Rode W, Kulikowski T, Kedzierska B, Shugar D
Drugs Exp Clin Res. 1986;12(6-7):545-9.
This paper presents improved synthetic methods for the modification of 2'-deoxyuridine-5'-monophosphate and its 5-fluoro derivative, using trimethylphosphate in aqueous medium at pH 10. These modifications include methylation of the pyrimidine ring N(3) and/or esterification of the phosphate group. The 5'-methyl ester of dUMP was neither a substrate nor an inhibitor of Ehrlich ascites carcinoma thymidylate synthetase. By contrast, the corresponding methyl ester of FdUMP was a tight-binding inhibitor of the enzyme from L1210, Ehrlich ascites carcinoma and CCRF-CEM cells. 3-Methyl-dUMP, fixed in the 4-keto form, exhibited only very weak substrate activity with the Ehrlich ascites carcinoma enzyme. The dUMP analogues 5-ethyl-dUMP and 5-propyl-dUMP were found to be competitive inhibitors of thymidylate synthetase from L1210, Ehrlich ascites carcinoma and HeLa cells, the former being the more potent inhibitor. Both analogues were shown to bind cooperatively to each of the mouse tumour enzymes. Two molecules of inhibitor interacted with a single enzyme molecule, reflected by the parabolic character of the replots of the slope versus inhibitor concentration. The parent dTMP was a stronger inhibitor of the mouse tumour enzymes than its higher alkyl homologues.
本文介绍了在pH值为10的水性介质中使用磷酸三甲酯对2'-脱氧尿苷-5'-单磷酸及其5-氟衍生物进行修饰的改进合成方法。这些修饰包括嘧啶环N(3)的甲基化和/或磷酸基团的酯化。dUMP的5'-甲酯既不是艾氏腹水癌胸苷酸合成酶的底物也不是其抑制剂。相比之下，FdUMP的相应甲酯是来自L1210、艾氏腹水癌和CCRF-CEM细胞的该酶的紧密结合抑制剂。以4-酮形式固定的3-甲基-dUMP对艾氏腹水癌酶仅表现出非常弱的底物活性。发现dUMP类似物5-乙基-dUMP和5-丙基-dUMP是来自L1210、艾氏腹水癌和HeLa细胞的胸苷酸合成酶的竞争性抑制剂，前者是更强效的抑制剂。两种类似物均显示与每种小鼠肿瘤酶协同结合。两个抑制剂分子与单个酶分子相互作用，这通过斜率对抑制剂浓度的重绘图的抛物线特征反映出来。母体dTMP对小鼠肿瘤酶的抑制作用比其高级烷基同系物更强。
