期刊
ANTIVIRAL RESEARCH
卷 84, 期 3, 页码 254-259出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.antiviral.2009.09.012
关键词
Herpes simplex virus; Human cytomegalovirus; Murine cytomegalovirus; Vaccinia virus; Cowpox virus; Ectromelia virus; Acyclic nucleoside phosphonates; Alkoxyalkyl prodrugs; Drug delivery
资金
- NIH [AI-071803, AI-074057, EY-07366]
- National Institute for Allergy and Infectious Disease
- Center for AIDS and HIV Research of the San Diego VA Healthcare System
- N.I.H., National Institutes of Allergy and Infectious Disease [NO1-AI-30049, NO1-AI-15436]
- NATIONAL EYE INSTITUTE [R01EY007366] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI074057, R01AI071803, R01AI066499] Funding Source: NIH RePORTER
Our previous studies showed that esterification of 9-(S)-[3-hydroxy-2-(phosphonomethoxy)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-(phosphonomethoxy)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 I (HSV-1), human cytomegalovirus (HCMV), and vaccinia, cowpox and ectromelia. Against HSV-1, subnanomolar EC50 values were observed with ODE-H]PMPA and ODE-HPMPC while ODE-HPMPG had intermediate antiviral activity with an EC50 of 40 nM. In HFF cells infected with HCMV, the lowest EC50 values were observed with ODE-HPMPC, 0.9 nM. ODE-HPMPA was highly active with an EC50 of 3 nM, while ODE-HPMPG and ODE-HPMPDAP were also highly active with EC(50)s of 22 and 77 nM, respectively. Against vaccinia and cowpox viruses, ODE-HPMPG and ODE-HPMPDAP were the most active and selective compounds' with EC50 values of 20-60 nM and selectivity index values of 600-3500. ODE-HPMPG was also active against ectromelia virus with an EC50 value of 410 nM 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. (C) 2009 Elsevier B.V. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据