Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease

Abstract

We review the rationale for the use of synthetic oleanane triterpenoids (SOs) for prevention and treatment of disease, as well as extensive biological data on this topic resulting from both cell culture and in vivo studies. Emphasis is placed on understanding mechanisms of action. SOs are noncytotoxic drugs with an excellent safety profile. Several hundred SOs have now been synthesized and in vitro have been shown to: 1) suppress inflammation and oxidative stress and therefore be cytoprotective, especially at low nanomolar doses, 2) induce differentiation, and 3) block cell proliferation and induce apoptosis at higher micromolar doses. Animal data on the use of SOs in neurodegenerative diseases and in diseases of the eye, lung, cardiovascular system, liver, gastrointestinal tract, and kidney, as well as in cancer and in metabolic and inflammatory/autoimmune disorders, are reviewed. The importance of the cytoprotective Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1/nuclear factor (erythroid-derived 2)-like 2/antioxidant response element (Keap1/Nrf2/ARE) pathway as a mechanism of action is explained, but interactions with peroxisome proliferator-activated receptor γ (PARPγ), inhibitor of nuclear factor-κB kinase complex (IKK), janus tyrosine kinase/signal transducer and activator of transcription (JAK/STAT), human epidermal growth factor receptor 2 (HER2)/ErbB2/neu, phosphatase and tensin homolog (PTEN), the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway, mammalian target of rapamycin (mTOR), and the thiol proteome are also described. In these interactions, Michael addition of SOs to reactive cysteine residues in specific molecular targets triggers biological activity. Ultimately, SOs are multifunctional drugs that regulate the activity of entire networks. Recent progress in the earliest clinical trials with 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) methyl ester (bardoxolone methyl) is also summarized.

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.]

Fig. 2.

Activation of the Keap1/Nrf2/ARE/pathway by the SOs is cytoprotective. Nrf2 has been described previously (Lee et al., 2005) as a “multiorgan protector,” because this system can protect against diseases in a number of organs, including the brain, lungs, kidney, heart, liver, and eye. The SOs are among the most potent known inducers of the Nrf2 pathway, and these drugs not only activate Nrf2 in all of these organs but also protect the organs against a variety of diseases driven by inflammatory or oxidative stress. SOs that cross the blood-brain barrier are beneficial in experimental models of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and ALS. These drugs also reduce damage to the eye from light, uveitis, or ischemia reperfusion and reduce cardiomyopathy induced by smoking and reduce the disease process in the lung in animal models of COPD, emphysema, asthma, and ALI/ARDS. In the liver and kidney, the SOs protect against toxicity from insults such as aflatoxin, ConA, acetaminophen, or cisplatin and against injury from ischemia reperfusion.

Fig. 3.

Biological responses to SOs are dependent on dose. Low concentrations (nanomolar) of SOs target Keap1 and activate the Nrf2/ARE cytoprotective and anti-inflammatory response. As the concentration of SO increases, SOs target Arp3 and other components of the cytoskeleton to inhibit cell proliferation, whereas even higher concentrations (micromolar) of SOs can selectively induce apoptosis in cancer cells by targeting a number of key regulatory proteins and pathways that are frequently constitutively activated or overexpressed in cancer cells. [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.]

Fig. 4.

The importance of context for SO biology. As summarized in the review, the SOs directly interact with a number of cellular targets, including Keap1, IKK, JAK1/STAT3, PPARγ, ErbB2, PTEN, mTOR, and Arp3; all of these are relevant targets because the SOs also affect downstream signaling pathways associated with each of these proteins. The molecular targets differ depending on cell type, because not all of these proteins are expressed in every cell. The SOs have been shown to regulate various biological outcomes such as inflammation in immune cells (macrophages, neutrophils, lymphocytes), angiogenesis in endothelial cells, and differentiation and cell proliferation/death in epithelial cells. Biological responses to the SOs also depend on dose, because low (nanomolar) concentrations induce anti-inflammatory and cytoprotective pathways, medium (mid-high nanomolar) concentrations affect cell growth and differentiation, and high (low micromolar) concentrations can induce apoptosis of cancer cells. It is noteworthy that the induction of apoptosis seems to depend on the mutational status of the cell, because the same concentrations of SOs that apoptose premalignant or malignant cancer cells have no effect on normal cells. Moreover, the pharmacokinetics (PK) of the SOs, including absorption, tissue distribution, metabolism, and excretion, differ depending on the specific SOs. For example, the amide derivatives of CDDO cross the blood brain-barrier better than other derivatives, and despite the exceptional potency of di-CDDO, its instability or rapid metabolism are not ideal for prolonged in vivo use. Thus, different protein targets within a cell, various cell types, the mutations within cells, the dose of the SOs, and the pharmacology of each unique derivative must be integrated and understood to determine the biological response to a SO and ideally to target specific compounds to the most relevant disease.