Norterpene Cyclic Peroxides from the Marine Sponge Diacarnus spinipoculum , Inhibitors of Transient Receptor Potential Ankyrin 1.

Bioassay-guided isolation of the extract from the marine sponge Diacarnus spinipoculum showing inhibitory activity against human transient receptor potential ankyrin 1 (hTRPA1) resulted in the isolation of 12 norditerpene cyclic peroxides ( 1 - 12 ) and eight norsesterterpene cyclic peroxides ( 13 - 20 ). Among these, 10 ( 5 - 7 , 11 , 12 , 16 - 20 ) are unprecedented analogs. Compounds with either a hydroxy ( 5 , 11 ) or a methoxy ( 6 , 12 ) group attached to the cyclohexanone moiety were obtained as epimeric mixtures at C-11, while compounds 4 , 6 , 10 , and 12 are likely the artifacts of isolation. The absolute configurations of the new compounds were established based on an NMR-based empirical method and comparison of specific rotation values. Mosher ester analysis revealed the absolute configurations of compounds 17 - 20 . The inhibitory activity of the isolated compounds against hTRPA1 varied significantly depending on their structures, with the norsesterterpenoid 19 displaying the most potent activity (IC 50 2.0 μM).