Fig. 1.

Triterpenoid structures. A, structure of oleanolic acid, the starting material for the synthetic oleanane triterpenoids (SOs), showing important positions and functionalities that have been modified to enhance the potency of the SOs: the C-28 carboxyl group (blue), the double bond at C-12/C-13 (red), and the hydroxyl group at C-3 (red). B, structures of the most useful SOs, the biological activities of which are summarized in the text. The numbering system and ring structure for all of the SOs are the same as for oleanolic acid. In CDDO, the A ring has been activated by formation of an enone function at C-1, C-2, and C-3 (red) and the insertion of a strong electron-withdrawing –CN group at C-2 (blue), which facilitates Michael addition at C-1; the C ring has been activated by the inclusion of another enone function at C-9, C-11, and C-12 (red). The rest of the SOs shown can be considered analogs of CDDO. Additional modification at C-28 (green) has been useful for generating biologically useful molecules with different pharmacokinetic properties. [A and B adapted from Liby KT, Yore MM, and Sporn MB (2007) Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat Rev Cancer 7:357–369. Copyright © 2007 Nature Publishing Group. Used with permission.] C, the importance of the presence and location of the enone function in both the A and C rings for enhancing potency is shown by the CD (concentration required to double the specific activity) values for the induction of NQO1 enzyme activity; NQO1 is a classic Nrf2 target gene. [Adapted from Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, Suh N, Williams C, Risingsong R, Honda T, Gribble GW, Sporn MB, and Talalay P (2005) Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci USA 102:4584–4589. Copyright © National Academies of Science, USA. Used with permission.]