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The mangrove-sediment-derived actinomycete strain <i>Streptomyces</i> <i>psammoticus</i> SCSIO NS126 was found to have productive piericidin metabolites featuring anti-renal cell carcinoma activities. In this study, in order to explore more diverse piericidin derivatives, and therefore to discover superior anti-tumor lead compounds, the NS126 strain was further fermented at a 300-L scale under optimized fermentation conditions. As a result, eight new minor piericidin derivatives (piericidins L-R (<b>1</b>–<b>7</b>) and 11-demethyl-glucopiericidin A (<b>8</b>)) were obtained, along with glucopiericidin B (<b>9</b>). The new structures including absolute configurations were determined by spectroscopic methods coupled with experimental and calculated electronic circular dichroism. We also proposed plausible biosynthetic pathways for these unusual post-modified piericidins. Compounds <b>1</b> and <b>6</b> showed selective cytotoxic activities against OS-RC-2 cells, and <b>2</b>–<b>5</b> exhibited potent cytotoxicity against HL-60 cells, with IC₅₀ values lower than 0.1 μM. The new piericidin glycoside <b>8</b> was cytotoxic against ACHN, HL-60 and K562, with IC₅₀ values of 2.3, 1.3 and 5.5 μM, respectively. The ability to arrest the cell cycle and cell apoptosis effects induced by <b>1</b> and <b>6</b> in OS-RC-2 cells, <b>2</b> in HL-60 cells, and <b>8</b> in ACHN cells were then further investigated. This study enriched the structural diversity of piericidin derivatives and confirmed that piericidins deserve further investigations as promising anti-tumor agents.