| Summary: | Three new cytochalasins, phomoparagins A-C (<b>1</b>–<b>3</b>), along with five known analogs (<b>4</b>–<b>8</b>), were isolated from <i>Phomopsis asparagi</i> DHS-48, a mangrove-derived endophytic fungus. Their structures, including their absolute configurations, were elucidated using a combination of detailed HRESIMS, NMR, and ECD techniques. Notably, <b>1</b> possessed an unprecedented 5/6/5/8/5-fused pentacyclic skeleton. These compounds were tested for their inhibitory activity against concanavalin A (ConA)/lipopolysaccharide (LPS)-induced spleen lymphocyte proliferation and calcineurin (CN) enzyme. Several metabolites (<b>2</b> and <b>4</b>–<b>6</b>) exhibited fascinating inhibitory activities with a relatively low toxicity. Furthermore, <b>2</b> was demonstrated to inhibit ConA-stimulated activation of NFAT1 dephosphorylation and block NFAT1 translocation in vitro, subsequently inhibiting the transcription of interleukin-2 (IL-2). Our results provide evidence that <b>2</b> may, at least partially, suppress the activation of spleen lymphocytes via the CN/NFAT signaling pathway, highlighting that it could serve as an effective immunosuppressant that is noncytotoxic and natural.
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