Synthesis and biological activities of ftorafur metabolites. 3'- and 4'-hydroxyftorafur.
Four isomers of ftorafur were synthesized as authentic samples of possible ftorafur (FT) metabolites. 2,3-Dihydrofuran was treated with perbenzoic acid in MeOH to give 2-methoxy-3-hydroxytetrahydrofuran, which upon treatment with Ac2O/pyridine yielded the key intermediate 2-methoxy-3-acetoxytetrahydrofuran. The other intermediate, 2-ethoxy-4-acetoxytetrahydrofuran, was prepared by acid hydrolysis (HCl/50% EtOH) of 1,1-diethoxy-3,4-dihydroxybutane, followed by acetylation (Ac2O/pyridine). Treatment of 2,4-bis(trimethylsilyl)-5-fluorouracil with either 2-methoxy-3-acetoxytetrahydrofuran or 2-ethoxy-4-acetoxytetrahydrofuran in 1,2-dichloroethane at room temperature using SnCl4 as catalyst afforded cis- and trans-3'-OAc-FT or 4'-OAc-FT, respectively. However, trans-3'-OAc-FT and cis-4'-OAc-FT were the major condensation products. In each case, separation of these cis and trans isomers was achieved by silica gel column chromatography. Treatment of 3'- or 4'-OAc-FT with NH3/CH3OH at 5 degrees C overnight yielded the described hydroxylated FT. Both trans-3'-OH-FT and cis-4'-OH-FT showed no significant activity against L1210 up to 100 mg/kg. These two agents produced an inhibitory effect on HeLa cell growth equal to that of ftorafur, with ID50 = 200 MICROGRAMS/KG.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis; D002455:Cell Division / Q000187:drug effects; D005472:Fluorouracil / Q000031:analogs & derivatives*; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D006900:Hydroxylation; D007939:Leukemia L1210 / Q000188:drug therapy; D013237:Stereoisomerism; D005641:Tegafur / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D000970:Antineoplastic Agents; D005641:Tegafur; D005472:Fluorouracil