Nucleosides. Part LX. Synthesis and Characterization of Monomeric Cordycepin‐Vitamin and Cordycepin‐Lipid Conjugates Model Substances for Biodegradable Ester and Carbonate Linkages in Conjugates and Potential Inhibitors of HIV‐1 Replication

Abstract

Abstract Monomeric 3′‐deoxyadenosine (cordycepin) was modified at the 2′‐ O ‐ ( 13–18 ) and 5′‐ O ‐position ( 25–29 ) by the vitamins E, D 2 , and A and by the two lipids 1,2‐di‐ O ‐palmitoylglycerol and 1,2‐di‐ O ‐hexadecylglycerol via succinate or carbonate linkages. The base‐labile conjugates afforded protection groups like the 2‐(4‐nitro‐phenyl)ethoxycarbonyl (npeoc) and monomethoxytrityl group (MeOTr) that are cleavable without harming the ester and carbonate bonds, respectively. Monomeric conjugates of cordycepin and vitamin E, vitamin D 2 , 1,2‐di‐ O ‐palmitoylglycerol, and 1,2‐di‐ O ‐hexadecylglycerol (see 13, 14, 17, 18, 25, 26, 28 , and 29 ) inhibited HIV‐1‐induced syncytia formation 1.7 to 6.2 fold compared to 1.5‐fold for cordycepin (see Table ); IC 50 values for 25 and 28 were 257 and 267 m̈ M , respectively. In addition, the monomeric cordycepin‐vitamin and ‐lipid conjugates inhibited HIV‐1 RT activity 28–49% which compares with a 13% inhibition of HIV‐1 RT observed for cordycepin. The minimal inhibition of HIV‐1‐induced syncytia formation and HIV‐1 RT activity did not proceed by the activation of RNase L. The monomeric conjugates tested ( 13, 14 ) increased PKR expression.