Synthesis and Pro-Apoptotic Activity of Novel Glycyrrhetinic Acid Derivatives

Triterpenoids are used for medicinal purposes in many countries. Some, such as oleanolic and glycyrrhetinic acids, are known to be anti‐inflammatory and anticarcinogenic. However, the biological activities of these naturally occurring molecules against their particular targets are weak, so the synthesis of new synthetic analogues with enhanced potency is needed. By combining modifications to both the A and C rings of 18βH‐glycyrrhetinic acid, the novel synthetic derivative methyl 2‐cyano‐3,12‐dioxo‐18βH‐olean‐9(11),1(2)‐dien‐30‐oate was obtained. This derivative displays high antiproliferative activity in cancer cells, including a cell line with a multidrug‐resistance phenotype. It causes cell death by inducing the intrinsic caspase‐dependent apoptotic pathway.

• Publication year

  2011

• Venue

  ChemBioChem

• Publication date

  2011-02-15

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1002/cbic.201000618PMID 21328513PMCID 3085123
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2004cited by this paper
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  2003cited by this paper
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  2003cited by this paper
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  2002cited by this paper
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  2002cited by this paper
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  2002cited by this paper
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  2002cited by this paper
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  2002cited by this paper
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  2001cited by this paper
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  2001cited by this paper
• Synthetic oleanane and ursane triterpenoids with modified rings A and C: a series of highly active inhibitors of nitric oxide production in mouse macrophages.

  2000cited by this paper
• Caspase-3 Is Required for DNA Fragmentation and Morphological Changes Associated with Apoptosis*

  1998cited by this paper
• Pharmacology of oleanolic acid and ursolic acid.

  1995cited by this paper
• A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry.

  1991cited by this paper
• Liquorice, Glycyrrhiza glabra L.—Composition, uses and analysis

  1990cited by this paper
• Blood.

  1989cited by this paper
• Leukemia

  1984cited by this paper
• Reagents for Organic Synthesis

  1967cited by this paper
• 144. Triterpene resinols and related acids. Part XVII. (A) The conversion of β-amyradienonyl acetate into allo-β-amyrenonyl acetate. (B) The conversion of β-amyrin into iso-β-amyradienonol

  1944cited by this paper
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  1942cited by this paper
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  1936cited by this paper

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