Metabolic Shunting in Marine-Derived Diaporthe sp. SYSU-MS4722 Yields Diverse γ‑Butyrolactone Derivatives with Anti-inflammatory Activity

Filamentous fungi have significant potential to produce
diverse
secondary metabolites. However, the majority of fungal biosynthetic
gene clusters (BGCs) remain cryptic under standard laboratory conditions,
thereby limiting the chances of discovering novel metabolites. In
our previous study, the marine fungus Diaporthe sp. SYSU-MS4722 was found to contain 130 BGCs, despite predominately
producing phomoxanthone A and its analogues. By deleting the polyketide
synthase gene phoE, which is responsible for the
skeleton construction in the biosynthesis of phomoxanthone A, we successfully
activated the metabolic shunting of Diaporthe sp. SYSU-MS4722, leading to the isolation of nine new γ-butyrolactone
derivatives, colletolides C–K (1–9), along with known compound colletolide B (10). Their structures were elucidated by 1D and 2D NMR, modified Mosher’s
method, ECD calculations, and DP4+ probability analysis.
All compounds were evaluated for anti-inflammatory activity by measuring
IL-6 inhibition in A549 cells using ELISA. Compounds 1–9 exhibited anti-inflammatory activity, with
EC50 values ranging from 24 to 106 μM. Among them,
colletolide D (2) and colletolide B (10)
showed the lowest EC50 values of 24 μM, indicating
relatively stronger activity within this series. These findings indicate
that colletolides D (2) and B (10) are promising
lead compounds for anti-inflammatory drug development.