Evofosfamide (TH-302)
Evofosfamide (TH-302)是一种选择性低氧激活的前体药物，靶向作用于实体瘤的hypoxic区域，IC50为19 nM，在缺氧条件下比在有氧条件下细胞毒性增强270倍，细胞色素P450代谢稳定。
Evofosfamide (TH-302) Chemical Structure
CAS: 918633-87-1
产品质控
批次：
纯度：
99.82%
99.82
Evofosfamide (TH-302)相关产品
细胞实验数据示例
| 细胞系 | 实验类型 | 给药浓度 | 孵育时间 | 活性描述 | 文献信息 |
|---|---|---|---|---|---|
| H460 | Cytotoxicity assay | 2 hrs | Cytotoxicity against human H460 cells under hypoxic condition after 2 hrs by clonogenic assay, IC90=0.1μM. | 18257544 | |
| H460 | Cytotoxicity assay | 2 hrs | Cytotoxicity against human H460 cells under hypoxic condition after 2 hrs by Alamar blue staining assay, IC50=0.019μM. | 18257544 | |
| HT29 | Cytotoxicity assay | 2 hrs | Cytotoxicity against human HT29 cells under hypoxic condition after 2 hrs by clonogenic assay, IC90=0.2μM. | 18257544 | |
| H460 | Cytotoxicity assay | 2 hrs | Cytotoxicity against human H460 cells under normoxic condition after 2 hrs by Alamar blue staining assay, IC50=5.1μM. | 18257544 | |
| H460 | Cytotoxicity assay | 2 hrs | Cytotoxicity against human H460 cells under normoxic condition after 2 hrs by clonogenic assay, IC90=30μM. | 18257544 | |
| HT29 | Cytotoxicity assay | 2 hrs | Cytotoxicity against human HT29 cells under normoxic condition after 2 hrs by clonogenic assay, IC90=40μM. | 18257544 | |
| NCI-H460 | Cytotoxicity assay | 24 hrs | Cytotoxicity against human NCI-H460 cells pretreated for 24 hrs under hypoxic condition followed by compound washout measured after 72 hrs by MTT assay, IC50=9.08μM. | 28350997 | |
| HT-29 | Cytotoxicity assay | 24 hrs | Cytotoxicity against human HT-29 cells pretreated for 24 hrs under hypoxic condition followed by compound washout measured after 72 hrs by MTT assay, IC50=49.51μM. | 28350997 | |
| NCI-H460 | Cytotoxicity assay | 24 hrs | Cytotoxicity against human NCI-H460 cells after 24 hrs under hypoxic condition by luminescence-based Cell-Titer Glo assay, IC50=0.0093μM. | 29079474 | |
| NCI-H460 | Cytotoxicity assay | 24 hrs | Cytotoxicity against human NCI-H460 cells after 24 hrs under normoxic condition by luminescence-based Cell-Titer Glo assay, IC50=6.65μM. | 29079474 | |
| DU145 | Cytotoxicity assay | 2 hrs | Cytotoxicity against human DU145 cells incubated for 2 hrs under hypoxic condition measured after 72 hrs by Alamar blue assay, IC50=4.14μM. | 29259746 | |
| PC3 | Cytotoxicity assay | 2 hrs | Cytotoxicity against human PC3 cells incubated for 2 hrs under hypoxic condition measured after 72 hrs by Alamar blue assay, IC50=6.49μM. | 29259746 | |
| HEMC-SS | Antiproliferative assay | 24 hrs | Antiproliferative activity against human HEMC-SS cells treated for 24 hrs under hypoxic condition followed by compound wash-out and incubated under normoxic condition for 48 hrs by alamar blue assay, IC50=0.13μM. | 30199705 | |
| HEMC-SS | Antiproliferative assay | 24 hrs | Antiproliferative activity against human HEMC-SS cells treated for 24 hrs under normoxic condition followed by compound wash-out and incubated under normoxic condition for 48 hrs by alamar blue assay, IC50=2.9μM. | 30199705 | |
| MDA-MB-468 | Cytotoxicity assay | 4 hrs | Cytotoxicity against human MDA-MB-468 cells incubated for 4 hrs under hypoxic condition followed by compound washout and measured after 5 days by SRB assay, IC50=0.0062μM. | 30885680 | |
| SW620 | Cytotoxicity assay | 4 hrs | Cytotoxicity against human SW620 cells incubated for 4 hrs under hypoxic condition followed by compound washout and measured after 5 days by SRB assay, IC50=0.052μM. | 30885680 | |
| MDA-MB-468 | Cytotoxicity assay | 4 hrs | Cytotoxicity against human MDA-MB-468 cells incubated for 4 hrs under aerobic condition followed by compound washout and measured after 5 days by SRB assay, IC50=4.403μM. | 30885680 | |
