SYNTHESIS AND EVALUATION OF SOME SYMMETRICAL PHOSPHATE DIMER DERIVATIVES OF 3'-MODIFIED NUCLEOSIDES AS POTENTIAL ANTI-HIV AGENTS

Novel symmetrical nucleotide-(5',5')-dimers of 3'-O-acetylthymidine, 3 '-O-methylthymidine, 3'-O-ethylthymidine, 3'-O-n-propylthymidine and 3 '-azido-3'-deoxythymidine (AZT) were synthesized as membrane soluble p ro-drugs. These were prepared using phosphorodichloridate chemistry an d were characterised by spectroscopic and analytical data. In-vitro ev aluation of the derivatives in cells acutely infected with the human i mmunodeficiency virus (HIV-1) demonstrated a range of activities. Thes e derivatives were generally found to display poor inhibition of HIV p roliferation. Derivatives containing AZT moieties were found to be pot ent, but such compounds were less active than the parent nucleoside. T he data indicated that the AZT-containing compounds act primarily via the release of the free nucleoside. However, in some cases, the dimers of certain inactive nucleoside analogues were found to be active. In these cases, release of the nucleoside alone cannot account for the ac tivity.