New Synthetic Triterpenoids: Potent Agents for Prevention and Treatment of Tissue Injury Caused by Inflammatory and Oxidative Stress

Abstract

We review the original rationale for the development and the chemistry of a series of new synthetic oleanane triterpenoids (SO), based on oleanolic acid (1) as a starting material. Many of the new compounds that have been made, such as 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (“CDDO”, 8), are highly potent (activities found at levels below 1 nM) anti-inflammatory agents, as measured by their ability to block the cellular synthesis of the enzyme inducible nitric oxide synthase (iNOS) in activated macrophages. Details of the organic synthesis of new SO and their chemical mechanisms of biological activity are reviewed, as is formation of biotin conjugates for investigation of protein targets. Finally, we give a brief summary of important biological activities of SO in many organ systems in numerous animal models. Clinical investigation of a new SO (methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, “CDDO-Me”, bardoxolone methyl, 13) is currently in progress.

Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease

“…The synthetic triterpenoid compounds belonging to the bardoxolone methyl (CDDO-Methyl ester) family are potent Nrf2 activators [24,25]. By interacting with the keap1 molecule these compounds facilitate nuclear translocation of Nrf2 and expression of its target genes [26].…”

Highly Potent Activation of Nrf2 by Topical Tricyclic Bis(Cyano Enone): Implications for Protection against UV Radiation during Thiopurine Therapy

“…Furthermore, they show remarkable protective efficacy in a number of preclinical animal models of chronic disease, including carcinogenesis, cardiovascular disease, and neurodegeneration, and in early clinical trials (reviewed in refs. 15,18,19).…”

Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer

“…Novel synthetic triterpenoids which mimic natural triterpenoids in physical and chemical properties have been found to be effective in suppressing inflammation and inducing apoptosis in a wide variety of tumor cells via diverse mechanisms [16,164]. This was first established by the exceptional ability of synthetic oleanane triterpenoids to inhibit inducible NOS induced by TNF-a, IL-1 and IFN-c [191].…”

“…Proteomic analysis has led to the identification of important protein targets of synthetic triterpenoids. In many instances, it has been observed that these compounds bind to the active cysteine residue in the proteins [16]. The key proteins that have been reported to be modulated by oleanane triterpenoids are Keap 1 [193,194], IKK, IkBa and NF-jB [164,166], JAK1 and STAT3 [165,195,196], PTEN [197], AKT [14,198,199], mTOR [200], ROS [201], DR5 and CHOP [202], GSK3b [203], cFLIP and VEGF [204,205], mitochondrial membrane potential [206], and cell cycle arrest [198,207,208].…”

“…Recent development of synthetic pentacyclic triterpenoids viz. cyano-3,12-dioxooleana-1,9 (11)-dien-28-oic acid (CDDO), its methyl ester (CDDO-Me), and imidazolide (CDDO-Im) that mimic natural triterpenoids in physical and chemical properties are effective in inducing apoptosis in a variety of cancer cells and retard tumor growth in vivo [14][15][16] has rejuvenated interest in this field of research. In this review, we will discuss the enormous potential of various plant-based triterpenoids that have in recent years shown great promise as chemopreventive and therapeutic agents by inhibiting key signaling molecules, inflammatory mediators, tumor cell proliferation, invasion, metastasis, and angiogenesis in various in vitro and in vivo models of cancer.…”