Tirapazamine
(Synonyms: 替拉扎明; SR259075; SR4233; Win59075; SML 0552; SR 259075; Tirazone) 目录号 : GC11150
Tirapazamine是一种抗肿瘤药物，对缺氧状态下的A549、HT-29、SW620和MDA-MB-468细胞具有细胞毒性作用，IC50值分别为6.8、9.45、1.2和1.304μM。
Cas No.:27314-97-2
Sample solution is provided at 25 µL, 10mM.
Tirapazamine is an anti-tumor agent showing cytotoxicity effect on A549, HT-29, SW620 and MDA-MB-468 cell in hypoxia condition with IC50 values of 6.8, 9.45, 1.2 and 1.304μM respectively[1][2]. Tirapazamine is converted by intercellular reductase to reactive radical species that can cause single- or double- strand DNA damage, and this reaction can be reversed under aerobic conditions. Tirapazamine is preferentially activated in solid tumors, which are characterized by a hypoxic environment[3]. Recognized as a commonly used bioreductive anticancer drug, Tirapazamine is extensively applied in the treatment of various cancer types, including hepatocellular carcinoma, colorectal carcinoma, and small cell lung cancer. Additionally, Tirapazamine is reported bactericidal and more active under anaerobic conditions, which reveals its potential as a antibacterial agents[4].
In vitro, Tirapazamine induces a dose-dependent increase in cell apoptosis under hypoxic conditions in murine C26 and MC38 colorectal carcinoma cells after a 24-hour treatment with concentrations ranging from 0 to 40μM, through the activation of caspase-3 cleavage[5]. Tirapazamine has been shown to inhibit the accumulation of HIF-1α in HeLa cells when exposed to a concentration of 20μM for 4 hours, an effect attributed to the reduction in HIF-1α protein synthesis via the phosphorylation of eIF2α[6]. Tirapazamine’s cytotoxic effect on LXFL 529 human lung carcinoma cells, within a concentration range of 0 to 100μM and a treatment duration of 1 hour, is mediated through topoisomerase II. This mediation occurs by stabilizing DNA-topoisomerase II complexes, resulting in the formation of DNA double-strand breaks (DSBs)[7].
In vivo, Tirapazamine was used to treat E.coli infected BALB/c mice by intraperitoneally adiministration at dosage of 25mg/kg, twice daily for 7 days, resulting in significant antibacterial activity and a prolonged survival period for the animal model[4]. Intraperitoneally administration of Tirapazamine (30mg/kg every 2 days) inhibited the tumor growth in HepG2 xenograft mouse model. Tirapazamine administration was observed to decrease the expression level of HIF-1α protein and increase p-eIF2α-positive staining in tumor tissues[6]. Tirapazamine (5,10mg/kg) was intraperitoneally injected into Wistar rats once a week for six weeks in combination with Doxorubicin (1.8mg/kg). Tirapazamine shows protective effect on rat myocardium by reduce oxidative stress and RyR2 protein level disturbed by Doxorubicin[8].
References:
[1] Cheng WY,Yuan YT, Ni Qiu N,et al.Identification of novel 4-anilinoquinazoline derivatives as potent EGFR inhibitors both under normoxia and hypoxia.Bioorganic & Medicinal Chemistry. 2014 Dec15,22(24):6796-6805
[2] Sansom N.G.,Kirk S.N.,Guise P.C.,et al.Prototyping kinase inhibitor-cytotoxin anticancer mutual prodrugs activated by tumour hypoxia: A chemical proof of concept study.Bioorg Med Chem Lett. 2019 May 15;29(10):1215-1219.
[3] Gandara R.D, Lara N.P.Jr,Goldberg Z,et al.Tirapazamine: prototype for a novel class of therapeutic agents targeting tumor hypoxia.Semin Oncol.2002 Feb;29(1 Suppl 4):102-9.
[4] Wu ZH,Wang Y,Li L,et al.New insights into the antimicrobial action and protective therapeutic effect of tirapazamine towards Escherichia coli-infected mice.Int J Antimicrob Agents. 2023 Sep;62(3):106923.
[5] Govaert K.M.,Nijkamp M.W.,Emmink B.L.,et al.Effects of tirapazamine on experimental colorectal liver metastases after radiofrequency ablation.Br J Surg.2012 Apr;99(4):567-75.
[6] Zhang J, Cao J, Weng QJ, et al.Suppression of hypoxia-inducible factor 1α (HIF-1α) by tirapazamine is dependent on eIF2α phosphorylation rather than the mTORC1/4E-BP1 pathway.PLoS One. 2010 Nov 9;5(11):e13910.
[7] Peters, K.B, Brown J.M.,Tirapazamine: a hypoxia-activated topoisomerase II poison.Cancer Res.2002 Sep 15;62(18):5248-53.
[8] Sliwinska J, et al. Tirapazamine-doxorubicin interaction referring to heart oxidative stress and Ca2+ balance protein levels. Oxid Med Cell Longev. 2012;2012:890826.
