Ganocochlearcins A-P: Acyclic meroterpenoids from Ganoderma mushrooms targeting extracellular matrix remodeling in cancer-associated fibroblasts.

Sixteen undescribed acyclic meroterpenoids, ganocochlearcins A-P (1-10 and 12-17) and two known meroterpenoids, cochlearin K (11) and fornicin C (18), were obtained from Ganoderma mushrooms, including nine pairs of enantiomers, 3, 6-8, 11-14, and 18. Spectroscopic and computational methods were used for elucidating their full structures, and the enantiomers of the racemates were afforded by chiral High-performance liquid chromatography (HPLC). For the secondary alcohol in 1, 4, 5, and 9, Rh2(OCOCF3)4-induced electronic circular dichroism (ECD) methods were employed to clarify the absolute configurations. The meroterpenoids were screened for bioactivity in triple negative breast cancer (TNBC) models (MDA-MB-231, HCC1806) and cancer-associated fibroblasts. At 20 μM, none showed cytotoxicity, but compounds (+)-3, (+)-8, 10, (+)-12, and 16 selectively altered extracellular matrix (ECM) protein expression in fibroblasts, counteracting tumor-promoting stromal remodeling. This non-cytotoxic modulation of fibroblast-derived ECM suggests their potential to reprogram the TNBC microenvironment, providing new chemical probes for stromal targeting and strategies to disrupt desmoplasia.