N4-chloroacetylcytosine arabinoside--a possible pro-drug of cytosine arabinoside.
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.
Ariatti
M
M
Department of Biochemistry, University of Durban-Westville, South Africa.
Jones
P A
PA
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003561:Cytarabine / Q000633:toxicity*; D003841:Deoxycytidine / Q000633:toxicity; D064420:Drug-Related Side Effects and Adverse Reactions; D005354:Fibrosarcoma; D011355:Prodrugs / Q000138:chemical synthesis / Q000633:toxicity*; D012513:Sarcoma, Experimental
D011355:Prodrugs; D003561:Cytarabine; D003841:Deoxycytidine