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Cited by 98Natural product bioactivities and synthesisBioactive Compounds and Antitumor AgentsNatural Compounds in Disease Treatment

Synthesis and anticancer activity of CDDO and CDDO-Me, two derivatives of natural triterpenoids

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Borella, Rebecca, Forti, Luca, Gibellini, Lara, De Gaetano, Anna, De Biasi, Sara, Nasi, Milena, Cossarizza, Andrea, Pinti, Marcello·2019·Molecules
DOI 10.3390/molecules24224097PMC PMC6891335
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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.

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Cited by

Sorted by citations

Authors
Borella, R., Forti, L., Gibellini, L., De Gaetano, A., De Biasi, S., Nasi, M., Cossarizza, A., & Pinti, M.
Affiliations
  • University of Modena and Reggio Emilia (IT)
  • Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
  • Department of Medical and Surgical Sciences of Children and Adults, University of Modena and Reggio Emilia, 41125 Modena, Italy
Corresponding author
Pinti, Marcello
ORCID
Venue
Molecules
Publisher
MDPI AG
Published
2019-11-13
Volume
24
Issue
22
Pages
4097
ISSN
1420-3049 (ISSN-L)
DOI
10.3390/molecules24224097
PMC
PMC6891335
OpenAlex
W2984375168
Cited by
98
References
2
Citations by year
2026: 7 · 2025: 16 · 2024: 22 · 2023: 11 · 2022: 14 · 2021: 17 · 2020: 9 · 2019: 1
FWCI
0.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecules (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
Funders
Associazione Italiana per la Ricerca sul Cancro (IG19876)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Natural product bioactivities and synthesis
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
  • Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
Keywords
CDDO, bardoxolone methyl, triterpenoids, oleanolic acid derivatives, anticancer activity, Nrf2, oxidative stress, apoptosis, autophagic cell death, telomerase inhibition, Lon protease, USP7, cell differentiation, anti-inflammatory activity, heart failure, clinical trials
MeSH terms
Antineoplastic Agents, Mitochondria, Oleanolic Acid, Triterpenes, Molecular Structure, Metabolic Networks and Pathways

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