Karren Deanne Beattie

Pyridocoumarin, aristolactam and aporphine alkaloids from the Australian rainforest plant Goniothalamus australis

Chemical investigation of the CH(2)Cl(2)/CH(3)OH extracts from aerial parts of the Australian plant Goniothalamus australis has resulted in the isolation of two pyridocoumarin alkaloids, goniothalines A (1) and B (2) as well as eight known natural products, aristolactam AII (3), enterocarpam II (4), caldensine (5), sauristolactam (6), (-)-anonaine (7), asimilobine (8), altholactone (9) and (+)-goniofufurone (10). The chemical structures of all compounds were determined by extensive spectroscopic and spectrometric analysis. Methylation of 2 using TMS-diazomethane afforded 1, which unequivocally established that both 1 and 2 possessed a 10-methyl-2H-pyrano[2,3-f]quinolin-2-one skeleton. These pyridocoumarin alkaloids are putatively proposed to arise biosynthetically from an aporphinoid precursor. Compounds 1-10 were evaluated for in vitro antimalarial activity against a chloroquine-sensitive Plasmodium falciparum line (3D7). Sauristolactam (6) and (-)-anonaine (7) exhibited the most potent antiparasitic activity with IC(50) values of 9 and 7 μM, respectively.

Antibacterial metabolites from Australian macrofungi from the genus Cortinarius

In this study, ethyl acetate and aqueous fractions from 117 collections of Australian macrofungi belonging to the mushroom genus Cortinarius were screened for antimicrobial activity against Staphylococcus aureus and Pseudomonas aeruginosa. Overall, the lipophilic fractions were more active than the aqueous fractions. The ethyl acetate fractions of most or all collections of 13 species, namely Cortinarius ardesiacus, C. archeri, C. austrosaginus, C. austrovenetus, C. austroviolaceus, C. coelopus, C. [Dermocybe canaria](2), C. clelandii, C. [D. kula], C. memoria-annae, C. persplendidus, C. sinapicolor, C. vinosipes and forty seven collections of un-described Cortinarius species exhibited IC(50) values of 0.09 mg/mL against S. aureus. In contrast, most or all collections of only four species, namely C. abnormis, C. austroalbidus, C. [D. kula], C. persplendidus, and eleven un-described Cortinarius collections exhibited similar effects against P. aeruginosa (IC(50) <or= 0.09 mg/mL). Anthraquinonoid pigments isolated from C. basirubescens together with emodin physcion and erythrogluacin were assessed for their antimicrobial activity. The fungal octaketides austrocortilutein, austrocortirubin, torosachrysone, physcion and emodin were found to strongly inhibit the growth of S. aureus (IC(50) 0.7-12 microg/mL) whereas only physcion and emodin exhibited potency against P. aeruginosa (IC(50) 1.5 and 2.0 microg/mL, respectively).

Chemical composition and cytotoxicity of oils and eremophilanes derived from various parts of Eremophila mitchellii Benth. (Myoporaceae).

A detailed investigation of the wood, leaf, branch and root oil of Eremophila mitchellii (Benth.) was carried out by a combination of GC-FID, GC-MS and NMR. The wood oil was composed predominantly of eremophilanes, a rare class of biologically active, bicyclic sesquiterpenoids. The root oil was also found to contain the eremophilanes together with the zizaene sesquiterpene, sesquithuriferone. 9-Hydroxy-1,7(11),9-eremophilatrien-8-one and the known 1(10),11-eremophiladien-9-one (eremophilone), 9-hydroxy-7(11),9-eremophiladien-8-one (2-hydroxyeremophilone), 8-hydroxy-11-eremophilen-9-one (santalcamphor), 8-hydroxy-10,11-eremophiladien-9-one, sesquithuriferone and 8-hydroxy-1,11-eremophiladien-9-one were purified and elucidated by NMR. Three approaches to the purification of the major eremophilanes from the wood oil are described. (+) Spathulenol, α-pinene, globulol, viridiflorene were the major constituents of the leaf oil. All of the essential oils and the eremophilanes exhibited cytotoxicity against P388D(1) mouse lymphoblast cells in-vitro.

