Marinocyanins, cytotoxic bromo-phenazinone meroterpenoids from a marine bacterium from the streptomycete clade MAR4.

Six cytotoxic and antimicrobial metabolites of a new bromo-phenazinone class, the marinocyanins A-F (1-6), were isolated together with the known bacterial metabolites 2-bromo-1-hydroxyphenazine (7), lavanducyanin (8, WS-9659A) and its chlorinated analog WS-9659B (9). These metabolites were purified by bioassay-guided fractionation of the extracts of our MAR4 marine actinomycete strains CNS-284 and CNY-960. The structures of the new compounds were determined by detailed spectroscopic methods and marinocyanin A (1) was confirmed by crystallographic methods. The marinocyanins represent the first bromo-phenazinones with an N-isoprenoid substituent in the skeleton. Marinocyanins A-F show strong to weak cytotoxicity against HCT-116 human colon carcinoma and possess modest antimicrobial activities against Staphylococcus aureus and amphotericin-resistant Candida albicans.

Acronyols A and B, new anti-inflammatory prenylated phloroglucinols from the fruits of Acronychia crassipetala.

Two new phloroglucinols, acronyols A (1) and B (2) along with the four known (3-6) pholoroglucinols were identified following anti-inflammatory activity guided fractionation from the fruits of Acronychia crassipetala (family Rutaceae). The pholoroglucinols (1-6) were evaluated for their inhibitory effects on NO production and downregulation of TNF-α in RAW 264.7 macrophage cell lines.

Potential anti-neuroinflammatory compounds from Australian plants - A review.

Neuroinflammation is a complex response to brain injury involving the activation of glia, release of inflammatory mediators, such as cytokines and chemokines, and generation of reactive oxygen and nitrogen species. Even though it is considered an event secondary to neuronal death or dysfunction, neuro-inflammation comprises a majority of the non-neuronal contributors to the cause and progression of neurodegenerative diseases like Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple Sclerosis (MS), Chronic Traumatic Encephalopathy (CTE) and others. As a result of the lack of effectiveness of current treatments for neurodegenerative diseases, neuroinflammation has become a legitimate therapeutic target for drug discovery, leading to the study of various in vivo and in vitro models of neuroinflammation. Several molecules sourced from plants have displayed anti-inflammatory properties in the study of neurodegenerative diseases. A group of these anti-inflammatory compounds has been classified as cytokine-suppressive anti-inflammatory drugs (CSAIDs), which target the pro-inflammatory AP1 and nuclear factor-κB signaling pathways and inhibit the expression of many pro-inflammatory cytokines, such as interleukin IL-1, IL-6, TNF-α, or nitric oxide. Australian plants, thriving amid the driest inhabited continent of the world, are an untapped source of chemical diversity in the form of secondary metabolites. These compounds are produced in response to biotic and abiotic stresses that the plants are exposed to in the highly biodiverse environment. This review is an attempt to highlight anti-inflammatory compounds isolated from Australian plants.

The reciprocal EC50 value as a convenient measure of the potency of a compound in bioactivity-guided purification of natural products.

Identification of potent natural products is a challenging task in which sophisticated separation processes including HPLC are employed. The bioactivity of HPLC fractions is determined with a bioassay, and the most potent compounds are progressed to structural elucidation. In pharmacology, the potency of a compound is expressed as the half-maximal effective concentration (EC50), which refers to the concentration of a drug that induces a response halfway between the baseline and maximum. While expressing the potency of a compound by its EC50 value makes sense in a clinical context, it is counterintuitive in the context of bioactivity-guided purification, as the potency of a compound is inversely related to its EC50 value, and the most potent compound is the one with the lowest EC50. In natural products chemistry, it would be more logical if an increase in potency would be reflected by an increase of a parameter reflecting the potency. In this study, we introduce the term "effective dilution volume (EDV50)" as the reciprocal of the EC50 (1/EC50). We show how the EDV50 can be used to identify potent compounds in chromatographic separations, allowing to easily graph and identify anti-inflammatory compounds. We show two examples of this approach by overlaying an HPLC chromatogram with the EDV50 to point out the most potent compounds. We hope that the EDV50 will make the illustration of active fractions containing potent compounds in a chromatogram obvious for the reader and will become a useful graphic tool in the natural products literature in the future.

