Structurally diverse cembranoids as natural TRPV3 agonists from gum resin of Boswellia sacra

Sacraoxides I-Q (1-9), nine undescribed cembranoids were isolated from the gum resin of Boswellia sacra as well as two known analogues (10 and 11). Their structures were determined by the analysis of 1D/2D NMR and HRESIMS data, quantum chemical calculations, modified Mosher's method, and a single-crystal X-ray diffraction study. Compounds 1 and 2 possess an unprecedented 15,16-dioxatricyclo[7.5.1.1^2,5]hexadecane polyether skeleton. Compound 3 has been identified as the first instance of nor-cembranoid bearing a 13-oxabicyclo[8.2.1]tridecane skeleton. Meanwhile, compounds 4 and 5 have been characterized as unusual 5,6-seco- and 7,8-seco-cembranoids. Plausible biosynthetic pathways were proposed from the naturally occurring cembranoids. The isolated cembranoids were evaluated for their activation towards transient receptor potential vanilloid 3 (TRPV3) by using calcium fluorescent assay and manual whole-cell patch-clamp technique. The results revealed that sacraoxide P (8) significantly activates TRPV3 at 50 μM. Molecular docking and molecular dynamic studies preliminarily undercover that compound 8 targets TRPV3 by forming hydrophobic interactions, hydrogen bond, and van der Waals forces with residues at the nexus of the linker domain, pre-S1 and TRP helices.