Trimetrexate (CI-898)
(Synonyms: 三甲曲沙; CI-898) 目录号 : GC33915
Trimetrexate (CI-898)是一种抗叶酸剂，可抑制弓形虫二氢叶酸还原酶（DHFR），IC50值为1.35nM。
Cas No.:52128-35-5
Sample solution is provided at 25 µL, 10mM.
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Trimetrexate (CI-898) is an antifolate agent that inhibits Toxoplasma gondii dihydrofolate reductase (DHFR) with the IC50 value of 1.35nM [1]. Trimetrexate has been widely used as an anti-cancer compound to inhibit the growth of many cancer cells[2]. Trimetrexate has been extensively used as a model compound to develop a range of derivatives and build a small molecule library to screen for inhibitors against S. mutans[3].
In vitro, Trimetrexate treatment for 96h inhibited the viability of U-2OS cells and Saos-2 cells with the IC50 values of 3.3±2.1µM and 6.5±2.1µM, respectively[4]. After a 24h exposure to Trimetrexate (1µM), the colony formation of H630 cells was decreased, and the apparent free DHFR binding capacity was reduced[5]. Trimetrexate treatment at 100µM for 14 days irreversibly inhibited the proliferation of murine haemopoietic progenitor cells[6].
In vivo, Trimetrexate treatment via intraperitoneal injection at a dose of 60mg/kg/day for 49 days reduced tumor progression and improved the survival of the murine 32Dp210 model of chronic myeloid leukemia[7]. Oral administration of Trimetrexate at a dose of 180mg/kg/day for 14 days extended the survival of T. gondii-infected mice[8].
References:
[1] Hopper A T, Brockman A, Wise A, et al. Discovery of selective Toxoplasma gondii dihydrofolate reductase inhibitors for the treatment of toxoplasmosis[J]. Journal of medicinal chemistry, 2019, 62(3): 1562-1576.
[2] Miyachi H, Takemura Y, Kobayashi H, et al. Cytotoxicity of Trimetrexate against Antifolate‐resistant Human T‐Cell Leukemia Cell Lines Developed in Oxidized or Reduced Folate[J]. Japanese journal of cancer research, 1997, 88(9): 900-906.
[3] Zhang Q, Nguyen T, McMichael M, et al. New small-molecule inhibitors of dihydrofolate reductase inhibit Streptococcus mutans[J]. International journal of antimicrobial agents, 2015, 46(2): 174-182.
[4] Serra M, Reverter-Branchat G, Maurici D, et al. Analysis of dihydrofolate reductase and reduced folate carrier gene status in relation to methotrexate resistance in osteosarcoma cells[J]. Annals of oncology, 2004, 15(1): 151-160.
[5] Grem J L, Voeller D M, Geoffroy F, et al. Determinants of trimetrexate lethality in human colon cancer cells[J]. British journal of cancer, 1994, 70(6): 1075-1084.
[6] Strømhaug A, Slørdal L, Warren D J. Differential effects of the antifolates methotrexate, aminopterin and trimetrexate on murine haemopoietic progenitor cells[J]. British journal of haematology, 1996, 92(3): 514-520.
[7] Sweeney C L, Frandsen J L, Verfaillie C M, et al. Trimetrexate inhibits progression of the murine 32Dp210 model of chronic myeloid leukemia in animals expressing drug-resistant dihydrofolate reductase[J]. Cancer research, 2003, 63(6): 1304-1310.
[8] Allegra C J, Kovacs J A, Drake J C, et al. Potent in vitro and in vivo antitoxoplasma activity of the lipid-soluble antifolate trimetrexate[J]. The Journal of clinical investigation, 1987, 79(2): 478-482.
Trimetrexate (CI-898)是一种抗叶酸剂，可抑制弓形虫二氢叶酸还原酶（DHFR），IC50值为1.35nM[1]。Trimetrexate作为抗癌剂广泛应用于抑制多种癌细胞生长[2]。Trimetrexate并作为先导化合物用于开发系列衍生物及构建靶向变形链球菌抑制剂的小分子库[3]。
在体外，Trimetrexate处理96小时可抑制U-2OS和Saos-2细胞活力，IC50值分别为3.3±2.1µM和6.5±2.1µM[4]。1µM的Trimetrexate处理H630细胞24小时能减少克隆形成并降低表观游离DHFR结合能力[5]。100µM的Trimetrexate处理小鼠造血祖细胞14天不可逆地抑制细胞增殖[6]。
在体内，慢性髓性白血病小鼠模型（32Dp210）每日腹腔注射Trimetrexate（60mg/kg/天；持续49天）可延缓肿瘤进展并提高生存率[7]。弓形虫感染小鼠每日口服180mg/kg剂量的Trimetrexate（持续14天）能延长生存期[8]。
| Cell experiment [1]: | |
Cell lines | U-2OS cells |
Preparation Method | U-2OS cells were cultured in Iscove’s modified Dulbecco’s medium (IMDM) supplemented with penicillin (100U/ml) and streptomycin (100µg/ml) and 10% fetal calf serum (FCS) at 37°C in a humidified atmosphere with 5% CO2. 2×104/cm2 were seeded in IMDM 10% FCS, and after 24h, the medium was replaced with 10% FCS containing Trimetrexate at various concentrations (0.1, 1, 10, 100, and 1000µM). After 96h, cells were harvested and counted by trypan blue exclusion. |
Reaction Conditions | 0.1, 1, 10, 100, and 1000µM; 96h |
Applications | Trimetrexate treatment reduced cell viability of U-2OS cells in a dose dependent manner. |
| Animal experiment [2]: | |
Animal models | C3F-F1 mice |
Preparation Method | 32Dp210+GFP tumor cells were dissolved in 0.5ml PBS and injected into C3F-F1 mice via the tail vein. From 1 day after tumor injection, mice were intraperitoneally injected with PBS and 60mg/kg/day of Trimetrexate daily for 49 days. The body weight and health status of mice were monitored daily, and the dying mice were euthanized by carbon dioxide asphyxia. The tumor and survival of mice were analyzed. |
Dosage form | 60mg/kg/day for 49 days; i.p. |
Applications | Trimetrexate treatment reduced tumor progression and improved the survival of tumor-bearing mice. |
References: | |
| Cas No. | 52128-35-5 | SDF | |
| 别名 | 三甲曲沙; CI-898 | ||
| Canonical SMILES | NC1=C(C(C)=C2CNC3=CC(OC)=C(OC)C(OC)=C3)C(C=C2)=NC(N)=N1 | ||
| 分子式 | C19H23N5O3 | 分子量 | 369.42 |
| 溶解度 | DMSO : ≥ 61.5 mg/mL (166.48 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 | 2.7069 mL | 13.5347 mL | 27.0695 mL |
| 5 mM | 541.4 μL | 2.7069 mL | 5.4139 mL |
| 10 mM | 270.7 μL | 1.3535 mL | 2.7069 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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