title: Antiviral nucleoside diphosphate diglycerides: improved synthesis and facilitated purification.
abstract: 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.
authors.affiliation: Center for Biomembranes and Lipid Enzymology, University of Utrecht, The Netherlands.
authors.forename: G M
authors.initials: GM
authors.lastname: van Wijk
authors.forename: K Y
authors.initials: KY
authors.lastname: Hostetler
authors.forename: H
authors.initials: H
authors.lastname: van den Bosch
mesh_terms: D000212:Acyclovir / Q000737:chemistry; D000998:Antiviral Agents / Q000737:chemistry*; D003567:Cytidine Diphosphate Diglycerides / Q000737:chemistry* / Q000302:isolation & purification; D004075:Diglycerides / Q000096:biosynthesis*; D007850:Lauric Acids / Q000737:chemistry; D019814:Myristic Acid; D009227:Myristic Acids / Q000737:chemistry; D009705:Nucleosides / Q000096:biosynthesis*; D010712:Phosphatidic Acids / Q000737:chemistry; D016047:Zalcitabine / Q000737:chemistry; D015215:Zidovudine / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; D003567:Cytidine Diphosphate Diglycerides; D004075:Diglycerides; D007850:Lauric Acids; D009227:Myristic Acids; D009705:Nucleosides; D010712:Phosphatidic Acids; D019814:Myristic Acid; C030358:lauric acid; D015215:Zidovudine; D016047:Zalcitabine; D000212:Acyclovir