Cytochalasin H Derivatives from the Marine-Derived Fungus Diaporthe sp. CS−HF−1 and Their Anti-Ferroptotic Activity in Human Proximal Tubular Epithelial Cells

Abstract Ferroptosis is a major driver of tubular necrosis, and its pharmacological inhibition markedly attenuates renal injury. In this study, chemical investigation of the marine-derived fungus Diaporthe sp. CS−HF−1 led to the identification of 30 cytochalasin H derivatives, including 12 previously undescribed derivatives (2−13) and 18 known congeners (1 and 14−30). Diachalasin A (2) features an unprecedented 5/6/5/4/6 pentacyclic framework bearing a cyclobutane ring. Diachalasin B (3) possesses a 5/6/6/5/6 pentacyclic skeleton with an α-oriented ether bridge. Diachalasin C (4) (13S,20R) and 13,14,20-triepi-phomopchalasin D (5) (13R,20R) represent uncommon examples of C-20 epimerization and C-13/C-20 double inversion, respectively, within the 5/6/5/8-fused cytochalasin H derivatives. Structures were established by spectroscopic analysis, supported by calculations of NMR chemical shifts, coupling constants, and ECD data. Compounds 3, 14, 21, 22, and 25 exhibited cytoprotective activity against RSL3-induced ferroptosis in HK-2 cells with EC50 values of 7.2, 5.4, 8.2, 6.7, and 6.4 μM, respectively. The active cytochalasans suppressed RSL3-induced lipid peroxidation and restored GSH levels, indicating their renoprotective potential.