PREPARATION AND ANTI-HIV ACTIVITY OF N-3-SUBSTITUTED THYMIDINE NUCLEOSIDE ANALOGS

A series of 22 derivatives of AZT substituted at the N-3 position of t he thymine base were prepared and evaluated for anti-HIV activity in c ell culture (Lai strain of HIV-1 in CEM-c113 cells). The AZT analogs b earing a N-3 amino group (7), a hydroxyalkyl chain (12f), and a phosph onomethyl (12k) substituent displayed activities in the 0.045-0.082 mu M range. The analogs 12d, 12e, 12q, 15, and 19 were active at <0.5 mu M concentration. Compound 18 in which two molecules of AZT are connec ted at N-3 via a two-carbon link and ''dimer'' II also displayed signi ficant; activity. To obtain information concerning the mechanism of RT inhibition by these AZT analogs, compounds 7, 12d, 12e, and 12q were incubated with recombinant HIV-1 RT in the presence of poly(A)-oligo[d T((12-18))] and poly(C)-oligo[dG((12-18))] template-primers. In contra st to AZT-TP (control), none of these nucleosides displayed any signif icant inhibition of RT in the recombinant enzyme assay, indicating tha t phosphorylation is a necessary prerequiste for activity.