Natural products, stylissadines A and B, specific antagonists of the P2X7 receptor, an important inflammatory Target
Natural products, stylissadines A and B, specific antagonists of the P2X7 receptor, an important inflammatory Target
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DOI：
10.1021/jo062007q
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发表时间：
2007-03-30
影响因子：
3.6
通讯作者：
Quinn, Ronald J.
中科院分区：
文献类型：
--
作者：
Buchanan, Malcolm S.;Carroll, Anthony R.;Quinn, Ronald J.
P2X(7)受体在炎症细胞中的分布表明P2X(7)拮抗剂在炎症性疾病的治疗中具有重要作用。我们进行了一项天然产物高通量筛选活动，以发现P2X(7)受体拮抗剂。从澳大利亚海绵体flabellata中分离得到两种新的双咪唑-吡喃-咪唑溴吡咯醚生物碱，花柱苷A （IC50为0.7 μ M）和B （IC50为1.8 μ M）作为特异性生物活性成分。这些化合物抑制bzatp介导的THP-1细胞的孔形成。在溶血素特异性试验中，该提取物还具有相当大的非特异性生物活性。此外，还分离出一种新的吡咯-咪唑类生物碱——孔布酸苷B，以及已知的吡咯-咪唑类生物碱4,5-二溴帕劳胺和马萨定，均具有非特异性活性。ROESY和质子偶联常数数据表明，4,5-二溴帕劳胺中C12、C17和C20的立体化学应修正为12R、17S、20S。以此类推，帕劳胺、4-溴帕劳胺、苯基胍、3-溴苯基胍、2,3-二溴苯基胍的相对立体化学也应修改为12R、17S、20S。styissadines A和B是迄今为止分离出的最有效的天然产物P2X(7)拮抗剂，并提供了一类新的P2X(7)受体抑制剂。它们也是四聚吡咯-咪唑类生物碱的第一个例子。
The distribution of the P2X(7) receptor in inflammatory cells suggests that P2X(7) antagonists have a significant role to play in the treatment of inflammatory disease. We conducted a natural product high-throughput screening campaign to discover P2X(7) receptor antagonists. The Australian marine sponge Stylissa flabellata yielded two new bisimidazo-pyrano-imidazole bromopyrrole ether alkaloids, stylissadines A (IC50 0.7 mu M) and B (IC50 1.8 mu M), 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 P2X(7) antagonists to be isolated to date and provide a novel class of P2X(7) receptor inhibitors. They are also the first examples of tetrameric pyrrole-imidazole alkaloids.