Synthesis and antiviral evaluation of alkoxyalkyl derivatives of 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)adenine against cytomegalovirus and orthopoxviruses
Synthesis and antiviral evaluation of alkoxyalkyl derivatives of 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)adenine against cytomegalovirus and orthopoxviruses
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DOI：
10.1021/jm050473m
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发表时间：
2006-03-23
影响因子：
7.3
通讯作者：
Hostetler, KY
中科院分区：
文献类型：
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作者：
Beadle, JR;Wan, WB;Hostetler, KY
9-（S）-（3-羟基-2-膦酰甲氧基丙基）腺嘌呤[（S）-HPMPA]是第一个被描述的无环核苷膦酸酯之一，并已被报道对大多数双链DNA病毒（包括疱疹组病毒和正痘病毒）具有良好的抗病毒活性。然而，（S）-HPMPA不具有口服生物利用度，并且尚未开发用于临床使用。我们已经制备了口服生物可利用的（S）-HPMPA的脂质酯，并报告了它们的合成和抗巨细胞病毒和正痘病毒的抗病毒评价。这些酯进行了评估，在体外细胞感染人巨细胞病毒（HCMV），鼠巨细胞病毒（MCMV），牛痘（VV），和牛痘病毒（CV）。发现最具活性的化合物油酰氧基乙基-（S）-HPMPA对HCMV的EC 50值为0.003 μ M，而未修饰的HPMPA为1.4 μ M。在VV和CV感染的细胞中，十八烷氧基乙基-（S）-HPMPA的EC 50值为0.01-0.02 μ M，而未修饰的HPMPA为2.7 - 4.0 μ M。当与西多福韦的烷氧基烷基酯相比时，（S）-HPMPA的相应烷氧基烷基酯对HCMV和MCMV具有相同的活性，但在体外对VV和CV的活性高15-20倍。（S）-HPMPA的烷氧基烷基酯是值得进一步研究用于治疗由疱疹病毒和正痘病毒引起的感染的有前景的新化合物。
9-(S)-(3-Hydroxy-2-phosphonomethoxypropyl)adenine [(S)-HPMPA] was one of the first acyclic nucleoside phosphonates described and has been reported to have good antiviral activity against most double-stranded DNA viruses, including the herpes group viruses and the orthopoxviruses. However, (S)-HPMPA is not orally bioavailable and has not been developed for clinical use. We have prepared orally bioavailable lipid esters of (S)-HPMPA and report their synthesis and antiviral evaluation against cytomegalovirus and orthopoxviruses. These esters were evaluated in vitro in cells infected with human cytomegalovirus (HCMV), murine cytomegalovirus (MCMV), vaccinia (VV), and cowpox viruses (CV). The most active compound, oleyloxyethyl-(S)-HPMPA, was found to have EC50 value of 0.003 mu M against HCMV vs 1.4 mu M for unmodified HPMPA. In cells infected with VV and CV, octadecyloxyethyl-(S)-HPMPA had EC50 values of 0.01-0.02 mu M versus 2.7 -4.0 mu M for unmodified HPMPA. When compared with the alkoxyalkyl esters of cidofovir, the corresponding alkoxyalkyl esters of (S)-HPMPA were equally active against HCMV and MCMV but were 15-20-fold more active against VV and CV in vitro. The alkoxyalkyl esters of (S)-HPMPA are promising new compounds worthy of further investigation for treatment of infections caused by herpes viruses and orthopoxviruses.