N4-(dialkylamino)methylene derivatives of 2'-deoxycytidine and arabinocytidine: physicochemical studies for potential prodrug applications.
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.
Kerr
S G
SG
Department of Medicinal Chemistry, School of Pharmacy, State University of New York at Buffalo 14260.
Kalman
T I
TI
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000627:therapeutic use; D004355:Drug Stability; D006207:Half-Life; D006868:Hydrolysis; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy; D008055:Lipids / Q000737:chemistry; D051379:Mice; D011355:Prodrugs / Q000737:chemistry*; D012995:Solubility
D008055:Lipids; D011355:Prodrugs; D003561:Cytarabine; D003841:Deoxycytidine