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首页> 外文期刊>Antiviral chemistry & chemotherapy >Synthesis and an antiviral activity evaluation of nucleoside 5 -O-(N-acyl) phosphoramidates.
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Synthesis and an antiviral activity evaluation of nucleoside 5 -O-(N-acyl) phosphoramidates.

机译：核苷5-o-（N-酰基）磷酰胺的合成与抗病毒活性评价。

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BACKGROUND: pyrimidine nucleoside analogues represent an established class of clinically useful antiviral agents. Once inside the cell, they are activated by a series of intracellular phosphorylation steps to produce 5 -triphosphate derivatives. In many cases, nucleoside analogues are poor substrates for the cellular kinases needed for their activation. It is clear that intracellular introduction of nucleoside analogues as phosphorylated metabolites (so called pronucleotides) could circumvent difficulties associated with the use of non-phosphorylated nucleoside analogues. METHODS: among the current diverse pronucleotide approaches, nucleoside phosphoramidate derivatives appear to be an interesting class of potential antiviral agents because of the known relatively low stability of the P-N bond in cellular media. On the basis of oxathiaphospholane chemistry, a series of novel conjugates of 5 -O-phosphorylated zidovudine (AZT) and stavudine (d4T) with amino acids carboxamidates were obtained. The synthesis was performed using N-(2-thiono-1,3,2-oxathiaphospholane) derivatives of amino acids carboxamides as precursors. RESULTS: all synthesized compounds were studied against DNA and RNA viruses. Specific antiviral activities were only detected against HIV type-1 and HIV type-2 in MT-4 cell cultures at compound concentrations that were equally active or slightly inferior to the activity of their parent drugs (2- to 20-fold for the AZT prodrugs and 6- to 40-fold for the d4T prodrugs). The compounds were also evaluated for their anti-HIV activity in CEM and in CEM thymidine-kinase-deficient (CEM/TK(-)) cell cultures. CONCLUSIONS: loss of compound antiviral potency in the CEM/TK(-) cells suggested an eventual conversion of the test compounds to the free nucleosides prior to further phosphorylation to the active 5 -triphosphate metabolite.
机译：背景：嘧啶核苷类似物代表了一类成熟的临床有用的抗病毒剂。一旦在细胞内，它们被一系列细胞内磷酸化步骤激活，以产生5-磷酸盐衍生物。在许多情况下，核苷类似物是其活化所需的细胞激酶的较差的底物。很明显，核苷类似物的细胞内引入作为磷酸化代谢物（所谓的原版）可以规避与使用非磷酸化核苷类似物相关的困难。方法：在目前的不同原版方法中，由于在细胞介质中的P-N键的已知的相对低的稳定性，核苷磷酸氨基甲酰胺衍生物似乎是潜在的抗病毒剂的有趣类。基于血磷胺化学的基础上，获得了具有氨基酸羧酰胺酸氨基酸的5-磷酸化的齐凡蛋白（AZT）和Stavudine（D4T）的一系列新型缀合物。使用氨基酸羧酰胺作为前体的氨基酸衍生物进行合成。结果：对DNA和RNA病毒研究了所有合成化合物。仅在MT-4细胞培养物中检测到特异性抗病毒活性，并在MT-4细胞培养物中以同等为活性或略微不如母体药物的活性（2-至20倍用于AZT前药的浓度）对于D4T前药的6至40倍）。还评估了化合物的CEM和CEM胸苷 - 激酶缺陷（CEM / TK（）细胞培养物中的抗HIV活性。结论：在CEM / TK化合物的抗病毒效力的损失（ - ）细胞之前进一步磷酸化表明测试化合物为游离核苷的最终转化为活性三磷酸5代谢物。

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