This project provides novel orally active tricyclic-bis-enone derivatives (TBEs) for prevention and/or treatment of cancer, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Alzheimer's disease, Parkinson's disease and other diseases whose pathogenesis may involve excessive production of nitric oxide (NO) and/or prostaglandins. On the basis of the structure of a synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), which is an extremely potent inhibitor of the de novo synthesis of inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) in macrophages and of proliferation of many human tumor cell lines, we designed TBEs to address the inadequacies (low oral potency in vivo, low water solubility, high cost of production, and so on) of CDDO. Our rationale for exploring the TBEs is as follows. (1) Because TBEs could be synthesized from commercially available small molecules, TBEs with various functionalities at different positions can be obtained. Such """"""""diversity oriented synthesis"""""""" of TBEs could lead to totally new cancer chemopreventive and anti-inflammatory drugs that are orally active and water-soluble for ease of administration and formulation, and that are low in cost for large scale synthesis. (2) This structural flexibility might provide us with new structure-activity relationships (SARs) and different compounds that are appropriate and specialized for each therapeutic area. (3) Some of the activities of CDDO might be absent because of the delineation of the pharmacophore of CDDO (Increase of selectivity). In our preliminary studies, we have found that TBE-9 shows high inhibitory activity (IC50 = 1 nM level) against production of NO induced by interferon-((IFN-gamma) in mouse macrophages, and is orally active at 15 mg/kg (single administration) in an in vivo study using mouse peritoneal inflammation induced by thioglycollate and IFN-gamma amongst TBEs initially synthesized. The present investigation thus will design and synthesize new orally active TBEs on the basis of our preliminary SARs, to improve their potency (in vitro and in vivo), to study their mechanism of action as anti-inflammatory and anti-proliferative agents, and to study these new TBEs in vivo for blocking inflammation and for growth inhibition and prevention of cancer.
