Priscila De Almeida Leone

Exiguaquinol: a novel pentacyclic hydroquinone from Neopetrosia exigua that inhibits Helicobacter pylori MurI.

Bioassay-guided fractionation of the methanol extract of the Australian sponge Neopetrosia exigua led to the isolation of exiguaquinol (2), a new pentacyclic hydroquinone that inhibited Helicobacter pylori glutamate racemase (MurI) with an IC(50) of 4.4 microM. Its structure and relative configuration were assigned on the basis of spectroscopic data. Exiguaquinol (2), bearing a novel pentacyclic ring skeleton, is the first natural product to show inhibition of H. pylori MurI. Its protein-ligand modeling is also discussed.

Sideroxylonal C, a new inhibitor of human plasminogen activator inhibitor type-1, from the flowers of Eucalyptus albens

Sideroxylonal C (3), a new phloroglucinol dimer, was isolated from the flowers of Eucalyptus albens through bioassay-guided fractionation. The structure elucidation was based on 1D and 2D NMR experiments, MS analysis, and comparison with sideroxylonals A (1) and B (2). Sideroxylonal C inhibited human plasminogen activator inhibitor type-1 at 4.7 microM without any significant effect on human tissue plasminogen activator.

Euodenine A: A Small-Molecule Agonist of Human TLR4

A small-molecule natural product, euodenine A (1), was identified as an agonist of the human TLR4 receptor. Euodenine A was isolated from the leaves of Euodia asteridula (Rutaceae) found in Papua New Guinea and has an unusual U-shaped structure. It was synthesized along with a series of analogues that exhibit potent and selective agonism of the TLR4 receptor. SAR development around the cyclobutane ring resulted in a 10-fold increase in potency. The natural product demonstrated an extracellular site of action, which requires the extracellular domain of TLR4 to stimulate a NF-κB reporter response. 1 is a human-selective agonist that is CD14-independent, and it requires both TLR4 and MD-2 for full efficacy. Testing for immunomodulation in PBMC cells shows the induction of the cytokines IL-8, IL-10, TNF-α, and IL-12p40 as well as suppression of IL-5 from activated PBMCs, indicating that compounds like 1 could modulate the Th2 immune response without causing lung damage.

Australian biodiversity via its plants and marine organisms. A high-throughput screening approach to drug discovery*

High-throughput screening (HTS) of extracts of Australian plants and marine organisms commenced in our laboratory in 1994. The biota collections commenced in late 1993. The collection has in excess of 30 000 biota samples including over 16 000 biota samples of vascular plants, algae, and macro fungi from Queensland, and over 4000 marine invertebrates from Australian waters. The plant collection represents ∼9 % of the world species diversity of higher plants, with representation from 73 % of the worlds plant families. The marine collection contains ∼10 % of the world diversity of sponges, ∼10 % of the world diversity of ascidians, and ∼5 % of the world diversity of soft corals and gorgonians. The lecture will highlight some of the advances to knowledge about Australian biodiversity as a result of the HTS project, discuss drug discovery using HTS, and give some examples of the chemistry arising from the screening of the extracts.

Ianthesine E, a new bromotyrosine-derived metabolite from the Great Barrier Reef sponge Pseudoceratina sp.

The new compound ianthesine E (1) was isolated from the Great Barrier Reef marine sponge Pseudoceratina sp. along with the known metabolites 11-hydroxyaerothionin (2), aerothionin (3) and 11,19-dideoxyfistularin 3 (4). Structures were determined on the basis of their spectroscopic data. The compounds were tested for inhibition of [3H] DPCPX binding to adenosine A1 receptors in a whole cell binding assay. At 100µM, aerothionin was the most potent, inhibiting 67% of binding, followed by ianthesine E and 11-hydroxyaerothionin which inhibited 61% of binding, and 11,19-dideoxyfistularin which initiated 51% of binding Ianthesine E (EC50 60µM), aerothionin (EC50 42 µM) and 11,19-dideoxyfistularin-3 (EC50 2.6 µM) exhibited moderate cytotoxicity against the HeLa cell line.