Ganoderic Acid A and Its Amide Derivatives as Potential Anti-Cancer Agents by Regulating the p53-MDM2 Pathway: Synthesis and Biological Evaluation

The mechanisms of action of natural products and the identification of their targets have long been a research hotspot. Ganoderic acid A (GAA) is the earliest and most abundant triterpenoids discovered in . The multi-therapeutic potential of GAA, in particular its anti-tumor activity, has been exten...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2023-03, Vol.28 (5), p.2374
Main Authors: Jia, Yi, Li, Yan, Shang, Hai, Luo, Yun, Tian, Yu
Format: Article
Language:English
Subjects:
Acids
Antimitotic agents
Antineoplastic agents
Antineoplastic Agents - pharmacology
Apoptosis
Cancer
Carboxyl group
Care and treatment
Cell cycle
derivatives
DNA damage
Drug therapy
Ganoderic acid
Ganoderic acid A
MDM2
MDM2 protein
mechanism of action
Metabolism
Metabolites
Mutation
Natural products
p53
Proteins
Signal transduction
Sterols
Toxicity
Triterpenes - chemistry
Triterpenoids
tumor
Tumor cell lines
Tumor proteins
Tumor Suppressor Protein p53
Tumors
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Summary:The mechanisms of action of natural products and the identification of their targets have long been a research hotspot. Ganoderic acid A (GAA) is the earliest and most abundant triterpenoids discovered in . The multi-therapeutic potential of GAA, in particular its anti-tumor activity, has been extensively studied. However, the unknown targets and associated pathways of GAA, together with its low activity, limit in-depth research compared to other small molecule anti-cancer drugs. In this study, GAA was modified at the carboxyl group to synthesize a series of amide compounds, and the in vitro anti-tumor activities of the derivatives were investigated. Finally, compound was selected to study its mechanism of action because of its high activity in three different types of tumor cell lines and low toxicity to normal cells. The results showed that could induce apoptosis by regulating the p53 signaling pathway and may be involved in inhibiting the interaction of MDM2 and p53 by binding to MDM2 (K = 1.68 µM). This study provides some inspiration for the research into the anti-tumor targets and mechanisms of GAA and its derivatives, as well as for the discovery of active candidates based on this series.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules28052374