title: Alpha-monoamides of methotrexate as potential prodrugs.
abstract: alpha-Monoamides of methotrexate were evaluated for their potential as prodrugs. Studies on 11 alpha-monoamides and 5 gamma-monoamides of methotrexate showed that the gamma-monoamides were about as strong inhibitors of Lactobacillus casei dihydrofolate reductase as methotrexate, while I50 of the alpha-monoamides were 1-2 orders higher. The concentration for growth inhibition of murine L1210 cells for methotrexate gamma-propylamide and alpha-propylamide were respectively 1-2 and 2-3 orders higher than that of methotrexate. In contrast, only alpha-monoamides caused significant increase in life span of mice with transplanted L1210 leukaemia, the highest effect being given by the alpha-propyl and the alpha-butylamide. The possibility that the in vivo activity of the alpha-monoamides might be related to in vivo transformation to methotrexate was studied by HPLC analysis of mice serum after administration of the alpha- and gamma-propylamides.
authors.affiliation: Department of Pharmacy, University of Sydney, Australia.
authors.forename: D J
authors.initials: DJ
authors.lastname: Antonjuk
authors.forename: D K
authors.initials: DK
authors.lastname: Boadle
authors.forename: H T
authors.initials: HT
authors.lastname: Cheung
authors.forename: M L
authors.initials: ML
authors.lastname: Friedlander
authors.forename: P M
authors.initials: PM
authors.lastname: Gregory
authors.forename: M H
authors.initials: MH
authors.lastname: Tattersall
mesh_terms: D000818:Animals; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000032:analysis / Q000138:chemical synthesis*; D051379:Mice; D008811:Mice, Inbred DBA; D011355:Prodrugs / Q000138:chemical synthesis*
chemical_list: D011355:Prodrugs; D008727:Methotrexate