生物活性
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。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。 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。
化学数据
分子量 | 449.04 |
分子式 | C9H16Br2N5O4P |
CAS号 | 918633-87-1 |
纯度 | 100.00% |
溶解性(25°C) | DMSO ≥ 60 mg/mL |
储存和运输条件 | 固体粉末: -20°C 冷藏长期储存 常温运输及临时存放 |
实验操作 来自于公开的文献,仅供相同实验参考(如实验材料、目的不同,请参考其他文献)
细胞实验 |
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细胞系 | H460, H82, DU145, A375 and PC3 cells line |
方法 | In vitro cytotoxicity assay Exponentially growing cells were seeded 24 hours before the addition of test compounds. After drug addition, the plates were incubated for 2 hours, or longer if indicated, under defined oxygen concentrations at 37°C in an anaerobic chamber (Bactron II), a hypoxia chamber (Hypoxystation), or a standard tissue-culture incubator. Using this method, cells equilibrated rapidly (<30 minutes) with the gas phase as shown by linearity of time course of cytotoxicity and use of dissolved oxygen probe (OxyLite, Oxford Optronics). Cells were cultured for 72 hours in complete medium after washing under normoxic conditions, and the viable cells were quantified using AlamarBlue. For DPI experiments, cells were pretreated with 100 μmol/L of DPI for 2 hours under air. Drug concentration resulting in growth inhibition of 50% (IC50) relative to untreated control was calculated using Prism software. |
浓度 | 0~100μM |
处理时间 | 2h |
动物实验 |
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动物模型 | PLC/PRF/5, hepatocellular carcoma (HCC) xenograft model with NCI SCID female mice |
配制 | saline (0.9% NaCl) |
剂量 | 50 mg/kg, QD 5/wk*2 wks |
给药处理 | intraperitoneally |
不同实验动物依据体表面积的等效剂量转换表(数据来源于FDA指南)
| 小鼠 | 大鼠 | 兔 | 豚鼠 | 仓鼠 | 狗 |
重量 (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
体表面积 (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
Km系数 | 3 | 6 | 12 | 8 | 5 | 20 |
动物 A (mg/kg) = 动物 B (mg/kg) × | 动物 B的Km系数 |
动物 A的Km系数 |
例如,依据体表面积折算法,将化合物用于小鼠的剂量20 mg/kg 换算成大鼠的剂量,需要将20 mg/kg 乘以小鼠的Km系数(3),再除以大鼠的Km系数(6),得到化合物用于大鼠的等效剂量为10 mg/kg。
储备液配制
以下数据基于产品分子量,对于特殊产品,请参照COA中的储备液配制条件和说明进行操作。
Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
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1 mM | 2.227 mL | 11.1349 mL | 22.2697 mL |
5 mM | 0.4454 mL | 2.227 mL | 4.4539 mL |
10 mM | 0.2227 mL | 1.1135 mL | 2.227 mL |