Tirapazamine是一种抗肿瘤药物，对缺氧状态下的A549、HT-29、SW620和MDA-MB-468细胞具有细胞毒性作用，IC50值分别为6.8、9.45、1.2和1.304μM[1][2]。Tirapazamine通过细胞还原酶转化为可引起单链或双链DNA损伤的活性自由基，并且该反应可在有氧条件下逆转。Tirapazamine在以缺氧环境为特征的实体肿瘤中优先被激活[3]。Tirapazamine是一种常用的生物还原性抗癌药物，广泛应用于肝细胞癌、结直肠癌、小细胞肺癌等多种类型癌症的治疗。Tirapazamine具有杀菌作用，在厌氧条件下更有活性，这显示了它作为抗菌药物的潜力[4]。
在体外，在缺氧环境下，使用0-40μM的Tirapazamine处理小鼠C26和MC38结直肠癌细胞24小时，Tirapazamine通过激活caspase-3切割剂量依赖性地诱导癌细胞凋亡[5]。当暴露于20μM的Tirapazamine 4小时，Tirapazamine可以通过磷酸化eIF2α和减少HIF-1α蛋白的合成从而抑制HeLa细胞中HIF-1α蛋白的积累[6]。此外，Tirapazamine（0-100μM, 1h）对LXFL 529人肺癌细胞的细胞毒性作用是通过topoisomerase II介导的，Tirapazamine稳定DNA-topoisomerase II复合物，从而导致DNA双链断裂（DSB）的形成[7]。
在体内，Tirapazamine （25mg/kg; i.p.; twice daily for 7 days）治疗大肠杆菌感染的BALB/c小鼠。Tirapazamine在动物模型中有明显的抗菌作用，并延长了感染小鼠的生存期[4]。腹腔注射Tirapazamine（30mg/kg/2 days）可通过降低肿瘤组织中HIF-1α蛋白表达水平，增加p-eIF2α阳性染色，从而抑制HepG2异种移植小鼠模型的肿瘤生长[6]。Tirapazamine（5 or 10mg/kg）联合Doxorubicin（1.8mg/kg）腹腔注射Wistar大鼠，每周1次，连用6周后发现Tirapazamine可以通过减少Doxorubicin引起的氧化应激和RyR2蛋白水平紊乱对大鼠心肌起到保护作用[8]
| Cell experiment [1]: | |
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Cell lines |
LXFL 529 human lung carcinoma cells |
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Preparation Method |
LXFL cells were grown in notched glass dishes, which were loaded into prewarmed aluminum jigs. For hypoxia treatment, jigs were evacuated and refilled five times with 95% air 5% CO2. The jigs were evacuated five times to 0.1 atmosphere with N2 5% CO2 reintroduction and constant shaking to achieve hypoxia (less than 200ppm O2). For aerobic treatment, jigs were evacuated and refilled five times with 95% air 5% CO2. The cells were then exposed to 0-100µM Tirapazamine for 1h at 37℃. |
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Reaction Conditions |
50, 75, 100µM; 1h |
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Applications |
The cytotoxic effect of Tirapazamine in hypoxic cells is mediated through topoisomerase II by stabilizing DNA-topoisomerase II complexes, which leads to the formation of DNA double-strand breaks (DSBs). Tirapazamine does not have the same effect on cells under aerobic environment. |
| Animal experiment [2]: | |
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Animal models |
Female BALB/c mice (5 weeks old) |
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Preparation Method |
Female BALB/c mice were randomly divided into three groups: control (C), E. coli infection (E), and E. coli infection+Tirapazamine treatment (ET). E. coli challenge tests were performed with a dose of 5.0×106 CFU/mouse via intraperitoneal injection. Three days after infection, Tirapazamine was administered to mice in the drug treatment group at 25mg/kg via intraperitoneal injection twice daily for 7 days, and the solvent without Tirapazamine was administered to the E. coli-infected group. The disease activity index (DAI) was calculated to evaluate colitis from days 0–14. |
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Dosage form |
25mg/kg; i.p.; twice daily for 7 days |
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Applications |
Tirapazamine treatment cleared bacteria from the liver, spleen, and colon in treated mice 9 days after infection. Tirapazamine increased animal survival following E. coli-induced damage. |
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References: |
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| Cas No. | 27314-97-2 | SDF | |
| 别名 | 替拉扎明; SR259075; SR4233; Win59075; SML 0552; SR 259075; Tirazone | ||
| 化学名 | 4-hydroxy-1-oxido-1,2,4-benzotriazin-1-ium-3-imine | ||
| Canonical SMILES | C1=CC=C2C(=C1)N(C(=N)N=[N+]2[O-])O | ||
| 分子式 | C7H6N4O2 | 分子量 | 178.15 |
| 溶解度 | ≥ 8.9mg/mL in DMSO | 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 | 5.6132 mL | 28.0662 mL | 56.1325 mL |
| 5 mM | 1.1226 mL | 5.6132 mL | 11.2265 mL |
| 10 mM | 0.5613 mL | 2.8066 mL | 5.6132 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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Quality Control & SDS
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- Purity: >98.00%
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