胸苷的5'-二硫代磷酸酯和5'-氟硫代磷酸酯的合成及其与胸苷酸合成酶的相互作用

Synthesis and interaction with thymidylate synthase of 5'-dithiophosphate and 5'-fluorothiophosphate of thymidine.

作者信息

Gołos B, Misiura K, Olesiak M, Okruszek A, Stec W J, Rode W

机构信息

Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw.

出版信息

Acta Biochim Pol. 1998;45(1):83-6.

Abstract

Thymidine-5'-fluorothiophosphate, dTMP(S)-F, was synthesized by the oxathiaphospholane, and thymidine 5'-dithiophosphate, dTMPS2, by the dithiaphospholane, method. To estimate the role of 5'-phosphate group ionization in binding of pyrimidine nucleotides by thymidylate synthase, dTMP(S)-F was studied as an inhibitor of mouse tumour (L1210) enzyme, and its inhibitory properties were compared with those of dTMPS2, a close dTMP analogue. While dTMPS2 proved to be an inhibitor, competitive vs dUMP, with K(i)app = 94 microM, the 5'-fluorothiophosphate congener displayed no activity, indicating that the enzyme requires for binding the presence of a dianionic 5'-phosphate group in a nucleotide.

摘要

通过氧硫磷杂环戊烷合成了胸苷-5'-氟硫代磷酸酯（dTMP(S)-F），并通过二硫磷杂环戊烷法合成了胸苷5'-二硫代磷酸酯（dTMPS2）。为了评估5'-磷酸基团离子化在胸苷酸合酶结合嘧啶核苷酸中的作用，对dTMP(S)-F作为小鼠肿瘤（L1210）酶抑制剂进行了研究，并将其抑制特性与结构相近的dTMP类似物dTMPS2的抑制特性进行了比较。虽然dTMPS2被证明是一种对dUMP具有竞争性的抑制剂，表观抑制常数（K(i)app）为94微摩尔，但5'-氟硫代磷酸酯类似物没有活性，这表明该酶结合核苷酸时需要二价阴离子形式的5'-磷酸基团。

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