.) in poultry. In this paper, we describe a convenient and low cost preparation method for the compound, as well as primary validation of its activity. Methods: First, 7-bromo-6-chloroquinazolin-4(3H)-one (2) was prepared from m-chlorotoluene by a conventional process, and then chloroacetone was creatively introduced in two steps. Finally, halofuginone hydrobromide (1) was obtained from 7-bromo-6-chloro-3-(3-cholroacetonyl) quinazolin-4(3H)-one (4) by a four-step reaction sequence including condensation, cyclization, deprotection and isomerization. The structures of the relative intermediates and target compound were characterized by melting point, IR, MS and ?H-NMR. Besides, the protective effect of compound 1-supplemented chicken diet at doses of 6, 3 and 1.5 mg per 1 kg were evaluated on chickens infected with E. tenella, by reduction in mortality, weight loss, fecal oocyst excretion and gut pathology, respectively. Results: Halofuginone hydrobromide (1) was prepared successfully by and improved and innovative method based on traditional research. Moreover, the synthesized halofuginone hydrobromide significantly exhibited an anti-coccidial property. Conclusions: The fruitful work described in this Communication has resulted in halofuginone hydrobromide, which has a good pharmaceutical development prospects, becoming more available for large-scale production.
Safety of a feed additive consisting of halofuginone hydrobromide (STENOROL?) for chickens for fattening and turkeys (Huvepharma N.V.)
Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety for the target species of the coccidiostat halofuginone hydrobromide from STENOROL? when used as a feed additive for chickens for fattening and turkeys. In its previous assessment, the FEEDAP Panel could not conclude on the safety of STENOROL? for the target species at the highest proposed use level of 3 mg halofuginone hydrobromide/kg complete feed. On the basis of the new data provided, the FEEDAP Panel updates its previous conclusions on the safety for the target species as follows: halofuginone hydrobromide from STENOROL? is safe for chickens for fattening and for turkeys up to a maximum of 12 weeks of age at the highest proposed concentration of 3 mg/kg complete feed. For chickens for fattening, a margin of safety of about 1.3 can be established while for turkeys for fattening a margin of safety cannot be established.
Safety and efficacy of STENOROL? (halofuginone hydrobromide) as a feed additive for chickens for fattening and turkeys
Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the coccidiostat STENOROL ? containing halofuginone hydrobromide (halofuginone HBr) as active substance. The FEEDAP Panel was not able to conclude on the safety of STENOROL ? for chickens and turkeys for fattening at the highest proposed use level. No incompatibilities or interactions with feedingstuffs, carriers, other approved additives or medicinal drugs are expected. Halofuginone HBr does not have antimicrobial activity at the highest dose proposed; it is not expected to exert adverse effects on chicken gut microbiota or select for resistance and cross-resistance with other antimicrobials. The Panel cannot conclude on the genotoxic potential of halofuginone HBr since an appropriate in vivo follow-up to exclude the mutagenic effect of the compound was not available. Therefore, the FEEDAP Panel cannot conclude on the safety of halofuginone HBr for the consumer. The additive is toxic by inhalation, dermal and ocular routes and is very irritant to both the eye and the skin. It is considered also a skin sensitiser. Inhalation exposure is considered a risk to persons handling the additive. Since the lack of genotoxic potential of halofuginone HBr has not been adequately demonstrated, it should be considered as an additional potential concern to users handling the additive. Due to limitations in some of the ecotoxicological studies, no conclusions can be drawn on the safety of the additive for the environment. The FEEDAP Panel is not in the position to conclude on the efficacy of STENOROL ? in chickens for fattening and in turkeys for fattening.
Anticoccidial effect of halofuginone hydrobromide against Eimeria tenella with associated histology
Halofuginone (stenorol) has been used as an effective anticoccidial reagent for decades but very little is known about its mode of action. In this study, chickens were inoculated with Eimeria tenella oocysts on 14-day-old and medicated with halofuginone at days 0, 1, 2, 3, 4, 5 and 6 post inoculations (groups 0, 1, 2, 3, 4, 5 and 6, respectively). Chickens in group 7 were taken as challenge-unmedicated control and in group 8 unchallenged-unmedicated control. The survival rate, body weight gains (BWG), oocysts production, cecal scores, bloody diarrhea and histological examinations were analyzed to evaluate the anticoccidial efficacy of halofuginone and to initially elucidate its mechanisms. Results showed that halofuginone which acted as a coccidiostatic can significantly enhance the BWG, and decrease both the oocyst shedding and cecal destruction caused by E. tenella infection. The histological slide examination noted that halofuginone was effective when provided 0-2 days post inoculation but only partially effective when applied 3-7 days post infection. The second-generation schizonts treated with halofuginone appeared vacuolated and degenerated. It is concluded that halofuginone can inhibit the parasite's invasion of host cecal hypothetical cell at the early stages of life cycle and later disturb the parasite's development by vacuolation of the schizonts. The resulting abnormal schizonts could not divide into schizoites and were eventually eliminated by the host's immune response.