Development of new drugs based on the metabolic activation by intestinal bacteria.

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1. Synthesis of paeonimetabolin derivatives and their anti-convulsant activityBy incubation of paeoniflorin from peony roots with a human intestinal bacterium Lactobacillus brevis in the presence of mercapto compounds, 17 different kinds of paeonimetabolin derivatives were prepared and examined their anti-convulsant activity ; 8-(n-hexylthio)-, 8-cyclopentylthio-, 8-(p-tolylthio)-, and 8-benzoylthiopaeonimetabolin showed potent activity. After separation of the last compound by column chromatography, 7S-derivative showed the most potent anti-convulsant activity, but 7R-derivative showed the muscle relaxation effect.2. Effects of a metabolite of ginsenoside by intestinal bacteria on metastasis and apoptosis of tumor cellsA metabolite (20S)-protopanaxadiol 20-O-glucoside of ginsenoside Rb1 showed potent anti-metastatic action in mice. As to the mechanism of the anti-metastatic action, it was demonstrated that this metabolite induced apoptosis of the tumor cells by modulating apoptosis related proteins such as cyclin D, p27 kip and c-myc etc.3. Development of new reactions mediated by intestinal bacteria.a. Conversion of rhein to rhein anthroneb. Demethylationc. DehydroxylationDuring the investigation under the above project, we islated three bacterial strains Bacteroides sp., Peptostreptococcus sp., and Eubacterium sp., from human feces, which catalyzed the new reactions a-c.