(2S,3S)-sulfated pterosin C, a cytotoxic sesquiterpene from the Bangladeshi mangrove fern Acrostichum aureum.

Two new sesquiterpenes, (2R,3S)-sulfated pterosin C (1) and (2S,3S)-sulfated pterosin C (2), along with two known derivatives, (2S,3S)-pterosin C and (2R)-pterosin P, were isolated from a methanolic extract of the aerial parts of Acrostichum aureum. The structures of 1 and 2 were determined by the interpretation of their spectroscopic data. The isolated pterosins were evaluated for their cytotoxic activity against the AGS, HT-29, MDA-MB-231, and MCF-7 human cancer cell lines and the NIH3T3 normal mouse fibroblast cell line, using the MTT assay. Compound 2 showed IC50 values in the range 23.9-68.8 μM. The lowest IC50 value (23.9 μM) was recorded against AGS gastric adenocarcinoma cells. Compound 2 was found to exert an apoptotic effect on AGS cells within 24 h of treatment, which increased with time and was greater than the positive control, cycloheximide. The cytotoxicity of 2 seems to be due in part to the sulfate group on C-14 and the configuration at C-2.

Isolation, structure determination and cytotoxicity studies of tryptophan alkaloids from an Australian marine sponge Hyrtios sp.

Mass-guided fractionation of the MeOH extract from a specimen of the Australian marine sponge Hyrtios sp. resulted in the isolation of two new tryptophan alkaloids, 6-oxofascaplysin (2), and secofascaplysic acid (3), in addition to the known metabolites fascaplysin (1) and reticulatate (4). The structures of all molecules were determined following NMR and MS data analysis. Structural ambiguities in 2 were addressed through comparison of experimental and DFT-generated theoretical NMR spectral values. Compounds 1-4 were evaluated for their cytotoxicity against a prostate cancer cell line (LNCaP) and were shown to display IC50 values ranging from 0.54 to 44.9 μM.

Ethanolic and aqueous extracts derived from Australian fungi inhibit cancer cell growth in vitro

Fifteen Australian macrofungi were investigated for cytotoxic activity. Ethanol, cold and hot water extracts of each species were screened for cytotoxic activity against normal mouse fibroblast cells (NIH/3T3), healthy human epithelial kidney cells (HEK-293), four cancer cell lines, gastric adenocarcinoma cells (AGS), two mammary gland adenocarcinoma cells (MDA-MB-231, MCF7) and colorectal adenocarcinoma cells (HT-29) with a validated MTT assay. Most extracts derived from Omphalotus nidiformis, Cordyceps cranstounii and Cordyceps gunnii demonstrated significant cytotoxic activity toward a variety of cancer cell lines. In contrast only some extracts from Coprinus comatus, Cordyceps hawkesii, Hypholoma fasciculare, Lepista nuda, Leratiomyces ceres and Ophiocordyceps robertsii displayed significant cytotoxic activity, which was usually selective for only one or two cancer cell lines tested. The least cytotoxic species evaluated in this study were Agaricus bitorquis, Coprinopsis atrametaria, Psathyrella asperospora, Russula clelandii, Tricholoma sp. AU2 and Xerula mundroola.

Entonalactams A–C: Isoindolinone derivatives from an Australian rainforest fungus belonging to the genus Entonaema

Bioassay-guided fractionation of an antimalarial DCM/MeOH extract derived from the Australian rainforest fungus Entonaema sp. resulted in the isolation of three new isoindolinone derivatives, entonalactams A-C (1-3), along with the known natural products 3-methoxy-5-methylbenzene-1,2-diol (4), daldinal B (5), and ergosta-4,6,8(14),22-tetraen-3-one (6). The chemical structures of the new secondary metabolites were determined following extensive 1D/2D NMR and MS data analysis. A single crystal X-ray structure for entonalactam A (1) confirmed the NMR-based structure assignment. Entonalactams A-C (1-3) were all determined to be racemic based on chiro-optical data. All secondary metabolites were tested in vitro against Plasmodium falciparum malaria parasites, and ergosta-4,6,8(14),22-tetraen-3-one (6) was identified as the most active compound with 66% inhibition at 50 μM.

