NUCLEOTIDES .52. SYNTHESIS AND BIOLOGICAL-ACTIVITY OF NEW BASE-MODIFIED (2'-5')OLIGOADENYLATE TRIMERS

Some new (2'-5')oligoadenylate trimers, i.e., 22-28, containing the an tiviral nucleoside ribavirin (= -D-ribofuranosyl)-1H-1,2,4-triazole-3- carboxamide; 7) and the synthetic cytokine 6-(benzylamino)purine ribos ide (= N-6-benzyladenosine; 1) in different positions of the trimer, h ave been synthesized by the phosphotriester method. The selectively bl ocked nucleosides 2-6 and 8-11 and the 2'-phosphodiesters 13 and 14, u sed for the oligonucleotide syntheses, were synthesized from the corre sponding unprotected ribonucleosides 1 and 7, and isolated by silica-g el column chromatography. The fully deblocked trimers 22-28 were purif ied by ion-exchange chromatography on DEAE-Servacell 23-SS. The newly synthesized compounds were characterized by physical means. The abilit y of synthesized trimers to inhibit HIV-1 replication and to improve R Nase L activation were investigated. Some of the synthesized trimers s howed also biological inhibition of HIV-1 reverse transcriptase and HI V-1-induced syncytia formation. It was shown that Ado(Bn)-containing t rimers inhibited HIV-1-induced syncytia formation > 1500-fold, indepen dently of the position of the Ado(Bn) residue in the oligomer chain.