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

Abstract
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.
AuthorsJin-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
JournalJournal of medicinal chemistry (J Med Chem) Vol. 59 Issue 16 Pg. 7410-30 (08 25 2016) ISSN: 1520-4804 [Electronic] United States
PMID27427902 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 1-piperidinylimidazole
  • Antineoplastic Agents
  • Imidazoles
  • Piperidines
Topics
  • Animals
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Cell Movement (drug effects)
  • Cell Proliferation (drug effects)
  • Cell Survival (drug effects)
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Female
  • HEK293 Cells
  • Humans
  • Imidazoles (chemical synthesis, chemistry, pharmacology)
  • Mammary Neoplasms, Experimental (drug therapy, pathology)
  • Molecular Structure
  • Piperidines (chemical synthesis, chemistry, pharmacology)
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • Zebrafish

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