Platforms and Networks in Triterpenoid Pharmacology

Using the pentacyclic, naturally occurring triterpenoids, oleanolic, ursolic, and betulinic acids, as starting materials, we have developed a new series of multifunctional drugs for potential clinical use. These agents have anti-inflammatory, anti-oxidative, anti-proliferative, pro-apoptotic, and differentiating activities. Two synthetic oleanane triterpenoids, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO)and its C-28 methyl ester (CDDO-Me), are presently in Phase I clinical trials in cancer patients. Three themes are emphasized in this review: (1)The importance of the unique structures of the triterpenoid platforms that have been used as a start for new synthesis; (2)The concept that these new drugs interact with entire physiological networks, rather than solely with single molecular targets; and (3)The coupling in real time between the triterpenoid platforms and the physiological networks with which they interact, as seen in the reversibility of the Michael reactions, which mediate their activity. We suggest that further development of such new, multifunctional drugs will most likely occur in the more flexible environment of small biotech or pharmaceutical companies.