title: (S)-form of alpha-methyl-N(alpha)-phthalimidoglutarimide, but not its (R)-form, enhanced phorbol ester-induced tumor necrosis factor-alpha production by human leukemia cell HL-60: implication of optical resolution of thalidomidal effects.
abstract: The rate of racemization of N(alpha)-phthalimidoglutarimide (thalidomide) was determined as its half life to be 566 min at pH 7.4/37 degrees C. This fast racemization of thalidomide resulted in no apparent difference between (S)- and (R)-forms of the compound on enhancing activity of phorbol ester-induced tumor necrosis factor (TNF)-alpha production by human leukemia HL-60 cells. Optically pure forms of structurally related analog of thalidomide, (S)- and (R)-alpha-methyl-N(alpha)-phthalimidoglutarimides (methylthalidomides), which do not racemize under the physiological condition, were prepared. Only (S)-form of methylthalidomide, but not its (R)-form, elicited TNF-alpha production-enhancing effect, suggesting that the (S)-isomer of thalidomide would be the active form in terms of thalidomidal biological response modifying effects.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nishimura
authors.forename: Y
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: S
authors.initials: S
authors.lastname: Iwasaki
mesh_terms: D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007942:Leukemia, Experimental; D013237:Stereoisomerism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D013755:Tetradecanoylphorbol Acetate