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JR Beadle, L-Y Cheng, KY Hostetler, WR Freeman; Phospholipid Prodrugs of Nucleosides for Intravitreal Injection: Synthesis of Hexadecyloxypropyl-phospho-Ara G for the Treatment of Proliferative Vitreoretinopathy . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2311.
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Purpose: To prepare an injectable phopholipid prodrug of the antiproliferative agent 9-(ß-D-arabinofuranosyl)guanine (Ara G) for evaluation as a long-lasting therapy against proliferative vitreoretinopathy (PVR). Methods: Previous studies in experimental models showed that hexadecyloxypropyl-phospho-ganciclovir provides sustained intravitreal release of ganciclovir. To extend this drug delivery strategy to Ara G and the treatment of PVR, the synthesis of the related compound hexadecyloxypropyl-phospho-Ara G (HDP-P-Ara G) was undertaken. Results: The reactive groups of guanosine were blocked with appropriate protecting groups and the 2'-hydroxyl was converted to trifluoromethanesulfonate. Reaction of the triflate intermediate with lithium acetate, followed by partial deblocking, provided the key blocked Ara G derivative 1 (see below). Compound 1 was then coupled to hexadecyloxypropylphosphate (DCC, pyridine). Complete deblocking afforded the target compound, HDP-P-Ara G, as a white crystalline solid. Conclusion: A procedure was developed for the synthesis of HDP-P-Ara G from the readily available starting material guanosine. Intravitreal injection of crystalline HDP-P-Ara G may provide a long-lasting antiproliferative effect for the treatment of PVR. View OriginalDownload SlideView OriginalDownload Slide
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