title: Natural products, stylissadines A and B, specific antagonists of the P2X7 receptor, an important inflammatory target.
abstract: 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.
authors.affiliation: Natural Product Discovery, Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland 4111, Australia.
authors.forename: Malcolm S
authors.initials: MS
authors.lastname: Buchanan
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Carroll
authors.forename: Rama
authors.initials: R
authors.lastname: Addepalli
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.forename: John N A
authors.initials: JN
authors.lastname: Hooper
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Quinn
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry*; D001688:Biological Products / Q000737:chemistry*; D007093:Imidazoles / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D011161:Porifera / Q000737:chemistry; D058919:Purinergic P2 Receptor Antagonists; D011758:Pyrroles / Q000737:chemistry*
chemical_list: D000893:Anti-Inflammatory Agents; D001688:Biological Products; D007093:Imidazoles; D058919:Purinergic P2 Receptor Antagonists; D011758:Pyrroles; C519418:stylissadine A; C519417:stylissadine B