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J Med Chem. 2013 Nov 14;56(21):8814-25. doi: 10.1021/jm401248x. Epub 2013 Oct 31.

Oridonin ring A-based diverse constructions of enone functionality: identification of novel dienone analogues effective for highly aggressive breast cancer by inducing apoptosis.

Author information

1
Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch , Galveston, Texas 77555, United States.

Abstract

Oridonin (1) has attracted considerable attention in recent years because of its unique and safe anticancer pharmacological profile. Nevertheless, it exhibits moderate to poor effects against highly aggressive cancers including triple-negative and drug-resistant breast cancer cells. Herein, we report the rational design and synthesis of novel dienone derivatives with an additional α,β-unsaturated ketone system diversely installed in the A-ring based on this class of natural scaffold that features dense functionalities and stereochemistry-rich frameworks. Efficient and regioselective enone construction strategies have been established. Meanwhile, a unique 3,7-rearrangement reaction was identified to furnish an unprecedented dienone scaffold. Intriguingly, these new analogues have been demonstrated to significantly induce apoptosis and inhibit colony formation with superior antitumor effects against aggressive and drug-resistant breast cancer cells in vitro and in vivo while also exhibiting comparable or lower toxicity to normal human mammary epithelial cells in comparison with 1.

PMID:
24128046
PMCID:
PMC3880594
DOI:
10.1021/jm401248x
[Indexed for MEDLINE]
Free PMC Article

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