Natural products, stylissadines A and B, specific antagonists of the P2X7 receptor, an important inflammatory target.
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.
Buchanan
Malcolm S
MS
Natural Product Discovery, Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland 4111, Australia.
Carroll
Anthony R
AR
Addepalli
Rama
R
Avery
Vicky M
VM
Hooper
John N A
JN
Quinn
Ronald J
RJ
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*
D000893:Anti-Inflammatory Agents; D001688:Biological Products; D007093:Imidazoles; D058919:Purinergic P2 Receptor Antagonists; D011758:Pyrroles; C519418:stylissadine A; C519417:stylissadine B