Structures and Mechanisms of Antitumor Agents: Xestoquinones Uncouple Cellular Respiration and Disrupt HIF Signaling in Human Breast Tumor Cells

The organic extract of a marine sponge, <i>Petrosia alfiani</i>, selectively inhibited iron chelator-induced hypoxia-inducible factor-1 (HIF-1) activation in a human breast tumor T47D cell-based reporter assay. Bioassay-guided fractionation yielded seven xestoquinones (<b>1</b>–<b>7</b>) including three new compounds: 14-hydroxymethylxestoquinone (<b>1</b>), 15-hydroxymethylxestoquinone (<b>2</b>), and 14,15-dihydroxestoquinone (<b>3</b>). Compounds <b>1</b>–<b>7</b> were evaluated for their effects on HIF-1 signaling, mitochondrial respiration, and tumor cell proliferation/viability. The known metabolites adociaquinones A (<b>5</b>) and B (<b>6</b>), which possess a 3,4-dihydro-2<i>H</i>-1,4-thiazine-1,1-dioxide moiety, potently and selectively inhibited iron chelator-induced HIF-1 activation in T47D cells, each with an IC₅₀ value of 0.2 μM. Mechanistic studies revealed that adociaquinones promote oxygen consumption without affecting mitochondrial membrane potential. Compound <b>1</b> both enhances respiration and decreases mitochondrial membrane potential, suggesting that it acts as a protonophore that uncouples mitochondrial respiration