Screening and Biological Effects of Marine Pyrroloiminoquinone Alkaloids: Potential Inhibitors of the HIF-1α/p300 Interaction

Inhibition of the hypoxia-inducible factor 1α (HIF-1α) pathway by disrupting its association with the transcriptional coactivator p300 inhibits angiogenesis and tumor development. Development of HIF-1α/p300 inhibitors has been hampered by preclinical toxicity; therefore, we aimed to identify novel HIF-1α/p300 inhibitors. Using a cell-free assay designed to test compounds that block HIF-1α/p300 binding, 170 298 crude natural product extracts and prefractionated samples were screened, identifying 25 active extracts. One of these extracts, originating from the marine sponge <i>Latrunculia</i> sp., afforded six pyrroloiminoquinone alkaloids that were identified as positive hits (IC₅₀ values: 1–35 μM). Luciferase assays confirmed inhibition of HIF-1α transcriptional activity by discorhabdin B (<b>1</b>) and its dimer (<b>2</b>), 3-dihydrodiscorhabdin C (<b>3</b>), makaluvamine F (<b>5</b>), discorhabdin H (<b>8</b>), discorhabdin L (<b>9</b>), and discorhabdin W (<b>11</b>) in HCT 116 colon cancer cells (0.1–10 μM, <i>p</i> < 0.05). Except for <b>11</b>, all of these compounds also reduced HIF-1α transcriptional activity in LNCaP prostate cancer cells (0.1–10 μM, <i>p</i> < 0.05). These effects occurred at noncytotoxic concentrations (<50% cell death) under hypoxic conditions. At the downstream HIF-1α target level, compound <b>8</b> (0.5 μM) significantly decreased VEGF secretion in LNCaP cells (<i>p</i> < 0.05). In COLO 205 colon cancer cells no activity was shown in the luciferase or cytotoxicity assays. Pyrroloiminoquinone alkaloids are a novel class of HIF-1α inhibitors, which interrupt the protein–protein interaction between HIF-1α and p300 and consequently reduce HIF-related transcription

Association between finasteride concentrations and genes in metabolism and target pathways among white men. ^#

<p>Association between finasteride concentrations and genes in metabolism and target pathways among white men. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0126672#t004fn001" target="_blank">^#</a></p

Associations of finasteride concentrations with prostate cancer risk in PCPT, overall and stratified by cancer grade.

<p>Associations of finasteride concentrations with prostate cancer risk in PCPT, overall and stratified by cancer grade.</p

Mean finasteride levels (ng/mL) stratified by categories of demographic measures among treatment-compliant men in the Prostate Cancer Prevention Trial finasteride arm.

<p>Mean finasteride levels (ng/mL) stratified by categories of demographic measures among treatment-compliant men in the Prostate Cancer Prevention Trial finasteride arm.</p

Demographics and lifestyle characteristics of cases and controls of the Prostate Cancer Prevention Trial participants in the treatment arm (n = 1273).

<p>Demographics and lifestyle characteristics of cases and controls of the Prostate Cancer Prevention Trial participants in the treatment arm (n = 1273).</p