Nucleotides. Part LII. Synthesis and biological activity of new base‐modified (2′–5′)oligoadenylate trimers

Abstract

Abstract Some new (2′–5′)oligoadenylate trimers, i.e., 22 – 28 , containing the antiviral nucleoside ribavirin (= 1‐(β‐ D ‐ribofuranosyl)‐1 H ‐1,2,4‐triazole‐3‐carboxamide; 7 ) and the synthetic cytokine 6‐(benzylamino)purine riboside (= N 6 ‐benzyladenosine; 1 ) in different positions of the trimer, have been synthesized by the phosphotriester method. The selectively blocked nucleosides 2 – 6 and 8 – 11 and the 2′‐phosphodiesters 13 and 14 , used for the oligonucleotide syntheses, were synthesized from the corresponding unprotected ribonucleosides 1 and 7 , and isolated by silica‐gel column chromatography. The fully deblocked trimers 22 – 28 were purified by ion‐exchange chromatography on DEAE ‐ Senacell 23 ‐ SS . The newly synthesized compounds were characterized by physical means. The ability of synthesized trimers to inhibit HIV‐1 replication and to improve RNase L activation were investigated. Some of the synthesized trimers showed also biological inhibition of HIV‐1 reverse transcriptase and HIV‐1‐induced syncytia formation. It was shown that Ado Bn ‐containing trimers inhibited HIV‐1‐induced syncytia formation > 1500‐fold, independently of the position of the Ado Bn residue in the oligomer chain.