title: Biotransformation and in vitro activity of an arabinosylcytosine 5'-chloro-5'-deoxy analog.
abstract: 5'-Chloro-5'-deoxyarabinosylcytosine (5'-chloro-araC), a lipophilic and cytidine-deaminase resistant analog of the cytotoxic agent arabinosylcytosine (araC) was evaluated in terms of bioactivation, transformation and its cytotoxic activity in vitro. 5'-Chloro-araC interferes with DNA synthesis (IC50 = 2.8 mumol/l) and inhibits the growth of L1210 cells in suspension culture (IC50 = 1.05 mumol/l) and in the soft agar assay (IC50 = 0.65 mumol/l). Being phosphorylated to the triphosphate of araC-araCTP (5'-triphosphate of araC), 5'-chloro-araC has the same mechanism of action as arabinosylcytosine. In alkaline solutions 5'-chloro-araC is transformed to another (cytostatically inactive) araC analog--2',5'-anhydroarabinosylcytosine--but at physiological pH and temperature conditions, it has sufficient stability to be phosphorylated and thus activated. A lower rate of araCTP formation from 5'-chloro-araC explains the somewhat lower cytotoxic effect of this compound against various established cell lines in vitro compared to araC. Lipophilicity that would allow an oral drug formulation and certain other superior physico-chemical and biochemical characteristics of 5'-chloro-araC make this compound an interesting candidate for further investigations.
authors.affiliation: Department of Experimental Therapy, Slovak Academy of Sciences, Bratislava, Czechoslovakia.
authors.forename: L
authors.initials: L
authors.lastname: Novotný
authors.forename: V
authors.initials: V
authors.lastname: Reichelová
authors.forename: E
authors.initials: E
authors.lastname: Balázová
authors.forename: W
authors.initials: W
authors.lastname: Scheithauer
authors.forename: M
authors.initials: M
authors.lastname: Benesová
authors.forename: V
authors.initials: V
authors.lastname: Ujházy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D001711:Biotransformation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000473:pathology; D003470:Culture Media; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000096:biosynthesis; D006863:Hydrogen-Ion Concentration; D007939:Leukemia L1210 / Q000473:pathology; D010766:Phosphorylation; D011741:Pyrimidine Nucleosides / Q000378:metabolism; D013696:Temperature; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003470:Culture Media; D004273:DNA, Neoplasm; D011741:Pyrimidine Nucleosides; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; C073835:5'-chloro-5'-deoxyarabinosylcytosine