Buchanan Malcolm S, Carroll Anthony R, Addepalli Rama, Avery Vicky M, Hooper John N A, Quinn Ronald J
Natural Product Discovery, Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland 4111, Australia.
J Org Chem. 2007 Mar 30;72(7):2309-17. doi: 10.1021/jo062007q. Epub 2007 Feb 22.
The distribution of the P2X7 receptor in inflammatory cells suggests that P2X7 antagonists have a significant role to play in the treatment of inflammatory disease. We conducted a natural product high-throughput screening campaign to discover P2X7 receptor antagonists. The Australian marine sponge Stylissa flabellata yielded two new bisimidazo-pyrano-imidazole bromopyrrole ether alkaloids, stylissadines A (IC50 0.7 microM) and B (IC50 1.8 microM), as the specific bioactive constituents. The compounds inhibit BzATP-mediated pore formation in THP-1 cells. Also present in this extract was considerable nonspecific bioactivity in the hemeolysin specificity assay. A new pyrrole-imidazole alkaloid, konbu'acidin B, and the known pyrrole-imidazole alkaloids 4,5-dibromopalau'amine and massadine were also isolated and had nonspecific activity. ROESY and proton coupling constant data indicated that the stereochemistry at C12, C17, and C20 in 4,5-dibromopalau'amine should be revised to 12R, 17S, 20S. By analogy, the relative stereochemistry of palau'amine, 4-bromopalau'amine, styloguanidine, 3-bromostyloguanidine, and 2,3-dibromostyloguanidine should also be revised to 12R, 17S, 20S. Stylissadines A and B are the most potent natural product P2X7 antagonists to be isolated to date and provide a novel class of P2X7 receptor inhibitors. They are also the first examples of tetrameric pyrrole-imidazole alkaloids.
P2X7受体在炎症细胞中的分布表明，P2X7拮抗剂在炎症性疾病的治疗中具有重要作用。我们开展了一项天然产物高通量筛选活动，以发现P2X7受体拮抗剂。澳大利亚海洋海绵扇形扁海绵产生了两种新的双咪唑并吡喃-咪唑溴吡咯醚生物碱，即扁海绵定A（IC50为0.7微摩尔）和B（IC50为1.8微摩尔），作为特定的生物活性成分。这些化合物可抑制THP-1细胞中BzATP介导的孔形成。在该提取物中，溶血素特异性试验中还存在相当大的非特异性生物活性。一种新的吡咯-咪唑生物碱，即海带酸B，以及已知的吡咯-咪唑生物碱4,5-二溴帕劳胺和马萨丁也被分离出来，且具有非特异性活性。ROESY和质子偶合常数数据表明，4,5-二溴帕劳胺中C12、C17和C20处的立体化学应修正为12R、17S、20S。以此类推，帕劳胺、4-溴帕劳胺、柱形胍、3-溴柱形胍和2,3-二溴柱形胍的相对立体化学也应修正为12R、17S、20S。扁海绵定A和B是迄今为止分离出的最有效的天然产物P2X7拮抗剂，提供了一类新型的P2X7受体抑制剂。它们也是四聚吡咯-咪唑生物碱的首个实例。
