The synthesis of a novel series of lipophilic prodrug derivatives of the anti-HIV drugs 2',3'-dideoxycytidine (ddC, 1) and 3'-fluoro-ddC (2), involving N4-substitution with (N,N-dialkylamino)methylene side chains, is described. The increase in the partition coefficients for the prodrug series, compared to those of the parent drugs 1 and 2, ranged from 1.5- to 122-fold and from 1.6- to 175-fold, respectively. At pH 7.4, 37 degrees C, the hydrolytic t1/2 values ranged from 2 to 52 h, the diisopropyl derivatives (3d and 4d) being most stable in the series. 3d and 4d were greater than or equal to 4-fold and 1.7-fold more soluble in water than 1 and 2, respectively. The in vitro antiretroviral activities of 3d, 4a, and 4d were evaluated; the results indicate efficient prodrug-to-drug conversion under the assay conditions. The results of this investigation demonstrate that it is indeed feasible to chemically modify certain nucleoside analogues with inferior solubility properties to simultaneously achieve significantly enhanced lipid and water solubility.