The synthesis and physicochemical parameters of a series of N4-(N,N-dialkyl)formamidine derivatives of 2'-deoxycytidine (dCyd, 1) and arabinocytidine (ara-C, 2), as
prodrug prototypes, are described. The lipophilicity of the
formamidine derivatives compared to that of the parent
nucleosides increased 1.26- to 145-fold. The corresponding half-lives of the derivatives in aqueous
solution at pH 7.4 and 37 degrees C ranged from 3.7 to 52 h. The analogues most stable to hydrolysis in both series (3 and 4) were the diisopropyl derivatives (3d and 4d). The substitution effects of the
sugar OH groups at the 2'- and 3'-positions on the corresponding partition coefficients gave pi-values of -0.16 and -0.55, respectively. These values are significantly more positive than those generally associated with aliphatic hydroxy substituents indicating that
sugar OH groups of
nucleosides have a decreased tendency to associate with the aqueous phase. The in vitro growth inhibitory activities of the
ara-C derivatives (4) against murine
lymphocytic leukemia L1210 cells indicate that
prodrug to
drug conversion readily occurs. The results confirm our previous findings about the versatility of the
formamidine modification of
nucleosides bearing exocyclic amino groups. The data facilitate optimization of lipophilicities and hydrolytic stabilities and thus contribute to the design and further development of the
formamidine type of
prodrug derivatives.