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

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.