Mulgravanols A and B, rare oxidized xanthenes and a new phloroglucinol isolated from the Australian rainforest plant Waterhousea mulgraveana (Myrtaceae).

Phytochemical investigation of the Australian rainforest plant leaves Waterhousia mulgraveana, yielded two rare oxidized xanthenes, mulgravanols A (1) and B (2) along with a new phloroglucinol, mulgravanol C (3). Mulgravanol A (1) is the first reported example of a complex xanthene flanked by a methine bridged phloroglucinol unit. All the compounds displayed moderate inhibitory effects on nitric oxide production and TNF-α release in RAW 264.7 macrophages (IC50) 42-55 µM. The structures of the new compounds were assigned based on a detailed spectroscopic interpretation.

Ternstroenols A - E: Undescribed pentacyclic triterpenoids from the Australian rainforest plant Ternstroemia cherryi.

Chromatographic separation of the extracts of the Australian rainforest plant Ternstroemia cherryi led to the isolation of five undescribed barrigenol-like triterpenoids, ternstroenols A - E, from the fruits and three known ones from the leaves. Ternstroenols A - E represent a new form of structural diversity, being the first in its kind to incorporate a trans- 2, 4, 6- decatrienoyl moiety at C-22. The structures of the ternstroenols were assigned by detailed spectroscopic analysis, degradation and chemical derivatization. All compounds exhibited potent anti-inflammatory activity in LPS and IFN- γ activated RAW 264.7 macrophages, with IC50 values as low as 0.7 µM. Despite the remarkable potency, high levels of unwanted cell growth inhibition was also observed, which prompted their cytotoxic evaluation in U87/U251 human glioblastoma cell lines.

Costatamins A - C, new 4-phenylcoumarins with anti-inflammatory activity from the Australian woodland tree Angophora costata (Myrtaceae).

The bioassay-guided isolation of new anti-inflammatory metabolites from the Australian Indigenous plant Angophora costata led to the discovery of three new 4-phenylcoumarins, costatamins A - C (1-3). The structures were determined by detailed spectroscopic analysis. Costatamins A - C were evaluated for their inhibitory effects on (a) NO production and (b) TNF-α release in RAW 264.7 macrophages, displaying an IC(50) value of 20-30 µg/mL for both the inflammatory markers.

Targeting Inflammatory Pathways in Alzheimer's Disease: A Focus on Natural Products and Phytomedicines.

Studies of the brains of Alzheimer's disease (AD) patients have revealed key neuropathological features, such as the deposition of aggregates of insoluble amyloid-ß (Aß) peptides and neurofibrillary tangles (NFTs). These pathological protein deposits, including Aß peptides (which form senile plaques) and hyperphosphorylated tau (which aggregates into NFTs), have been assumed to be 'the cause of AD'. Aß has been extensively targeted to develop an effective disease-modifying therapy, but with limited clinical success. Emerging therapies are also now targeting further pathological processes in AD, including neuroinflammation. This review focuses on the inflammatory and oxidative stress-related changes that occur in AD, and discusses some emerging anti-inflammatory natural products and phytomedicines. Many of the promising compounds are cytokine-suppressive anti-inflammatory drugs (CSAIDs), which target the proinflammatory AP1 and nuclear factor-κB signalling pathways and inhibit the expression of many proinflammatory cytokines, such as interleukin (IL)-1, IL-6, tumour necrosis factor-α, or nitric oxide produced by inducible nitric oxide synthase. However, many of these phytomedicines have not been tested in rigorous clinical trials in AD patients. It is not yet clear if the active compounds reach an effective concentration in the brain (due to limited bioavailability) or if they can slow down AD progression in long-term trials. The authors suggest that it is crucial for both the pharmacological and complementary medicine industries to conduct and fund those studies to significantly advance the field.