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 furo2,3bfuran ring, a caged 3,10-oxa-tricyclo5.2.1.0^4,9decane moiety, and 6/6/5/5/5/5/6/6 octocyclic skeleton. Compounds 2−3 exhibited a spiro-tetrahydrofuran ring, while compound 4 incorporated a caged spiro-2,5,9-oxa-tricyclo5.2.1.0^4,10decane 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.