(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

Chem Pharm Bull (Tokyo). 1994 May;42(5):1157-9. doi: 10.1248/cpb.42.1157.

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.

MeSH terms

  • Cell Division / drug effects
  • Chromatography, High Pressure Liquid
  • Humans
  • Leukemia, Experimental
  • Stereoisomerism
  • Tetradecanoylphorbol Acetate / pharmacology*
  • Thalidomide / analogs & derivatives*
  • Thalidomide / pharmacology*
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / biosynthesis*

Substances

  • Tumor Necrosis Factor-alpha
  • Thalidomide
  • Tetradecanoylphorbol Acetate