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两种嘧啶无环核苷膦酸酯的新型前药：合成与抗病毒活性。

New prodrugs of two pyrimidine acyclic nucleoside phosphonates: Synthesis and antiviral activity.

作者信息

Krečmerová Marcela, Dračínský Martin, Snoeck Robert, Balzarini Jan, Pomeisl Karel, Andrei Graciela

机构信息

Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, CZ-166 10, Prague 6, Czech Republic.

Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, CZ-166 10, Prague 6, Czech Republic.

出版信息

Bioorg Med Chem. 2017 Sep 1;25(17):4637-4648. doi: 10.1016/j.bmc.2017.06.046. Epub 2017 Jul 6.

DOI:10.1016/j.bmc.2017.06.046
PMID:28757102
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7126465/
Abstract

New 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidine (PMEO-DAPy) and 1-[2-(phosphonomethoxy)ethyl]-5-azacytosine (PME-5-azaC) prodrugs were prepared with a pro-moiety consisting of carbonyloxymethyl esters (POM, POC), alkoxyalkyl esters, amino acid phosphoramidates and/or tyrosine. The activity of the prodrugs was evaluated in vitro against different virus families. None of the synthesized prodrugs demonstrated activity against RNA viruses but some of them proved active against herpesviruses [including herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV)]. The bis(POC) and the bis(amino acid) phosphoramidate prodrugs of PMEO-DAPy inhibited herpesvirus replication at lower doses than the parent compound although the selectivity against HSV and VZV was only slightly improved compared to PMEO-DAPy. The mono-octadecyl ester of PME-5-azaC emerged as the most potent and selective PME-5-azaC prodrug against HSV, VZV and HCMV with EC's of 0.15-1.12µM while PME-5-azaC only had marginal anti-herpesvirus activity. Although the bis(hexadecylamido-l-tyrosyl) and the bis(POM) esters of PME-5-azaC were also very potent anti-herpesvirus drugs, these were less selective than the mono-octadecyl ester prodrug.

摘要

新型2,4-二氨基-6-[2-(膦酰甲氧基)乙氧基]嘧啶(PMEO-DAPy)和1-[2-(膦酰甲氧基)乙基]-5-氮杂胞苷(PME-5-azaC)前药是由羰氧基甲酯(POM、POC)、烷氧基烷基酯、氨基酸磷酰胺和/或酪氨酸组成的前体部分制备而成。对这些前药的活性进行了体外抗不同病毒家族的评估。合成的前药均未显示出对RNA病毒的活性，但其中一些对疱疹病毒[包括单纯疱疹病毒(HSV)、水痘带状疱疹病毒(VZV)和人巨细胞病毒(HCMV)]具有活性。PMEO-DAPy的双(POC)和双(氨基酸)磷酰胺前药在较低剂量下比母体化合物更能抑制疱疹病毒复制，尽管与PMEO-DAPy相比，对HSV和VZV的选择性仅略有提高。PME-5-azaC的单十八烷基酯成为针对HSV、VZV和HCMV最有效和最具选择性的PME-5-azaC前药，其半数有效浓度(EC)为0.15 - 1.12µM，而PME-5-azaC仅具有微弱的抗疱疹病毒活性。尽管PME-5-azaC的双(十六烷酰胺基-L-酪氨酰)酯和双(POM)酯也是非常有效的抗疱疹病毒药物，但它们的选择性不如单十八烷基酯前药。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/163af2f6dfaf/gr3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/b8b010213f51/fx1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/d0a9f44bd94f/gr1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/e2732fef208b/gr2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/7d40123b259b/gr4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/d0a086ed61d0/gr5_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/84f0b939c508/gr6_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/519f6efa1ad2/gr7_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/6221ce24e221/gr8_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/163af2f6dfaf/gr3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/b8b010213f51/fx1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/d0a9f44bd94f/gr1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/e2732fef208b/gr2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/7d40123b259b/gr4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/d0a086ed61d0/gr5_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/84f0b939c508/gr6_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/519f6efa1ad2/gr7_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/6221ce24e221/gr8_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/523d/7126465/163af2f6dfaf/gr3_lrg.jpg

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