van Wijk G M, Hostetler K Y, van den Bosch H
Center for Biomembranes and Lipid Enzymology, University of Utrecht, The Netherlands.
J Lipid Res. 1992 Aug;33(8):1211-9.
Cytidine diphosphate diglyceride and its analogs have previously been synthesized by condensing phosphatidic acid with the monophosphomorpholidates of the various nucleosides. Yields have been low and purification of the product has been difficult. We report here an improved method for the synthesis of nucleoside diphosphate diglycerides with potential antiviral activity. Phosphatidic acid was activated with morpholine in the presence of dicyclohexylcarbodiimide to phosphatidic acid morpholidate. This compound was condensed with the 5'-monophosphate of the anti-HIV agents 3'-azido-3'-deoxythymidine, 3'-deoxythymidine or 2',3'-dideoxycytidine, and the monophosphate of the anti-HSV agent acyclovir. The resulting nucleoside diphosphate diglycerides are potential candidates for improved antiviral action when compared to the parent nucleoside analogs. Compared to the older method for the preparation of cytidine diphosphate diglyceride and analogs thereof, the new method has several advantages: reaction times are reduced from several days to several hours and the yield of the reactions is generally increased from 20-40% to between 50 and 80%. In addition, the purification of the compounds is greatly facilitated due to the small amount of phosphatidic acid remaining in the reaction mixture.
胞苷二磷酸甘油酯及其类似物先前是通过将磷脂酸与各种核苷的单磷酸吗啉代物缩合来合成的。产率较低，且产物的纯化困难。我们在此报告一种合成具有潜在抗病毒活性的核苷二磷酸甘油酯的改进方法。在二环己基碳二亚胺存在下，磷脂酸用吗啉活化生成磷脂酸吗啉代物。该化合物与抗HIV药物3'-叠氮基-3'-脱氧胸苷、3'-脱氧胸苷或2',3'-二脱氧胞苷的5'-单磷酸，以及抗HSV药物阿昔洛韦的单磷酸缩合。与母体核苷类似物相比，所得的核苷二磷酸甘油酯是具有改善抗病毒作用的潜在候选物。与制备胞苷二磷酸甘油酯及其类似物的旧方法相比，新方法有几个优点：反应时间从几天减少到几小时，反应产率一般从20 - 40%提高到50%至80%之间。此外，由于反应混合物中残留的磷脂酸量很少，大大便于了化合物的纯化。
