Antiviral activities of novel 5-phosphono-pent-2-en-1-yl nucleosides and their alkoxyalkyl phosphonoesters
Antiviral activities of novel 5-phosphono-pent-2-en-1-yl nucleosides and their alkoxyalkyl phosphonoesters
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DOI：
10.1128/aac.00444-06
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发表时间：
2007-02-01
影响因子：
4.9
通讯作者：
Hostetler, Karl Y.
中科院分区：
文献类型：
--
作者：
Choo, Hyunah;Beadle, James R.;Hostetler, Karl Y.
三种无环核苷膦酸盐目前被批准用于临床治疗由巨细胞病毒（Vistide）、乙型肝炎病毒（Hepsera）和人类免疫缺陷病毒1型（Viread）引起的感染。这种重要的抗病毒药物类在细胞摄取并转化为二磷酸盐后抑制病毒聚合酶，绕过常规核苷类抗病毒药物所需的第一次磷酸化。无环侧链的微小化学改变导致无环核苷膦酸盐对不同类型病毒制剂的抗病毒活性和活性谱的显着差异。我们合成了一类新的基于5-磷酸-戊-2-烯-1-基基基基的无环核苷膦酸酯，其中氧杂原子通常存在于无环核苷膦酸酯被一个双键取代。由于固有的膦酸部分导致低口服生物利用度和细胞渗透受损，我们还制备了5-磷酸-戊-2-烯-1-基核苷的十六烷基氧丙基酯。我们早期的工作表明，这显着增加抗病毒活性和口服生物利用度。虽然5-磷酸-2-烯-1-基核苷本身没有活性，但十六烷基氧丙酯在体外对DNA病毒和乙型肝炎病毒有活性。值得注意的是，9-（5-磷酸-戊烯-2-烯基）腺嘌呤的十六烷基氧基丙基酯对拉米夫定、恩曲他滨和阿德福韦耐药的乙型肝炎病毒突变体有活性。
Three acyclic nucleoside phosphonates are currently approved for clinical use against infections caused by cytomegallovirus (Vistide), hepatitis B virus (Hepsera), and human immunodeficiency virus type 1 (Viread). This important antiviral class inhibits viral polymerases after cellular uptake and conversion to their diphosphates, bypassing the first phosphorylation, which is required for conventional nucleoside antivirals. Small chemical alterations in the acyclic side chain lead to marked differences in antiviral activity and the spectrum of activity of acyclic nucleoside phosphonates against various classes of viral agents. We synthesized a new class of acyclic nucleoside phosphonates based on a 5-phosphono-pent-2-en-1-yl base motif in which the oxygen heteroatom usually present in acyclic nucleoside phosphonates has been replaced with a double bond. Since the intrinsic phosphonate moiety leads to low oral bioavailabillity and impaired cellular penetration, we also prepared the hexadecyloxypropyl esters of the 5-phosphono-pent-2-en-1-yl nucleosides. Our earlier work showed that this markedly increases antiviral activity and oral bioavailability. Although the 5-phosphonopent-2-en-1-yl nucleosides themselves were not active, the hexadecyloxypropyl esters were active against DNA viruses and hepatitis B virus, in vitro. Notably, the hexadecyloxypropyl ester of 9-(5-phosphono-pent-2-en-lyl)-adenine was active against hepatitis B virus mutants resistant to lamivudine, emtricitabine, and adefovir.