Nucleotides: Part LI - Synthesis and Biological Activities of (2′-5′)Adenylate Trimer Conjugates with 2′-Terminal 3′-O-(ω-Hydroxyalkyl) and 3′-O-(ω-Carboxyalkyl) Spacers

Article abstract of DOI:10.1002/hlca.19970800313

An efficient strategy for the synthesis of (2′-5′)adenylate trimer conjugates with 2′-terminal 3′-O-(ω-hydroxyalkyl) and 3′-O-(ω-carboxyalkyl) spacers is reported. Npeoc-protected adenosine building blocks 37-40 for phosphoramidite chemistry carrying a 3′-O-[11-(levulinoyloxy)undecyl], 3′-O-{2-[2-(levulinoyloxy)ethoxy]ethyl}, 3′-O-[5-(2-cyanoethoxycarbonyl)pentyl], and 3′-O-{5-[(9H-fluoren-9-ylmethoxy)carbonyl]pentyl} moiety, respectively, were prepared (npeoc = 2-(4-nitrophenyl)ethoxycarbonyl). Condensation with the cordycepin (3′-deoxyadenosine) dimer 1 led to the corresponding trimers 42, 43, 47, and 48. Whereas the levulinoyl (lev) and 9H-fluoren9-ylmethyl (fm) blocking groups could be cleaved off selectively from the trimers 42, 43, and 48 yielding the intermediates 44, 45, and 49 for the synthesis of the 3′-O-(ω-hydroxyalkyl)trimers 53, 54 and the cholesterol conjugates 59-61, the 2-cyanoethyl (ce) protecting group of 47, however, could not be removed in a similar manner from the carboxy function. Trimer 47 served as precursor for the preparation of the trimer 55 with a terminal 3′-O-(5-carboxypentyl)adenosine moiety. The metabolically stable 3′-O-alkyl-(2′-5′)A derivatives were tested regarding inhibition of HIV-1 syncytia formation and HIV-1 RT activity. Only the conjugate 59 showed significant effects, whereas the trimers 53-55 and the conjugates 60 and 61 were less potent inhibitors, even at 100-fold larger concentrations.