3'-N-膦酸酰胺和 3'-N-硫代膦酸酰胺胸苷基-3'，5'-胸苷类似物的水解反应。

Hydrolytic reactions of 3'-N-phosphoramidate and 3'-N-thiophosphoramidate analogs of thymidylyl-3',5'-thymidine.

机构信息

Department of Chemistry, University of Turku, FIN-20014 Turku, Finland.

出版信息

Org Biomol Chem. 2004 Feb 21;2(4):593-600. doi: 10.1039/b313470a. Epub 2004 Jan 26.

Abstract

The diastereomeric thiophosphoramidate analogs [(R(P))- and (S(P))-3[prime or minute],5[prime or minute]-Tnp(s)T] and the phosphoramidate analog [3[prime or minute],5[prime or minute]-TnpT] of thymidylyl-3[prime or minute],5[prime or minute]-thymidine were prepared and their hydrolytic reactions over the pH-range 1-8 at 363.2 K were followed by RP HPLC. At pH < 6, an acid-catalyzed P-N3[prime or minute] bond cleavage (first-order in [H(+)]) takes place with both 3[prime or minute],5[prime or minute]-Tnp(s)T and 3[prime or minute],5[prime or minute]-TnpT, the former being about 12 fold more stable than the latter. At pH > 4, Tnp(s)T undergoes two competing pH-independent reactions, desulfurization (yielding TnpT) and depyrimidination (cleavage of the N-glycosidic bond) the rates of which are of the same order of magnitude. Also with 3[prime or minute],5[prime or minute]-TnpT the pH-independent depyrimidination competes with P-N3[prime or minute] cleavage at pH > 5.

摘要

(R(P))-和(S(P))-3[prime 或 minute],5[prime 或 minute]-Tnp(s)T 与胸苷酰基-3[prime 或 minute],5[prime 或 minute]-胸苷的非对映异构硫代磷酰胺酯类似物 [(R(P))- 和 (S(P))-3[prime 或 minute],5[prime 或 minute]-Tnp(s)T] 和磷酰胺酯类似物 [3[prime 或 minute],5[prime 或 minute]-TnpT] 被制备出来，并在 363.2 K 下 pH 值为 1-8 的范围内通过反相高效液相色谱法跟踪它们的水解反应。在 pH < 6 时，两种物质均发生酸催化的 P-N3[prime 或 minute]键断裂（[H(+)])呈一级反应，3[prime 或 minute],5[prime 或 minute]-Tnp(s)T 和 3[prime 或 minute],5[prime 或 minute]-TnpT 的稳定性前者约为后者的 12 倍。在 pH > 4 时，Tnp(s)T 经历两种竞争的 pH 无关反应，脱硫（生成 TnpT）和去嘧啶化（N-糖苷键断裂），其速率处于相同数量级。对于 3[prime 或 minute],5[prime 或 minute]-TnpT，pH 无关的去嘧啶化反应与 pH > 5 时的 P-N3[prime 或 minute]断裂竞争。