Candosins A-L: potential antiparkinsonian agents from Candolleomyces sp

Three fractions of Candolleomyces sp. cultured on Chinese yam agar solid medium were tested for the neuroprotective activity against Parkinson's disease (PD) induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) with model mice. Assessments including in vivo open field test (OFT), α-synuclein (α-syn) and tyrosine hydroxylase (TH) expression, pathological examination, and in vitro neuroprotective effects revealed that the dichloromethane fraction exhibited anti-PD effect. The work led to the isolation of 12 undescribed guanacastane diterpenoids candosins A-L (1-12). Candosin B (2) was an unprecedented diterpenoid with 6/6/6/5-fused tetracyclic backbone containing one [5.5] spiro ring. Candosins A and C (1 and 3) were undescribed diterpenoid skeletons with 6/6/7/5-fused tetracyclic backbone containing a pyran ring, and a furan ring. The structures were elucidated according to the NMR, HRESIMS, and ECD spectra. Compounds 2-5, 7-9, 11, and 12 exhibited significant neuroprotective effects on MPP ⁺ induced PC-12 cell injury, with viability ranging from 68.63% to 87.97%. The docking results indicated that active diterpenoids produced by fungus Candolleomyces sp. might exert a protective effect on PD through α-syn mediated signaling pathway.