Abstract
Triterpenoids are natural compounds synthesized by plants through cyclization of squalene, known for their weak anti-inflammatory activity. 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), and its C28 modified derivative, methyl-ester (CDDO-Me, also known as bardoxolone methyl), are two synthetic derivatives of oleanolic acid, synthesized more than 20 years ago, in an attempt to enhance the anti-inflammatory behavior of the natural compound. These molecules have been extensively investigated for their strong ability to exert antiproliferative, antiangiogenic, and antimetastatic activities, and to induce apoptosis and differentiation in cancer cells. Here, we discuss the chemical properties of natural triterpenoids, the pathways of synthesis and the biological effects of CDDO and its derivative CDDO-Me. At nanomolar doses, CDDO and CDDO-Me have been shown to protect cells and tissues from oxidative stress by increasing the transcriptional activity of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2). At doses higher than 100 nM, CDDO and CDDO-Me are able to modulate the differentiation of a variety of cell types, both tumor cell lines or primary culture cell, while at micromolar doses these compounds exert an anticancer effect in multiple manners; by inducing extrinsic or intrinsic apoptotic pathways, or autophagic cell death, by inhibiting telomerase activity, by disrupting mitochondrial functions through Lon protease inhibition, and by blocking the deubiquitylating enzyme USP7. CDDO-Me demonstrated its efficacy as anticancer drugs in different mouse models, and versus several types of cancer. Several clinical trials have been started in humans for evaluating CDDO-Me efficacy as anticancer and anti-inflammatory drug; despite promising results, significant increase in heart failure events represented an obstacle for the clinical use of CDDO-Me.
Highlights
Triterpenoids are natural compounds synthesized by plants through cyclization of squalene and represent one of the most numerous and diverse group of secondary metabolites, ubiquitously distributed in the plant kingdom [1]
In an attempt to improve and enhance the biological activity of natural triterpenoids, a series of chemical modifications have been introduced to the structure of the molecules, and synthetic triterpenoids derived from oleanolic acid and ursolic acid have been obtained that exhibit optimized bioactivity such as potent anti-inflammatory and antitumorigenic activities [12]
Synthesis of triterpenoids is obtained through a condensation of two isopentenyl pyrophosphate (IPP) units with a dimethylallyl pyrophosphate (DMAPP) unit, which generates the C15 farnesyl pyrophosphate (FPP)
Summary
Triterpenoids are natural compounds synthesized by plants through cyclization of squalene and represent one of the most numerous and diverse group of secondary metabolites, ubiquitously distributed in the plant kingdom [1]. One of these naturally-occurring triterpenoids, has a mild anti-inflammatory effect and a weak antitumorigenic activity [6,7,8]. Most of the natural triterpenoids, including oleanolic acid, display their pharmacological activity at high concentration, up to. In an attempt to improve and enhance the biological activity of natural triterpenoids, a series of chemical modifications have been introduced to the structure of the molecules, and synthetic triterpenoids derived from oleanolic acid and ursolic acid have been obtained that exhibit optimized bioactivity such as potent anti-inflammatory and antitumorigenic activities [12]. We discuss the chemical properties of natural triterpenoids, the pathways of synthesis and the biological effects of CDDO and its derivative CDDO-Me
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