Candosins A-L: potential antiparkinsonian agents from Candolleomyces sp.

Candolleomyces sp. showed anti-PD in mice, and in vitro neuroprotective effect. • Candosin B had an unprecedented spiral 6/6/6/5-fused tetracyclic backbone. • Candosins A, C were undescribed 6/6/7/5-fused tetracyclic diterpenoid skeletons. • Candosins B-E, G-I, K and L showed obvious neuroprotective effects. 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. The dichloromethane fraction of Candolleomyces sp., cultured on Chinese yam agar solid medium, exhibited anti-PD activity, leading to the isolation of 12 previously undescribed guanacastane diterpenoids, candosins A–L ( 1 – 12 ). Molecular docking suggested that α-synuclein (α-syn) may serve as a potential molecular target for the neuroprotective effects of compounds 2 – 5 , 7 – 9 , 11 , and 12 . Download: Download high-res image (433KB) Download: Download full-size image