Synergistic TRAIL Sensitizers from <i>Barleria alluaudii</i> and <i>Diospyros maritima</i>

<i>Barleria alluaudii</i> and <i>Diospyros maritima</i> were both investigated as part of an ongoing search for synergistic TRAIL (tumor necrosis factor-α-related apoptosis-inducing ligand) sensitizers. As a result of this study, two naphthoquinone epoxides, 2,3-epoxy-2,3-dihydrolapachol (<b>1</b>) and 2,3-epoxy-2,3-dihydro-8-hydroxylapachol (<b>2</b>), both not previously isolated from natural sources, and the known 2-methylanthraquinone (<b>3</b>) were identified from <i>B. alluaudii.</i> Time-dependent density functional theory (TD-DFT) calculations of electronic circular dichroism (ECD) spectra were utilized to establish the absolute configuration of <b>1</b> and <b>2</b>. Additionally, five known naphthoquinone derivatives, maritinone (<b>4</b>), elliptinone (<b>5</b>), plumbagin (<b>6</b>), (+)-<i>cis</i>-isoshinanolone (<b>7</b>), and ethylidene-6,6′-biplumbagin (<b>8</b>), were isolated from <i>D. maritima</i>. Compounds <b>1</b>, <b>2</b>, and <b>4</b>–<b>6</b> showed varying levels of synergy with TRAIL. Maritinone (<b>4</b>) and elliptinone (<b>5</b>) showed the highest synergistic effect, with more than a 3-fold increase in activity observed with TRAIL than with compound alone

Inhibition of Hypoxia Inducible Factor‑2 Transcription: Isolation of Active Modulators from Marine Sponges

Renal or kidney cancer accounts for about 3% of all cancer cases reported each year in the U.S. Molecular signatures that define the cancer, such as the loss of functional VHL, are found in both sporadic and familial cases of cancer. In clear cell renal cancer, the transcription factor HIF-2α has been shown to have a distinct role in tumorigenesis. Our laboratories developed a cell-based screen to identify modulators of HIF-2α. Screening of the NCI’s Natural Product Extract Repository resulted in the identification of 10 sponge extracts, from which 12 compounds were isolated. The biological evaluation of these compounds will be discussed including evaluation of HIF-1α vs HIF-2α selectivity and the isolated compounds’ effects on mRNA from several pathways regulated by HIF

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

Characterization and Synthesis of Eudistidine C, a Bioactive Marine Alkaloid with an Intriguing Molecular Scaffold

An extract of <i>Eudistoma</i> sp. provided eudistidine C (<b>1</b>), a heterocyclic alkaloid with a novel molecular framework. Eudistidine C (<b>1</b>) is a racemic natural product composed of a tetracyclic core structure further elaborated with a <i>p</i>-methoxyphenyl group and a phenol-substituted aminoimidazole moiety. This compound presented significant structure elucidation challenges due to the large number of heteroatoms and fully substituted carbons. These issues were mitigated by application of a new NMR pulse sequence (LR-HSQMBC) optimized to detect four- and five-bond heteronuclear correlations and the use of computer-assisted structure elucidation software. Synthesis of eudistidine C (<b>1</b>) was accomplished in high yield by treating eudistidine A (<b>2</b>) with 4­(2-amino-1<i>H</i>-imidazol-5-yl)­phenol (<b>4</b>) in DMSO. Synthesis of eudistidine C (<b>1</b>) confirmed the proposed structure and provided material for further biological characterization. Treatment of <b>2</b> with various nitrogen heterocycles and electron-rich arenes provided a series of analogues (<b>5</b>–<b>10</b>) of eudistidine C. Chiral-phase HPLC resolution of epimeric eudistidine C provided (+)-(<i>R</i>)-eudistidine C (<b>1a</b>) and (−)-(<i>S</i>)-eudistidine C (<b>1b</b>). The absolute configuration of these enantiomers was assigned by ECD analysis. (−)-(<i>S</i>)-Eudistidine C (<b>1b</b>) modestly inhibited interaction between the protein binding domains of HIF-1α and p300. Compounds <b>1</b>, <b>2</b>, and <b>6</b>–<b>10</b> exhibited significant antimalarial activity against <i>Plasmodium falciparum</i>