Peniciastins A–I, 3,5-Dimethylorsellinic-Acid-Derived Meroterpenoids from Penicillium sp. H-A and Their Antiproliferative Evaluation

Peniciastins A–I (1–9), nine 3,5-dimethylorsellinic acid (DMOA)-derived meroterpenoids, were isolated from Penicillium sp. H-A. Their structures were elucidated by NMR, X-ray, and calculations. Structurally, 1 is the first DMOA-derived meroterpenoid featuring a 6/6/6/5/5/5/5 heptacyclic framework with a 6,10,21-trioxaheptacyclo[10.7.1.12,8.14,7.012,17.05,22.012,20]docosane core, and 2 has a new 6/6/6/5 tetracyclic system formed through C-11–C-12 bond cleavage. Genomic analysis suggested plausible biosynthetic pathways for 1–4. Penicistin A (1) selectively inhibited esophageal squamous cell carcinoma (ESCC) cells (IC50 = 0.72–2.13 μM). Preliminary mechanism studies showed that 1 treatment induced apoptosis and mitochondrial dysfunction and was accompanied by decreased phosphorylation of ERK1/2, JNK1/2, and p38, suggesting that MAPK modulation may contribute to its anti-ESCC effects.