4 research outputs found
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-Ī±-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-6,6ā²-biplumbagin (<b>8</b>), were isolated from <i>D. maritima</i>. Compounds <b>1</b>, <b>2</b>, and <b>4</b>ā<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 Factorā2 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-2Ī± has been shown to have a distinct role in tumorigenesis.
Our laboratories developed a cell-based screen to identify modulators
of HIF-2Ī±. Screening of the NCIās 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-1Ī± vs
HIF-2Ī± selectivity and the isolated compoundsā effects
on mRNA from several pathways regulated by HIF
Screening and Biological Effects of Marine Pyrroloiminoquinone Alkaloids: Potential Inhibitors of the HIF-1Ī±/p300 Interaction
Inhibition of the hypoxia-inducible
factor 1Ī± (HIF-1Ī±) pathway by disrupting its association
with the transcriptional coactivator p300 inhibits angiogenesis and
tumor development. Development of HIF-1Ī±/p300 inhibitors has
been hampered by preclinical toxicity; therefore, we aimed to identify
novel HIF-1Ī±/p300 inhibitors. Using a cell-free assay designed
to test compounds that block HIF-1Ī±/p300 binding, 170āÆ298
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 (IC<sub>50</sub> values: 1ā35 Ī¼M). Luciferase assays
confirmed inhibition of HIF-1Ī± 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 (0.1ā10 Ī¼M, <i>p</i> < 0.05). Except for <b>11</b>, all of these compounds
also reduced HIF-1Ī± transcriptional activity in LNCaP prostate
cancer cells (0.1ā10 Ī¼M, <i>p</i> < 0.05).
These effects occurred at noncytotoxic concentrations (<50% cell
death) under hypoxic conditions. At the downstream HIF-1Ī± target
level, compound <b>8</b> (0.5 Ī¼M) 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-1Ī± inhibitors, which interrupt the proteināprotein
interaction between HIF-1Ī± 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 4Ā(2-amino-1<i>H</i>-imidazol-5-yl)Āphenol (<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>ā<b>10</b>) of eudistidine C. Chiral-phase HPLC resolution of epimeric
eudistidine C provided (+)-(<i>R</i>)-eudistidine C (<b>1a</b>) and (ā)-(<i>S</i>)-eudistidine C (<b>1b</b>). The absolute configuration of these enantiomers was assigned
by ECD analysis. (ā)-(<i>S</i>)-Eudistidine C (<b>1b</b>) modestly inhibited interaction between the protein binding
domains of HIF-1Ī± and p300. Compounds <b>1</b>, <b>2</b>, and <b>6</b>ā<b>10</b> exhibited significant
antimalarial activity against <i>Plasmodium falciparum</i>