期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 21, 页码 8814-8825出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm401248x
关键词
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资金
- National Institutes of Health [P50 CA097007, P30 DA028821, R21 MH093844]
- R. A. Welch Foundation Chemistry and Biology Collaborative Grant from the Gulf Coast Consortia (GCC)
- Keck Center for Interdisciplinary Bioscience Training of the GCC (NIGMS) [T32 GM089657-03]
- Sealy and Smith Foundation
- John Sealy Memorial Endowment Fund
- Center for Addiction Research (CAR) at University of Texas Medical Branch (UTMB)
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 alpha,beta-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.
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