DISCOVERY AND EVALUATION OF NOVEL TRITERPENOID CHEMOPREVENTIVES IN A NEW COLON CA

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DESCRIPTION (provided by applicant): The field of cancer chemoprevention represents a unique opportunity for the fruitful cooperation of basic scientists and clinical researchers to tackle a problem of acute need. One of the best examples to date of a potential cancer chemopreventive is the semisynthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), which was born out of a structure activity relationship (SAR) with the natural product oleanolic acid (from Chinese herbs). The proposed work described herein will expand our knowledge of triterpenoids as small molecule chemopreventives by focusing on bryonolic acid, a natural product abundantly produced in the roots of germinating Curcubita pepo L. (common zucchini). We aim to study the effect of this molecule on key inflammation-related markers of carcinogenesis and determine its potential as a pharmacologic chemopreventive with a special emphasis on colon cancer. To date we have devised a purification of this molecule yielding sub-gram quantities and illustrated its ability to inhibit the expression of iNOS and COX-2 in cell culture models. We are currently purifying multi-gram quantities of bryonolic acid and the goals of this proposal are centered on exploring the chemistry and biology of this molecule. Our two specific aims are: 1) to study the skeletal requirement of triterpenoid activity (for bryonolic acid and the entire triterpenoid family) using a diversity oriented synthesis (DOS) approach, and 2) determine whether triterpenoids are effective agents for the prevention of gastrointestinal carcinogenesis using cell culture and animal models. This proposal is strategically placed to potentially identify new chemopreventive agents which could be obtained from an abundant dietary source, but also to answer more fundamental questions about triterpenoids as chemopreventives. This project represents a collaborative endeavor between a synthetic organic chemist and a cancer biologist to address problems of cancer chemoprevention. The described aims will yield new molecules to be tested for their chemopreventive properties.