Potent Suppressive Effects of 1-Piperidinylimidazole Based Novel P2X7 Receptor Antagonists on Cancer Cell Migration and Invasion

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• 作者：Jin-Hee Park ; Darren R. Williams ; Ji-Hyung Lee ; So-Deok Lee ; Je-Heon Lee ; Hyojin Ko ; Ga-Eun Lee ; Sujin Kim ; Jeong-Min Lee ; Aliaa Abdelrahman ; Christa E. Müller ; Da-Woon Jung ; Yong-Chul Kim
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：August 25, 2016
• 年：2016
• 卷：59
• 期：16
• 页码：7410-7430
• 全文大小：986K
• 年卷期：0
• ISSN：1520-4804

文摘

The P2X7 receptor (P2X7R) has been reported as a key mediator in inflammatory processes and cancer invasion/metastasis. In this study, we report the discovery of novel P2X7R antagonists and their functional activities as potential antimetastatic agents. Modifications of the hydantoin core-skeleton and the side chain substituents of the P2X7R antagonist 7 were performed. The structure–activity relationships (SAR) and optimization demonstrated the importance of the sulfonyl group at the R₁ position and the substituted position and overall size of R₂ for P2X7R antagonism. The optimized novel analogues displayed potent P2X7 receptor antagonism (IC₅₀ = 0.11–112 nM) along with significant suppressive effects on IL-1β release (IC₅₀ = 0.32–210 nM). Moreover, representative antagonists (12g, 13k, and 17d) with imidazole and uracil core skeletons significantly inhibited the invasion of MDA-MB-231 triple negative breast cancer cells and cancer cell migration in a zebrafish xenograft model, suggesting the potential therapeutic application of these novel P2X7 antagonists to block metastatic cancer.