1-O-十八烷基-2-O-烷基-sn-甘油-3-膦甲酸盐缀合物在人巨细胞病毒感染细胞中的合成及抗病毒活性

Synthesis and antiviral activity of 1-O-octadecyl-2-O-alkyl-sn-glycero-3-foscarnet conjugates in human cytomegalovirus-infected cells.

作者信息

Kini G D, Hostetler S E, Beadle J R, Aldern K A

机构信息

Department of Medicine, University of California, San Diego, La Jolla 92093-0676, USA.

出版信息

Antiviral Res. 1997 Nov;36(2):115-24. doi: 10.1016/s0166-3542(97)00048-x.

DOI:10.1016/s0166-3542(97)00048-x

PMID:9443668

Abstract

A series of new lipid prodrugs with the general structure, 1-O-octadecyl-2-X-sn-glycero-3-PFA were synthesized and evaluated for antiviral activity in HCMV-infected human lung fibroblasts (X is -H, -OH or an O-alkyl group of increasing chain length) in order to study structure-activity relationships of PFA lipid prodrugs. The EC50 values for the 2-O-octyl, 2-O-butyl, 2-H, 2-OH, 2-O-methyl and 2-O-ethyl substituted analogs were 1.96, 0.36, 1.0, 0.7, 0.53 and 0.18 microM respectively versus 40 microM for PFA, representing increases in antiviral activity of 20-220 fold. We also synthesized the enantiomer of ODG-PFA, 3-O-octadecyl-sn-glycero-1-PFA, and found that the antiviral activity of both enantiomers as well as the racemate were not significantly different, with EC50 values in the range of 0.67-0.71 microM.

摘要

合成了一系列具有通式1-O-十八烷基-2-X-sn-甘油-3-磷酸脂肪酸（PFA）的新型脂质前药，并在人巨细胞病毒（HCMV）感染的人肺成纤维细胞中评估了其抗病毒活性（X为-H、-OH或链长递增的O-烷基），以研究PFA脂质前药的构效关系。2-O-辛基、2-O-丁基、2-H、2-OH、2-O-甲基和2-O-乙基取代类似物的半数有效浓度（EC50）值分别为1.96、0.36、1.0、0.7、0.53和0.18微摩尔，而PFA的EC50值为40微摩尔，这表明抗病毒活性提高了20至220倍。我们还合成了ODG-PFA的对映体3-O-十八烷基-sn-甘油-1-PFA，发现两种对映体以及外消旋体的抗病毒活性没有显著差异，EC50值在0.67至0.71微摩尔范围内。