CDDO and Its Role in Chronic Diseases
There has been a continued interest in translational research focused on both natural products and manipulation of functional groups on these compounds to create novel derivatives with higher desired activities. Oleanolic acid, a component of traditional
- PDF / 452,197 Bytes
- 24 Pages / 439.37 x 666.142 pts Page_size
- 45 Downloads / 227 Views
Abstract There has been a continued interest in translational research focused on both natural products and manipulation of functional groups on these compounds to create novel derivatives with higher desired activities. Oleanolic acid, a component of traditional Chinese medicine used in hepatitis therapy, was modified by chemical processes to form 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO). This modification increased anti-inflammatory activity significantly and additional functional groups on the CDDO backbone have shown promise in treating conditions ranging from kidney disease to obesity to diabetes. CDDO’s therapeutic effect is due to its upregulation of the master antioxidant transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) through conformational change of Nrf2-repressing, Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1) and multiple animal and human studies have verified subsequent activation of Nrf2-controlled antioxidant genes via upstream Antioxidant Response Element (ARE) regions. At the present time, positive results have been obtained in the laboratory and clinical trials with CDDO derivatives treating conditions such as lung injury, inflammation and chronic kidney disease. However, clinical trials for cancer and cardiovascular disease have not shown equally positive results and further exploration of CDDO and its derivatives is needed to put these shortcomings into context for the purpose of future therapeutic modalities.
Keywords CDDO dh404 TFEA Nrf2 Bardoxolone CDDO-Me CDDO-Im Vascular Hepatotoxic Cardiorenal Apoptosis Keap1
B.J. Mathis Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA T. Cui (&) Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, 6439 Garners Ferry Rd., Columbia, SC 29209, USA e-mail: [email protected] © Springer International Publishing Switzerland 2016 S.C. Gupta et al. (eds.), Drug Discovery from Mother Nature, Advances in Experimental Medicine and Biology 929, DOI 10.1007/978-3-319-41342-6_13
291
292
B.J. Mathis and T. Cui
Definitions CDDO CDDO-Im CDDO-Me CDDO-dhTFEA
2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid CDDO imidazolide CDDO-methyl ester CDDO-dihydrotrifluoroamide
1 Introduction Triterpenoids are natural saponin compounds (such as cholesterol and phytosterols) with a multi-carbon skeleton that can be manipulated synthetically, adding various chemical groups for functionality. CDDO, or 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, is a synthetic triterpenoid derived from oleanolic acid that was purposely constructed for anti-inflammatory purposes in macrophages and has, over time, been modified with methyl, amine, and imidazolide groups to further affect various signaling pathways such as FLIP/TRAIL, caspase, SMAD, and mTOR. However, the primary target of CDDO and its related compounds is the Kelch-like erythroid cell-derived protein with CNC homology-associa
Data Loading...
