新型醚脂核苷缀合物的合成及其抗HIV-1活性评估

Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HIV-1 activity.

作者信息

Piantadosi C, Marasco C J, Morris-Natschke S L, Meyer K L, Gumus F, Surles J R, Ishaq K S, Kucera L S, Iyer N, Wallen C A

机构信息

University of North Carolina, School of Pharmacy, Division of Medicinal Chemistry and Natural Products, Chapel Hill 27599.

出版信息

J Med Chem. 1991 Apr;34(4):1408-14. doi: 10.1021/jm00108a025.

DOI:10.1021/jm00108a025

PMID:1901911

Abstract

Combinations of an amidoalkylphosphocholine, 8, and AZT have been found to cause an apparent synergistic action in suppressing infectious HIV-1 replication. In addition, amidoalkyl, oxyalkyl, and thioalkyl ether lipids have been chemically linked to anti-HIV-1 nucleosides (AZT and DDI) through phosphate and phosphonate linkages. These conjugates have shown promising in vitro anti-HIV-1 activity. Also, the conjugates have a 5-10-fold reduction in cell cytotoxicity compared to AZT alone. The most active compound, an amidoalkyl ether lipid-AZT conjugates, 4A, was found to have a differential selectivity of 1793 in a syncytial plaque assay. In comparison, AZT alone has a value of 1281.

摘要

已发现氨基烷基磷酸胆碱8与齐多夫定（AZT）的组合在抑制传染性HIV-1复制方面表现出明显的协同作用。此外，氨基烷基、氧烷基和硫代烷基醚脂质已通过磷酸酯和膦酸酯键与抗HIV-1核苷（AZT和双脱氧肌苷）化学连接。这些缀合物已显示出有前景的体外抗HIV-1活性。而且，与单独的AZT相比，这些缀合物的细胞毒性降低了5至10倍。在合胞体斑块试验中，发现活性最高的化合物——一种氨基烷基醚脂质-AZT缀合物4A，其差异选择性为1793。相比之下，单独的AZT的值为1281。