Development of herb glycoside-mimic prodrugs for colon-specific delivery -A trial research-

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Herbs contain many kinds of glycosides as main and effective constituents. Through our studies regarding metabolic fates and actions of popular natural glycosides in relation to intestinal bacteria, we have clarified that these glycosides are prodrugs delivered to colon and activated by intestinal bacteria.The aim of our project is to develop glycoside-mimic prodrugs of anti-inflammatory and anti-cancer prodrugs, which are delivered to colon and activated by intestinal bacteria there, for therapeutics of ulcerative colitis and colonic cancer, respectively.Recently, salicylate, an anti-inflammatory drug, attracts notice by means of inhibiting COX-2, suppressing inducible COX-2 gene transcription, inhibiting NF-ィイD2κィエD2B, anti-oxidative action, etc.In this project, I synthesized salicylic acid glycosides. They were much poorly absorbed in rat everted intestine in comparison with salicylic acid, delivered to rat cecum after oral administration, and hydrolyzed to salicylic acid by intestinal bacteria there. The glycosides showed mild antipyretic effects against yeat-induced fever without causing stomach ulcer in rats. Moreover, salicylic acid-o-glucoside improved dextran sulfate-induced colitis in rats in relation to suppressing wheight loss, the decrease of hematocrit value, ocult bleeding, and the formation of colonic erosion. Thus, it is clear that salicylic acid glycosides are prodrugs for colon-specific delivery without adverse effects and suggested to be a good drug for ulcerative colitis.Also, ginsenoside Rb1, a major glycoside of Panax ginseng, was shown to be a prodrug delivered to rat cecum and activated to compound K by intestinal bacteria.