Solving the supply of resveratrol tetramers from Papua New Guinean rainforest Anisoptera species that inhibit bacterial type III secretion systems

The supply of (-)-hopeaphenol (1) was achieved via enzymatic biotransformation in order to provide material for preclinical investigation. High-throughput screening of a prefractionated natural product library aimed to identify compounds that inhibit the bacterial virulence type III secretion system (T3SS) identified several fractions derived from two Papua New Guinean Anisoptera species, showing activity against Yersinia pseudotuberculosis outer proteins E and H (YopE and YopH). Bioassay-directed isolation from the leaves of A. thurifera, and similarly A. polyandra, resulted in three known resveratrol tetramers, (-)-hopeaphenol (1), vatalbinoside A (2), and vaticanol B (3). Compounds 1-3 displayed IC50 values of 8.8, 12.5, and 9.9 μM in a luminescent reporter-gene assay (YopE) and IC50 values of 2.9, 4.5, and 3.3 μM in an enzyme-based YopH assay, respectively, which suggested that they could potentially act against the T3SS in Yersinia. The structures of 1-3 were confirmed through a combination of spectrometric, chemical methods, and single-crystal X-ray structure determinations of the natural product 1 and the permethyl ether analogue of 3. The enzymatic hydrolysis of the β-glycoside 2 to the aglycone 1 was achieved through biotransformation using the endogenous leaf enzymes. This significantly enhanced the yield of the target bioactive natural product from 0.08% to 1.3% and facilitates ADMET studies of (-)-hopeaphenol (1).

Antibacterial and antifungal screening of natural products sourced from Australian fungi and characterisation of pestalactams D-F

Eighteen natural products sourced from Australian micro- or macro-fungi were screened for antibacterial and antifungal activity. This focused library was comprised of caprolactams, polyamines, quinones, and polyketides, with additional large-scale isolation studies undertaken in order to resupply previously identified compounds. Chemical investigations of the re-fermented culture from the endophytic fungus Pestalotiopsis sp. yielded three caprolactam analogues, pestalactams D-F, along with larger quantities of the known metabolite pestalactam A, which was methylated using diazomethane to yield 4-O-methylpestalactam A. The chemical structures of the previously undescribed fungal metabolites were determined by analysis of 1D/2D NMR and MS data. The structure of 4-O-methylpestalactam A was confirmed following single crystal X-ray diffraction analysis. The antibacterial and antifungal activity of all compounds was assessed, which identified three compounds, (1S,3R)-austrocortirubin, (1S,3S)-austrocortirubin, and 1-deoxyaustrocortirubin with mild activity (100 μM) against Gram-positive isolates and one compound, 2-hydroxy-6-methyl-8-methoxy-9-oxo-9H-xanthene-1-carboxylic acid, with activity against Cryptococcus neoformans and Cryptococcus gattii at 50 μM.

(3R,4S,5S,8S,10R,13R)-3-Hydroxykaura- 9(11),16-dien-18-oic acid

The title compound, C20H28O3, was isolated during our investigation into the chemical composition and pharmacological activity of Centipeda cunninghamii (DC.) A. Braun & Asch. (Asteraceae). The enantiopure compound, a diterpene with a carbon skeleton, is composed of three six- and one five-membered rings in chair, twist-boat, half-chair and envelope conformations, respectively. Each molecule makes one intra- and one intermolecular O—H⋯O hydrogen bond in the crystal lattice, forming hydrogen-bonded chains along [010]. The absolute configuration of the compound was assigned on the basis of optical rotation measurements.