Korytnyk W, Angelino N
J Med Chem. 1977 Jun;20(6):745-9. doi: 10.1021/jm00216a002.
The 2-methyl group of pyridoxol was replaced with various other groups, including 2-amino and 2-methylamino as examples of electron-donating substituents and including 2-carboxyl, 2-carboxamide, and 2-halo as examples of electron-withdrawing substituents. The key intermediate in the synthesis was 3-O-benzyl-alpha4,alpha5-O-isopropylidene-alpha2-pyridoxol (15) or the corresponding 2-aldehyde (2). Another approach for modifying the 2 position, but chemically less successful, started with 3-O-methylpyridoxol, which was oxidized to the tricarboxylic acid, decarboxylated, esterfied, and reduced with LiAlH4, providing derivatives in which the 2-CH3 group was replaced with H. The analogues were tested for their growth-inhibitory activity against mouse mammary adenocarcinoma cells in culture. The 2-azine, 2-chloro, and 2-amino analogues were active as inhibitors at ID50 approximately or equal to 10(-5) M, whereas the 2-fluoro and 2-carboxylic acid analogues were inactive at 1 X 10(-4) M. The results are contrasted with those found earlier for similar modifications in other positions of the vitamin B6 molecule. Although the 2-chloro analogue was found to inhibit pyridoxal phosphokinase (KI=24 micron), the 6-chloro analogue was inactive as an inhibitor at 1 mM.
将吡哆醇的2-甲基用各种其他基团取代，包括作为供电子取代基示例的2-氨基和2-甲氨基，以及作为吸电子取代基示例的2-羧基、2-羧酰胺和2-卤基。合成中的关键中间体是3-O-苄基-α4,α5-O-异亚丙基-α2-吡哆醇（15）或相应的2-醛（2）。另一种修饰2位的方法，但在化学上不太成功，从3-O-甲基吡哆醇开始，将其氧化为三羧酸，脱羧，酯化，并用LiAlH4还原，得到其中2-CH3基团被H取代的衍生物。测试这些类似物对培养的小鼠乳腺腺癌细胞的生长抑制活性。2-嗪、2-氯和2-氨基类似物作为抑制剂具有活性，ID50约为或等于10^(-5) M，而2-氟和2-羧酸类似物在1×10^(-4) M时无活性。将这些结果与早期在维生素B6分子其他位置进行类似修饰时发现的结果进行对比。尽管发现2-氯类似物可抑制吡哆醛磷酸激酶（KI = 24 μM），但6-氯类似物在1 mM时作为抑制剂无活性。
