Antiviral evaluation of octadecyloxyethyl esters of (S)-3-hydroxy-2-(phosphonomethoxy)propyl nucleosides against herpesviruses and orthopoxviruses.
Antiviral evaluation of octadecyloxyethyl esters of (S)-3-hydroxy-2-(phosphonomethoxy)propyl nucleosides against herpesviruses and orthopoxviruses.
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DOI：
10.1016/j.antiviral.2009.09.012
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发表时间：
2009-12
影响因子：
7.6
通讯作者：
Hostetler, Karl Y.
中科院分区：
文献类型：
--
作者：
Valiaeva, Nadejda;Prichard, Mark N.;Buller, R. Mark;Beadle, James R.;Hartline, Caroll B.;Keith, Kathy A.;Schriewer, Jill;Trahan, Julissa;Hostetler, Karl Y.
关键词：
我们的前期研究表明，（S）-3-羟基-2-（膦酰甲氧基）丙基]腺嘌呤（HPMPA）或1-（S）-[3-羟基-2-（膦酰甲氧基）丙基]胞嘧啶（HPMPC）与烷氧基烷基如十六烷氧基丙基（HDP）或十八烷氧基乙基（ODE）的酯化可显著提高抗病毒活性和口服生物利用度。HPMPA的HDP-和ODE-酯在感染人类免疫缺陷病毒1型（HIV-1）的细胞中显示出活性，而HPMPA本身实际上无活性。为了更详细地探索这种方法，我们合成了该系列中的四个新化合物，9-（S）-[3-羟基-2-（3-羟基-2-甲基苯基）-2-（4-羟基苯基（膦酰甲氧基）-丙基]鸟嘌呤（HPMPG），1-（S）-[3-羟基-2-（膦酰基-甲氧基）丙基]胸腺嘧啶（HPMPT），9-（S）-[3-羟基-2-（膦酰甲氧基）丙基]-2，6-二氨基嘌呤（HPMPDAP）和9-（S）-[3-羟基-2-（膦酰甲氧基）丙基]-2-氨基-6-环丙基氨基嘌呤。（HPMP-cPrDAP），并评估它们对单纯疱疹病毒1型（HSV-1）、人巨细胞病毒（HCMV）以及牛痘、牛痘和肢脱病的抗病毒活性。对于HSV-1，用ODE-HPMPA和ODE-HPMPC观察到亚纳摩尔EC 50值，而ODE-HPMPG具有中等抗病毒活性，EC 50为40纳摩尔。在感染HCMV的HFF细胞中，ODE-HPMPC的EC 50值最低，为0.9纳摩尔。ODE-HPMPA具有高活性，EC 50为3纳摩尔，而ODE-HPMPG和ODE-HPMPDAP也具有高活性，EC 50分别为22和77纳摩尔。针对牛痘和牛痘病毒，ODE-HPMPG和ODE-HPMPDAP是最具活性和选择性的化合物，EC 50值为20至60纳摩尔，选择性指数值为600至3，500。ODE-HPMPG对鼠痘病毒也有活性，EC 50值为410纳摩尔，选择性指数值为166。ODE-HPMPG和ODE-HPMPDAP被提议作为治疗HSV、HCMV或正痘病毒疾病的可能候选物用于进一步的临床前评价。
Our previous studies showed that esterification of (S)-3-hydroxy-2-(phosphono-methoxy)propyl]adenine (HPMPA) or 1-(S)-[3-hydroxy-2-(phosphonomethoxy)-propyl]cytosine (HPMPC) with alkoxyalkyl groups such as hexadecyloxypropyl (HDP) or octadecyloxyethyl (ODE) resulted in large increases in antiviral activity and oral bioavailability. The HDP- and ODE- esters of HPMPA were shown to be active in cells infected with human immunodeficiency virus, type 1 (HIV-1), while HPMPA itself was virtually inactive. To explore this approach in greater detail, we synthesized four new compounds in this series, the ODE esters of 9-(S)-[3-hydroxy-2-(phosphonomethoxy)-propyl]guanine (HPMPG), 1-(S)-[3-hydroxy-2-(phosphono-methoxy)propyl]thymine (HPMPT), 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (HPMPDAP) and 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-2-amino-6-cyclopropylaminopurine. (HPMP-cPrDAP) and evaluated their antiviral activity against herpes simplex virus, type 1 (HSV-1), human cytomegalovirus (HCMV), and vaccinia, cowpox and ectromelia. Against HSV-1, subnanomolar EC50 values were observed with ODE-HPMPA and ODE-HPMPC while ODE-HPMPG had intermediate antiviral activity with an EC50 of 40 nanomolar. In HFF cells infected with HCMV, the lowest EC50 values were observed with ODE-HPMPC, 0.9 nanomolar. ODE -HPMPA was highly active with an EC50 of 3 nanomolar, while ODE-HPMPG and ODE-HPMPDAP were also highly active with EC50s of 22 and 77 nanomolar, respectively. Against vaccinia and cowpox viruses, ODE-HPMPG and ODE-HPMPDAP were the most active and selective compounds with EC50 values of 20 to 60 nanomolar and selectivity index values of 600 to 3,500. ODE-HPMPG was also active against ectromelia virus with an EC50 value of 410 nanomolar and a selectivity index value of 166. ODE-HPMPG and ODE-HPMPDAP are proposed for further preclinical evaluation as possible candidates for treatment of HSV, HCMV or orthopoxvirus diseases.
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影响因子：
3.6
作者：
Aldern, KA;Ciesla, SL;Hostetler, KY
通讯作者：
Hostetler, KY
影响因子：
4.9
作者：
Magee, Wendy C.;Aldern, Kathy A.;Evans, David H.
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Evans, David H.
影响因子：
4.9
作者：
Choo, Hyunah;Beadle, James R.;Hostetler, Karl Y.
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Hostetler, Karl Y.
影响因子：
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作者：
Beadle, JR;Wan, WB;Hostetler, KY
通讯作者：
Hostetler, KY
影响因子：
4.9
作者：
Magee, WC;Hostetler, KY;Evans, DH
通讯作者：
Evans, DH