Natural Products, Stylissadines A and B, Specific Antagonists of the P2X7 Receptor, an Important Inflammatory Target1

详细信息    查看全文

• 作者：Malcolm S. Buchanan ; Anthony R. Carroll ; Rama Addepalli ; Vicky M. Avery ; John N. A. Hooper ; Ronald J. Quinn
• 刊名：Journal of Organic Chemistry
• 出版年：2007
• 出版时间：March 30, 2007
• 年：2007
• 卷：72
• 期：7
• 页码：2309 - 2317
• 全文大小：337K
• 年卷期：v.72,no.7(March 30, 2007)
• ISSN：1520-6904

文摘

SRC="/isubscribe/journals/joceah/72/i07/figures/jo062007qn00002.gif" ALIGN="left" HSPACE=5>

The distribution of the P2X₇ receptor in inflammatory cells suggests that P2X₇ antagonists have a significantrole to play in the treatment of inflammatory disease. We conducted a natural product high-throughputscreening campaign to discover P2X₇ receptor antagonists. The Australian marine sponge Stylissa flabellatayielded two new bisimidazo-pyrano-imidazole bromopyrrole ether alkaloids, stylissadines A (IC₅₀ 0.7s/entities/mgr.gif">M) and B (IC₅₀ 1.8 s/entities/mgr.gif">M), as the specific bioactive constituents. The compounds inhibit BzATP-mediatedpore formation in THP-1 cells. Also present in this extract was considerable nonspecific bioactivity inthe hemeolysin specificity assay. A new pyrrole-imidazole alkaloid, konbu'acidin B, and the knownpyrrole-imidazole alkaloids 4,5-dibromopalau'amine and massadine were also isolated and had nonspecificactivity. ROESY and proton coupling constant data indicated that the stereochemistry at C12, C17, andC20 in 4,5-dibromopalau'amine should be revised to 12R, 17S, 20S. By analogy, the relativestereochemistry 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 mostpotent natural product P2X₇ antagonists to be isolated to date and provide a novel class of P2X₇ receptorinhibitors. They are also the first examples of tetrameric pyrrole-imidazole alkaloids.