Korytnyk W, Potti P G
J Med Chem. 1977 Jan;20(1):1-5. doi: 10.1021/jm00211a001.
Methods for the simultaneous and stepwise modification of the 2 and 4 positions of vitamin B6 have been devloped and have been applied to the synthesis of several analogues of this vitamin. 3,alpha5-O-Dibenzylpyridoxol was converted to its N-oxide and was rearranged to an alpha2-hydroxy derivative with (CF3CO)2O. The 2,4-bis(hydroxymethyl) intermediate was oxidized (MnO2) to the 2,4-dialdehyde, which was converted by a Wittig reaction with triphenylmethylphosphorane to the 2,4-divinyl derivative. Removal of the benzyl groups with acid gave the 2,4-divinylpyridioxol analogue, which was phosphorylated in the 5' position to give the cofactor analogue. The 2-CH3 in the known vitamin B6 antagonists, 4-deoxypyridoxol and 4-vinylpyridoxal, was similarly modified to CH2OH, CHO, and CH = CH2. Modifications of the 2 position in the vitamin B6 antagonists are expected to be associated with changes in selectivity for enzymes in various tissues without a concomitant loss of biological activity, because of the well-established bulk tolerance in this position. Active analogues are expected to undergo, in vivo 5-phosphorylation, which is probably a prerequisite for their antagonist activity. Some of the compounds (e.g., the 2,4-divinyl analogue) have substantial growth-inhibitory activity for cultured mouse mammary adenocarcinoma. In contrast to that of the parent compounds, this activity was only partially reversed by pyridoxal.
已开发出同时和逐步修饰维生素B6的2位和4位的方法，并已应用于该维生素几种类似物的合成。3,α5 - O - 二苄基吡哆醇转化为其N - 氧化物，并用（CF3CO）2O重排为α2 - 羟基衍生物。2,4 - 双（羟甲基）中间体用MnO2氧化为2,4 - 二醛，通过与三苯基甲基磷叶立德的维蒂希反应将其转化为2,4 - 二乙烯基衍生物。用酸除去苄基得到2,4 - 二乙烯基吡哆醇类似物，其在5'位磷酸化得到辅因子类似物。已知的维生素B6拮抗剂4 - 脱氧吡哆醇和4 - 乙烯基吡哆醛中的2 - CH3同样被修饰为CH2OH、CHO和CH = CH2。由于该位置已确定的体积耐受性，预计维生素B6拮抗剂中2位的修饰将与对各种组织中酶的选择性变化相关，而不会伴随生物活性的丧失。活性类似物预计在体内会发生5 - 磷酸化，这可能是其拮抗剂活性的先决条件。一些化合物（例如2,4 - 二乙烯基类似物）对培养的小鼠乳腺腺癌具有显著的生长抑制活性。与母体化合物不同，这种活性仅被吡哆醛部分逆转。
