Tetramic acid-motif natural products from a marine fungus FB06 and their anti-Parkinson activities.

UNLABELLED

Tetramic acid-containing natural products are attracting significantly increasing attention from biologists and chemists due to their intriguing structures and biological activities. In the present study, two new tetramic acid alkaloids tolypyridone I () and tolypyridone J (), together with five known ones (-), were isolated from cultures of a marine fungus FB06 isolate obtained from a marine sediment in Beaufort sea of North Alaska. Their structures were elucidated using 1D, 2D NMR, and HRESIMS. Their configurations were established on the basis of H coupling constants, ROESY correlations and DP4 calculations. Compound was isolated as mixtures of rotational isomers with C-3 to C-7 axis between 4-hydroxy-2-pyridone and 1-ethyl-3,5-dimethylcyclohexane, hindering rotation. In our unbiased screening to discover neuroprotective compounds in an in vitro Parkinson's disease (PD) model, SH-SY5Y dopaminergic cells were treated with isolated compounds followed by treatment with 1-methyl-4-phenylpyridinium (MPP), a parkinsonian neurotoxin. Among tested compounds, F-14329 () significantly protected cells from MPP-induced cytotoxicity. MPP-mediated cell death is known to be related to the regulation of Bcl-2 family proteins, specifically the down-regulation of anti-apoptotic Bcl-2 and the up-regulation of pro-apoptotic Bax levels. Treatment with 2 mmol/L of MPP for 24 h significantly reduced Bcl-2 levels compared to control treated with vehicle. However, treatment with F-14329 () attenuated such reduction. This study demonstrates that tetramic acid-motif compounds could be potential lead compounds for treating PD.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1007/s42995-023-00198-7.