5‘-Phosphoramidates and 5‘-Diphosphates of 2‘-O-Allyl-β-d-arabinofuranosyl- uracil, -cytosine, and -adenine: Inhibition of Ribonucleotide Reductase

化学 核苷酸还原酶 胞嘧啶 尿嘧啶 立体化学 脱氧胞苷激酶 胸苷 激酶 核苷 胸苷激酶 核糖核苷 核苷酸 酶抑制剂 生物化学 磷酸化 鸟嘌呤 体外 核苷酸 脱氧胞苷 DNA 核糖核酸 蛋白质亚单位 生物 遗传学 化疗 单纯疱疹病毒 吉西他滨 病毒学 基因 病毒
作者
Stefano Manfredini,Pier Giovanni Baraldi,Elisa Durini,Silvia Vertuani,Jan Balzarini,Erik De Clercq,Anna Karlsson,Valentina Buzzoni,Lars Thelander
出处
期刊:Journal of Medicinal Chemistry [American Chemical Society]
卷期号:42 (17): 3243-3250 被引量:19
标识
DOI:10.1021/jm9807095
摘要

Continuing our studies on ribonucleotide reductase (RNR) mechanism-based inhibitors, we have now prepared the diphosphates (DP) of 2‘-O-allyl-1-β-d-arabinofuranosyl-uracil and -cytosine and 2‘-O-allyl-9-β-d-arabinofuranosyl-adenine and evaluated their inhibitory activity against recombinant murine RNR. 2‘-O-Allyl-araUDP proved to be inhibitory to RNR at an IC50 of 100 μM, whereas 2‘-O-allyl-araCDP was only marginally active (IC50 1 mM) and 2‘-O-allyl-araADP was completely inactive. The susceptibility of the parent nucleosides to phosphorylation by thymidine kinase and 2‘-deoxycytidine kinase was also investigated, and all nucleosides proved to be poor substrates for the above-cited kinases. Moreover, prodrugs of 2‘-O-allyl-araU and -araC monophosphates, namely 2‘-O-allyl-5‘-(phenylethoxy-l-alanyl phosphate)-araU and -araC, were prepared and tested against tumor cell proliferation but proved to be inactive. A molecular modeling study has been conducted in order to explain our results. The data confirm that for both the natural and analogue nucleoside diphosphates, the principal determinant interaction with the active site of RNR is with the diphosphate group, which forms strong hydrogen bonds with Glu623, Thr624, Ser625, and Thr209. Our findings indicate that the poor phosphorylation may represent an explanation for the lack of marked in vitro cytostatic activity of the test compounds.
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