| SW620 | Cytotoxicity assay | 4 hrs | Cytotoxicity against human SW620 cells incubated for 4 hrs under aerobic condition followed by compound washout and measured after 5 days by SRB assay, IC50=20.6μM. | 30885680 | |
| NCI-H460 | Antiproliferative assay | Antiproliferative activity against human NCI-H460 cells in presence of N2, IC50=2μM. | 30295477 | ||
| NCI-H460 | Antiproliferative assay | Antiproliferative activity against human NCI-H460 cells in presence of O2, IC50=25μM. | 30295477 | ||
| 点击查看更多细胞系数据 | |||||
生物活性
| 产品描述 | Evofosfamide (TH-302)是一种选择性低氧激活的前体药物，靶向作用于实体瘤的hypoxic区域，IC50为19 nM，在缺氧条件下比在有氧条件下细胞毒性增强270倍，细胞色素P450代谢稳定。 |
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| 体外研究(In Vitro) | ||||
| 体外研究活性 | TH-302是低氧激活的前体药物，目前处于临床评测阶段。在含氧情况下，TH-302作用于椭圆形细胞比作用于单分子层细胞效果强很多。[2] 在有氧情况下，TH-302是非常有效的，且在肝脏微粒体中很稳定。在N2环境下，TH-302作用于人类肺癌H460细胞和人类结肠癌HT29细胞，具有高毒性。 TH-302抑制H460细胞和HT29细胞，IC90分别为0.1和0.2 μM。[1] TH-302作用于多发性骨髓瘤具有低氧选择性和剂量依赖性。在低氧条件下，TH-302诱导细胞周期停在G0/G1 期。通过下调cyclin D1/2/3, CDK4/6, p21cip-1, p27kip-1, 和 pRb表达来调节TH-302作用于细胞周期的影响,而CDK2表达对此没有作用效果。在低氧条件下，TH-302作用于人类和鼠多发性骨髓瘤细胞，诱导细胞凋亡，这种作用存在剂量依赖性。通过下调抗凋亡蛋白BCL-2和BCL-xL, 还有上调裂开的凋亡前体蛋白caspase-3,-8,和-9，及ＰＡＲＰ的表达来调节TH-302激活的凋亡。与低氧环境下特殊的毒性相比，在含氧正常的环境下或者高氧环境下，TH-302 显示低毒性。[3] |
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|---|---|---|---|---|
| 细胞实验 | 细胞系 | 人类H460或HT29细胞 | ||
| 浓度 | 0.01 -1 μM | |||
| 孵育时间 | 2小时 | |||
| 方法 | 指数生长的人类H460或HT29细胞按每孔3×105个细胞接种在60 mm有缺口的玻璃板上，在含10%FBS的RPMI培养基上生长2天。实验开始第一天,已知浓度TH-302溶液准备在完全培养基中，玻璃板上每孔加入2 mL溶液。玻璃板置于厌氧培养室或标准组织培养孵育器。在厌氧培养室中充满厌氧气体混合物(90% N2/5% CO2/5% H2)，形成低氧环境。细胞和TH-302在37oC下温育2小时。处理到最后，移除板，用PBS冲洗，然后用胰蛋白酶-EDTA使胰蛋白酶化，在37oC下进行5分钟。分离的细胞用培养基和血清中和，然后在100g转速下旋转5分钟。细胞按1×106个细胞/mL再悬浮，然后稀释10倍。测定每组溶液的确切浓度。已知数目的细胞在第9天和第13天接种和置于孵育器中。菌落混合，用95%乙醇和0.25%结晶紫染色。计数超过50个细胞的菌落，测定存活率。 |
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| 体内研究(In Vivo) | ||
| 体内研究活性 | 实验移植第25天，TH302抑制肿瘤生长，抑制率达41% ，但是TH302联用抑制肿瘤生长，抑制率达 96%。[1]TH-302按 6.25, 12.5, 25, 或50 mg/kg剂量腹腔注射到H460 NSCLC移植模型，每天处理一次，每周处理5次，持续2周，在第22天，肿瘤生长抑制率分别为43%, 51%, 75%,和 89%。TH-302 按100 mg/kg剂量作用于血细胞，处理后3天，血细胞下降，但是在处理后7天完全恢复。TH-302诱导细胞死亡，依赖于氧浓度，当作用于携带肿瘤的鼠在低氧浓度环境下，则毒性最高。TH-302作用于呼吸氧气需10% O2的动物，抑制肿瘤生长明显低于呼吸需95% O2的动物。TH-302处理后48小时, pimonidazole阳性区明显降低(对照组为6.3±1.2%，TH-302实验组为1.8±1.1%)。 [4] |
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|---|---|---|
| 动物实验 | Animal Models | 雌性NCI SCID鼠 |
| Dosages | 50 mg/kg | |
| Administration | 腹腔注射 | |
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT02020226 | Unknown status | Solid Tumors |
Threshold Pharmaceuticals |
November 2013 | Phase 1 |
| NCT01833546 | Completed | Solid Tumor|Pancreatic Cancer |
Merck KGaA Darmstadt Germany|Threshold Pharmaceuticals |
April 18 2013 | Phase 1 |
化学信息&溶解度
| 分子量 | 449.04 | 分子式 | C9H16Br2N5O4P |
| CAS号 | 918633-87-1 | SDF | Download Evofosfamide (TH-302) SDF |
| Smiles | CN1C(=CN=C1[N+](=O)[O-])COP(=O)(NCCBr)NCCBr | ||
| 储存条件(自收到货起) | |||
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体外溶解度 |
DMSO : 90 mg/mL ( (200.42 mM) ；DMSO吸湿会降低化合物溶解度，请使用新开封DMSO) Ethanol : 90 mg/mL (200.42 mM) Water : 10 mg/mL (22.26 mM) |
摩尔浓度计算器 |
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体内溶解度 现配现用，请按从左到右的顺序依次添加，澄清后再加入下一溶剂 |
动物体内配方计算器 | ||||
实验计算
动物体内配方计算器（澄清溶液）
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）
mg/kg
g
μL
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Selleck为您提供正确的澄清溶液配方）
% DMSO
%
% Tween 80
% ddH2O
%DMSO
%
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，注：如该浓度超过该批次药物DMSO溶解度，请先联系Selleck）；
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 ddH2O，混匀澄清。
体内配方配制方法：取μL DMSO母液，加入μL Corn oil，混匀澄清。
注意：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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