Atractylodimers A-D, unprecedented sesquiterpenoid dimers with cage-like skeletons from Atractylodes macrocephala and their neuroprotective activities.

Atractylodimers A-D (1-4), sesquiterpenoid dimers (SDs) featuring a unique cage-like structure, were isolated from the rhizomes of Atractylodes macrocephala. The most distinctive characteristic of these isolates was the highly twisted "cap" structure based on highly twisted five-membered oxygen heterocyclic rings. Notably, compound 1 contained a furo[2,3b]furan ring, a caged 3,10-oxa-tricyclo[5.2.1.04,9]decane moiety, and 6/6/5/5/5/5/6/6 octocyclic skeleton. Compounds 2-3 exhibited a spirotetrahydrofuran ring, while compound 4 incorporated a caged spiro2,5,9-oxa-tricyclo[5.2.1.04,10]decane scaffold for unit linkage. Their structures were definitively established through spectroscopic methods and X-ray diffraction experiments. Plausible biosynthetic pathways of compounds 1-4 were proposed. Compounds 1 and 2 demonstrated significant neuroprotective effects against serum deprivation-induced PC12 cell damage.