Unique Polybrominated Hydrocarbons from the Australian Endemic Red Alga <i>Ptilonia australasica</i>

The red alga <i>Ptilonia australasica</i> is endemic to Australian temperate waters. Chemical investigation of <i>P. australasica</i> led to the identification of four new polybrominated compounds, ptilones A–C (<b>1</b>–<b>3</b>) and australasol A (<b>4</b>). Their planar structures were established by extensive NMR and MS analyses. The low H/C ratio and the presence of a large number of heteroatoms made the structure elucidation challenging. The absolute configurations of <b>1</b>, <b>2</b>, and <b>4</b> were determined by quantum chemical ECD calculations employing time-dependent density functional theory. Ptilones A–C (<b>1</b>–<b>3</b>) show unique 4-ethyl-5-methylenecyclopent-2-enone (<b>1</b> and <b>2</b>) and 2-methyl-6-vinyl-4<i>H</i>-pyran-4-one (<b>3</b>) skeletons not previously reported in algal metabolites. Ptilone A displayed the most potent cytotoxicity against the human prostate cancer PC3 cells with an IC₅₀ value of 0.44 μM and induced the PC3 cell cycle arrest in the G0/G1 phase

Bromotyrosine Alkaloids from the Australian Marine Sponge <i>Pseudoceratina verrucosa</i>

Two new bromotyrosine alkaloids, pseudoceralidinone A (<b>1</b>) and aplysamine 7 (<b>2</b>), along with three known compounds were isolated from the Australian sponge <i>Pseudoceratina verrucosa</i>. Their structures were characterized by NMR and MS data and the synthetic route. Their cytotoxicity was evaluated against cancer cell lines (HeLa and PC3) and a noncancer cell line (NFF)

Fragment-Based Screening of a Natural Product Library against 62 Potential Malaria Drug Targets Employing Native Mass Spectrometry

Natural products are well known for their biological relevance, high degree of three-dimensionality, and access to areas of largely unexplored chemical space. To shape our understanding of the interaction between natural products and protein targets in the postgenomic era, we have used native mass spectrometry to investigate 62 potential protein targets for malaria using a natural-product-based fragment library. We reveal here 96 low-molecular-weight natural products identified as binding partners of 32 of the putative malarial targets. Seventy-nine (79) fragments have direct growth inhibition on <i>Plasmodium falciparum</i> at concentrations that are promising for the development of fragment hits against these protein targets. This adds a fragment library to the published HTS active libraries in the public domain

Euodenine A: A Small-Molecule Agonist of Human TLR4

A small-molecule natural product, euodenine A (<b>1</b>), 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. <b>1</b> 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 <b>1</b> could modulate the Th2 immune response without causing lung damage