期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 19, 期 11, 页码 3527-3539出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2011.04.016
关键词
Adefovir; Cidofovir; Antivirals; Prodrugs; Acyclic nucleoside phosphonate; Phosphonate ester; In vitro evaluation
资金
- Ministry of Education, Youth and Sports of the Czech Republic [AV0Z40550506, 1M0508]
- Gilead Sciences Inc. (Foster City, CA, USA)
- K.U. Leuven [10/014]
New Adefovir (PMEA) prodrugs with a pro-moiety consisting of decyl or decyloxyethyl chain bearing hydroxyl function(s), hexaethyleneglycol or a (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl unit were prepared starting from the tetrabutylammonium salt of the phosphonate drug and an appropriate alkyl bromide or tosylate. Analogously, two esters of Cidofovir [(S)-HPMPC] bearing a hexaethyleneglycol moiety were prepared. The activity of the prodrugs was evaluated in vitro against different virus families. A loss in the antiviral activities of the hydroxylated decyl or decyloxyethyl esters and hexaethyleneglycol esters of PMEA against human immunodeficiency virus (HIV) and herpesviruses [ including herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (CMV)] occurred in comparison with the parent compound. On the other hand, the (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester of PMEA showed significant activities against HIV and herpesviruses. (S)-HPMPC prodrugs exhibited anti-cytomegalovirus activities in the same range as the parent drug, whereas the anti-HSV and anti-VZV activities were one-to seven-fold lower than that of Cidofovir. (C) 2011 Elsevier Ltd. All rights reserved.
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