title: Antileukemic activity of sulfonamide conjugates of arabinosylcytosine.
abstract: OBJECTIVE
  Cytosine arabinoside is routinely used for treatment of leukemias and lymphomas. However, because of its extensive metabolic inactivation and limited activity in chemotherapy, new analogues of araC are being tested. The aim of this work was to synthetize two araC conjugates and evaluates their cytotoxic/antileukemic activity.
  
  
  METHODS
  Synthesis of araC-sulfonamide conjugates A and B was performed in anhydrous conditions using cyclostyling and 5'-chlorocyclocytidine as starting material. Elemental analysis and NMR, IR and UV spectrometry were used for structure confirmation. The synthesized araC conjugates were tested for their cytotoxicity in L1210 leukemia cells in vitro and for therapeutic activity and toxicity in vivo in leukemia L1210-bearing mice.
  
  
  RESULTS
  The cytotoxic activities of araC and two synthesized conjugates A and B were expressed as IC(50) (micromol/l) and were compared respectively. The conjugate A is 303-times less active and the conjugate B is 757-times less active than araC. Consequently, the antileukemic activity and the acute toxicity of these compounds were examined in experiments involving leukemia L1210-bearing mice. Statistically significant therapeutic outcome was observed when the dosage of both araC conjugates was increased 10-times compared to araC. Next, the ration of cytotoxicity vs therapeutic activity for araC and both conjugates was performed. It was recorded that the ration between cytotoxicity and therapeutic activity for araC is 3333, for the conjugate A and B, the ration is significantly lower (110 and 44). This indicates that the inactivation of araC conjugate A is 30-times slower and the inactivation of conjugate B is 75-times slower as araC inactivation.
  
  
  CONCLUSIONS
  The differences in cytotoxic and therapeutic activity registered in araC treatment and between two araC-analogues are most probably caused by slow liberation of araC from both conjugates. We are considered that prolonged araC liberation protected them from inactivation and extended the time period of therapeutic action both araC conjugates. The obtained results can serve as stimuli for further investigation of new araC-analogues.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, Kuwait.
authors.forename: L
authors.initials: L
authors.lastname: Novotny
authors.forename: O A
authors.initials: OA
authors.lastname: Phillips
authors.forename: P
authors.initials: P
authors.lastname: Rauko
authors.forename: E
authors.initials: E
authors.lastname: Miadokova
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003561:Cytarabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D005260:Female; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D051379:Mice; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000964:Antimetabolites, Antineoplastic; D013449:Sulfonamides; D003561:Cytarabine