Park Jin-Hee, Williams Darren R, Lee Ji-Hyung, Lee So-Deok, Lee Je-Heon, Ko Hyojin, Lee Ga-Eun, Kim Sujin, Lee Jeong-Min, Abdelrahman Aliaa, Müller Christa E, Jung Da-Woon, Kim Yong-Chul
School of Life Sciences, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea.
Department of Pharmaceutical Industry, Korea Health Industry Development Institute (KHIDI) , Chungcheongbuk-do 363-700, Republic of Korea.
J Med Chem. 2016 Aug 25;59(16):7410-30. doi: 10.1021/acs.jmedchem.5b01690. Epub 2016 Aug 9.
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.
P2X7受体（P2X7R）已被报道为炎症过程和癌症侵袭/转移中的关键介质。在本研究中，我们报告了新型P2X7R拮抗剂的发现及其作为潜在抗转移剂的功能活性。对P2X7R拮抗剂7的乙内酰脲核心骨架和侧链取代基进行了修饰。构效关系（SAR）研究和优化表明，R1位的磺酰基、R2的取代位置和整体大小对P2X7R拮抗作用很重要。优化后的新型类似物表现出强效的P2X7受体拮抗作用（IC50 = 0.11 - 112 nM），同时对IL-1β释放具有显著的抑制作用（IC50 = 0.32 - 210 nM）。此外，具有咪唑和尿嘧啶核心骨架的代表性拮抗剂（12g、13k和17d）在斑马鱼异种移植模型中显著抑制了MDA-MB-231三阴性乳腺癌细胞的侵袭和癌细胞迁移，表明这些新型P2X7拮抗剂在阻断转移性癌症方面具有潜在的治疗应用价值。
