Talarotetramates A-F, Decalin-Containing Tetramic Acids as Ferroptosis Inhibitors from the Deep-Sea-Derived Fungus...

Talarotetramates A-F (1-6), six novel 3-decalinoyltetramic acids (3-DTAs), were discovered from the deep-sea-derived fungus Talaromyces sp. gb505, along with a structurally related analogue, talaroconvolutin A (7). Their structures were elucidated by comprehensive analysis of NMR spectra, HRESIMS, and quantum chemical calculations of ECD and NMR data. Compounds 1-4 represent the first examples of unique 3-DTA heterodimers, formed via intermolecular ketalization between talaroconvolutin-type 3-DTAs and a C₁₀ polyketide. Compound 5 is the first nor-talaroconvolutin-type 3-DTA with the reduction of the para-hydroxybenzyl, while 6 contains a unique epoxy ring system, unprecedented in 3-DTAs. We discovered for the first time that compounds 6 and 7 exhibit inhibitory activity against RSL3-induced ferroptosis. Notably, 6 exhibited potent ferroptosis inhibition with an EC₅₀ value of 7.77 μM. Mechanistic investigations indicate that 6 suppresses ferroptosis by alleviating lipid peroxidation and upregulating NRF2 expression. The present work provides new insights into the structural diversity and pharmaceutical potential of 3-DTAs.