Synthesis and study of cyclic pronucleotides of 5-fluoro-2′-deoxyuridine

Abstract

A one-step method for the synthesis of cyclic pronucleotide (cProTide) derivatives of 5-fluoro-2′-deoxyuridine (FdUrd), utilizing a novel phosphoramidating reagent, is described. Stereochemistry at phosphorus was established by NMR studies and modeling. Cytotoxicity data of representative cProTide derivatives of FdUrd are presented. The observed cell-to-cell variations in activity suggests that it is feasible to screen for structural variations in the cProTide moiety favoring metabolic activation in cancer cells, which may lead to an increase in the therapeutic effectiveness of FdUrd. The method described is applicable to all anticancer and antiviral nucleoside analogs having both the 5′- and the 3′-OH groups available for modification, forming cProTide derivatives capable of delivering the 5′-monophosphates to cells.