Synthetic Analogs of Green Tea Catechins for Breast Cancer Chemoprevention Abstract #: F-07 Current initial human studies to evaluate dose and efficacy (called Phase I trials) of green tea and its most abundant active compound (a catechin, (-) epigallocatechin-3-gallate, or EGCG) recommend a daily intake of 7-8 cups of green tea daily for a beneficial effect. The neurological and gastrointestinal side effects of this dose however, are caffeine-related. A significant problem with the use of green tea as a chemopreventive is the extremely low oral bioavailability of EGCG (<1%) and its extensive metabolic conjugation (deactivation this compound by the digestive system). Such poor absorption requires one to drink at least 7-8 cups of green tea a day to gain its chemopreventive benefit. Green tea consumption has been associated with decreased risk of breast, pancreatic, colon, esophageal, and lung cancers in humans. A recent study showed that the principal site of the (antioxidant) activity of EGCG thought responsible for its anit-cancer properties, is the trihydroxyphenyl B ring and not the 3-galloyl D-ring. Given the low bioavailability of EGCG, we believe that it is possible to modify parts of the EGCG molecule, particularly the A-ring and possibly the D-ring, to modulate and improve oral absorption, without affecting chemopreventive potency. With our previous grant (2KB-0083), we successfully developed the first versatile chemical synthesis of EGCG (and other catechins in green tea) which allows us to modify the various portions of the EGCG molecule. We synthesized several analogs (i.e., similar compounds) using our synthesis approach, one of which was found to be nearly as potent as EGCG itself in in vitro ("test tube") growth inhibition assays in breast cancer cell lines irrespective of estrogen receptor (ER) status. Our current grant (6JB-0068) proposes to use our devised synthesis approach in a preclinical drug discovery effort with the overall goal of rapidly identifying a potent, orally active potential breast cancer chemopreventive drug candidate. We will test these analogs for their in vitro growth inhibition and chemopreventive properties, but more importantly, the active analogs will concurrently be evaluated in in vitro models of intestinal permeability and oral bioavailability, the Caco-2 human intestinal cell line monolayer model, as well as in metabolism models, to provide immediate feedback on our design of the appropriate, orally bioavailable analogs and the validity of our approach. Completion of these studies will enable us to identify a potential preclinical drug candidate for further development as a safe breast cancer chemopreventive drug based on a natural product. Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.