Lipophilic N4-acetyl (1b-d) and N4-chloroacetyl (2b-d) derivatives of cytidine, 2'-deoxycytidine and cytosine arabinoside (ara-C) were synthesized and their toxicity for A(T1)Cl-3 hamster fibrosarcoma cells determined. 2b-d proved potent with no colonies surviving at concentrations of 10(-4), 10(-4) and 10(-6) M, respectively. lb-d showed comparatively poor cytotoxicity with 95, 77 and 87% survival of colonies respectively. N4-chloroacetyl 2'-deoxycytidine (2c) and N4-chloroacetyl ara-C (2d) were shown to undergo hydrolytic deprotection in phosphate buffered saline at 50 degrees C to yield the parent nucleosides (circa 85%) and the N3-carboxymethyl derivatives (5c,d) via 1-H-2,3 dihydro-2,5-dioxoimidazo [1,2-c] pyrimidine intermediates (4c,d). This treatment abolished the toxicity of 2c at 10(-4) M whilst the potency of 2d remained undiminished at 10(-6) M. These results indicate that further investigation of N(-4)-chloroacetyl-ara C (2d) as a potential pro-drug of ara-C is warranted.