Enzymatic assays for 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline, a promising new "nonclassical" antifolate.
Enzymatic assays for 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline, a promising new "nonclassical" antifolate.
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2,4-二氨基-5-甲基-6-[(3,4,5-三甲氧基苯胺基)甲基]喹唑啉（一种有前途的新型“非经典”抗叶酸剂）的酶法测定。
DOI：
10.1002/jps.2600700737
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发表时间：
1981
影响因子：
3.8
通讯作者：
McCormack,JJ
中科院分区：
文献类型：
--
作者：
Heusner,JJ;McCormack,JJ
2，4-二氨基-5-甲基-6-[（3，4，5-三甲氧基苯胺基）-甲基]喹唑啉（I）是一种很有前途的新型“非经典”抗叶酸剂。从细菌（干酪乳杆菌）和哺乳动物（牛肝）来源的二氢叶酸还原酶的抑制，开发有用的酶测定这种化合物。通过绘制I浓度与1/V的关系图获得线性关系。所得标准曲线在30和70%对照范围之间保持特别好的线性，两种酶系统的相关系数为0.99。两种酶系统的特征在于灵敏度、稳定性和日常变化的差异。牛肝还原酶系统的ID_（50）为1.6 × 10 - 9 M（±0.3）;平均值为1.35 × 10 - 8 M（±0.2）。牛肝酶的明显优势在一定程度上被其相对不稳定性和较高的日间变异性所抵消。在小鼠中的研究表明，这些测定方法适用于体内药代动力学研究，这些研究表明，I在小鼠中的血清t1/2为45 min;在使用14 C标记的6位I的研究中估计了类似的血清t1/2（50 min）。
2,4‐Diamino‐5‐methyl‐6‐[(3,4,5‐trimethoxyanilino)‐methyl]quinazoline (I) is a promising new “nonclassical” antifolate. Inhibition of dihydrofolate reductase from bacterial (Lactobacillus casei) and mammalian (beef liver) sources was employed to develop useful enzymatic assays for this compound. A linear relationship was obtained by plotting the I concentration versus 1/V. The resultant standard curves maintained linearity particularly well between the 30 and 70% control range, with a correlation coefficient of 0.99 for both enzyme systems. The two enzyme systems are characterized by differences in sensitivity, stability, and day‐to‐day variation. The ID50for the beef liver reductase system was 1.6 × 10−9M(±0.3); for theL. caseisystem, it was 1.35 × 10−8M(±0.2). The apparent advantage for the beef liver enzyme was offset somewhat by its relative instability and its higher day‐to‐day variability. Studies in mice demonstrated that these assays are suitable for pharmacokinetic studiesin vivo.Such studies indicated that I has a serum t1/2of 45 min in mice; a similar serum t1/2(50 min) was estimated in studies with14C‐labeled I in position 6.