Studies on Antitumor Agents. VII. Antitumor Activities of O-Alkoxyalkyl Derivatives of 2'-Deoxy-5-trifluoromethyluridine

抄録

Various O-alkoxyalkyl derivatives of 2'-deoxy-5-trifluoromethyluridine (F₃Thd) were synthesized, and the antitumor activities of the compounds against sarcoma 180 were examined by oral administration to mice. Among the formal-type derivatives, 3', 5'-di-O-ethoxymethyl (3), 3', 5'-di-O-benzyloxymethyl (12), 5'-O-benzyloxymethyl (13) and 3'-O-benzyloxymethyl (14) compounds showed high activities, which were six-fold higher than that of F₃Thd itself. Since acetal-type derivatives were unstable under acidic conditions, antitumor testing of the compounds was also carried out with co-administration of sodium bicarbonate. 5'-O- (1-Ethoxypropyl) -F₃Thd (25) and 5'-O- (1-benzyloxypropyl) -F₃Thd (37) showed the highest activities among the acetal-type derivatives, but the ED₅₀ values of the compounds were not lower than those of effective formal-type compounds.
These O-alkoxyalkyl derivatives of F₃Thd are resistant to degradation by thymidine phosphorylase and are activated by microsomal drug-metabolizing enzymes after absorption.