Hong C I, Nechaev A, Kirisits A J, Vig R, West C R, Manouilov K K, Chu C K
Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
J Med Chem. 1996 Apr 26;39(9):1771-7. doi: 10.1021/jm950620o.
A series of the anti-HIV nucleoside conjugates of either (1-O-alkyl) and thioether (1-S-alkyl) lipids linked by a pyrophosphate diester bond has been synthesized as micelle-forming prodrugs of the nucleosides to improve their therapeutic efficiency. These include AZT 5'-diphosphate-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (1), 3'-azido-2',3'-dideoxyuridine 5'-diphosphate-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (2) 2',3'-dideoxycytidine 5'-diphosphate-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (3), and AZT 5'-diphosphate-rac-1-O-tetradecyl-2-O-palmitoylglycerol (4). The conjugates form micelles by sonication (mean diameters ranging 6.8-55.5 nm). Conjugate 1 protected 80% of HIV-infected CEM cells as low as 0.58 microM and lost the protection at 180 microM due to prevailing cytotoxicity, while the conjugate started to show the cytotoxicity at 100 microM. Pharmacokinetics studies showed a significant increase of half-life values (t1/2) of AZT and AZddU2 (respective t1/2 = 5.69 and 6.5 h) after administration of conjugates 1 and 2, while those after administration of AZT and AZddU were 0.28 and 0.89 h, respectively. The fractions of the prodrugs 1 and 2 converted to the parent compounds AZT and AZddU were 36% and 55%, respectively. The results indicate that AZT and AZddU thioether lipid conjugates 1 and 2 warrant further investigation.
一系列通过焦磷酸二酯键连接的（1-O-烷基）和硫醚（1-S-烷基）脂质的抗HIV核苷共轭物已被合成为核苷的胶束形成前药，以提高其治疗效果。这些包括叠氮胸苷5'-二磷酸-rac-1-S-十八烷基-2-O-棕榈酰-1-硫代甘油（1）、3'-叠氮-2',3'-二脱氧尿苷5'-二磷酸-rac-1-S-十八烷基-2-O-棕榈酰-1-硫代甘油（2）、2',3'-二脱氧胞苷5'-二磷酸-rac-1-S-十八烷基-2-O-棕榈酰-1-硫代甘油（3）以及叠氮胸苷5'-二磷酸-rac-1-O-十四烷基-2-O-棕榈酰甘油（4）。共轭物通过超声处理形成胶束（平均直径范围为6.8 - 55.5纳米）。共轭物1在低至0.58微摩尔时可保护80%的HIV感染的CEM细胞，但在180微摩尔时由于普遍的细胞毒性而失去保护作用，而该共轭物在100微摩尔时开始显示细胞毒性。药代动力学研究表明，在给予共轭物1和2后，叠氮胸苷和叠氮双脱氧尿苷2的半衰期值（t1/2）显著增加（分别为t1/2 = 5.69和6.5小时），而给予叠氮胸苷和叠氮双脱氧尿苷后的半衰期分别为0.28和0.89小时。前药1和2转化为母体化合物叠氮胸苷和叠氮双脱氧尿苷的比例分别为36%和55%。结果表明，叠氮胸苷和叠氮双脱氧尿苷硫醚脂质共轭物1和2值得进一步研究。
