A Review of the Ethnobotanical Use, Chemistry and Pharmacological Activities of Constituents Derived from the Plant Genus Geijera (Rutaceae).

Geijera Schott is a plant genus of the Rutaceae Juss. (rue and citrus) family, comprising six species which are all native to Oceania. Of the plants belonging to this genus, the most significant species that has a customary use is Geijera parviflora, which was used by Indigenous Australians, primarily as a pain reliever. Herein, a comprehensive review of the literature published on the genus Geijera from 1930 to 2023 was conducted. This is the first review for this plant genus, and it highlights the chemical constituents reported to date, together with the range of pharmacological properties described from the various species and different parts of the plant. These properties include anti-inflammatory, anti-microbial, anti-parasitic, insect repellent, analgesic, neuroactive, and anti-cancer activities. Finally, a reflection on some of the important areas for future focused studies of this plant genus is provided.

Phytochemical Profiling and Biological Testing of the Constituents of the Australian Plant Haemodorum brevisepalum.

Phytochemical profiling was undertaken on the crude extracts of the bulbs, stems, and the fruits of Haemodorum brevisepalum, to determine the nature of the chemical constituents present. This represents the first study to investigate the fruits of a species of Haemodorum. In total, 13 new and 17 previously reported compounds were isolated and identified. The new compounds were of the phenylphenalenone-type class, with a representative of a novel structural form, named tentatively "oxabenzochromenone" (1), a compound akin to an intermediate in a recently proposed phenylphenalenone metabolic network (2), seven new phenylphenalenones (4-10), four new phenylbenzoisochromenones (11-14), and a new phenylbenzoisochromenone derivative (18). The previously reported compounds identified were of the following structure classes: oxabenzochrysenone (3, 23-26), flavonol (15, 16), phenylbenzoisochromenone (17, 21, 22, 27-30), and phenylphenalenone (19, 20). Compounds 2-4, 6-9, 15-18, 21, 22, and 26 were subjected to antimicrobial evaluation with moderate activity observed against Staphylococcus aureus MRSA and slight activity against Pseudomonas aeruginosa and Candida albicans. Compounds 4, 6-9, 17, and 21 were also evaluated for anthelminthic activity against larvae of the blood-feeding parasitic nematode Haemonchus contortus.

Distribution, biosynthesis, and biological activity of phenylphenalenone-type compounds derived from the family of plants, Haemodoraceae.

Covering: up to 2018 The Haemodoraceae family is a monocotyledonous family in the order Commelinales consisting of 14 genera. Many species from the family are endemic to Australia and their use by the Aboriginal People of Australia as both pigments or remedies has been ethnobotanically documented. Phenylphenalenones are phenolic specialised metabolites consisting of a tricyclic phenalene nucleus with a ketone moiety and a lateral phenyl ring. Depending on their structural variance, four classes can be distinguished including the phenylphenalenones, oxabenzochrysenones, phenylbenzoisochromenones and phenylbenzoisoquinolinediones. The phenylphenalenone class has become the order's chemotaxonomic marker with a documented range of biological activities. This biological activity arises from the phototoxic properties of their ring system, a phenomenon most comprehensively observed amongst a widely cultivated family of the Commelinales order, Musaceae (banana). Within the family Haemodoraceae, the formation of the phenylphenalenone-class phytoanticipins is an intrinsic function of their growth, whereas within the family Musaceae these compounds are formed as phytoalexins in response to pathogenic attack or stress. The compounds produced within these two families differ in their substitution, with Musaceae-derived phytoalexins tending to be the more phototoxic 4-phenylphenalenones and the Haemodoraceae-derived phytoanticipins being of the more inert 9-phenylphenalenone type structure. Various other substitution patterns have been documented across the class, yet their biosynthetic mechanism is consistent, proceeding from simple phenylpropanoids through a diarylheptanoid intermediate, which cyclises to form the phenylphenalenone nucleus. Phenylphenalenone-related compounds have also been observed within the fungal kingdom, yet their biosynthetic route is based upon an alternative polymalonate pathway. This review focuses on Haemodoraceae-derived phenylphenalenone-type compounds, their distribution amongst species, throughout the plant organism, their biological activity and their biosynthesis.

Application of the Crystalline Sponge Method to Revise the Structure of the Phenalenone Fuliginone.

The structure of fuliginone was revised from a phenyl substituted phenalenone to a hydroxyl substituted phenalenone as a result of its re-purification via HPLC with subsequent NMR analysis together with an independent synthesis and analysis of the crystal structure, which was secured via the crystalline sponge method. On-flow High Performance Liquid Chromatography coupled to Nuclear Magnetic Resonance spectroscopy (HPLC-NMR) was employed to confirm the presence of the natural product in the plant extract and to monitor for any possible degradation or conversion of the compound.

Comparison of cytotoxicity between extracts of Clinacanthus nutans (Burm. f.) Lindau leaves from different locations and the induction of apoptosis by the crude methanol leaf extract in D24 human melanoma cells.

BACKGROUND: Clinacanthus nutans (Burm. f.) Lindau leaves are widely used by cancer patients and the leaf extracts possess cytotoxic and antiproliferative effects on several human cancer cell lines. However, the effect of C. nutans leaf extract on human melanoma, which is the least common but most fatal form of skin cancer and one of the most common cancers diagnosed in both sexes worldwide, is unknown. There is also limited information on whether the bioactivity of extracts differs between C. nutans leaves grown in different geographical locations with varying environmental conditions. METHODS: The present study, for the first time, compared and demonstrated the cytotoxicity of the crude methanol extracts of C. nutans leaves from 11 different locations in Malaysia, Thailand and Vietnam, with diverse environmental conditions against D24 melanoma cells through WST-8 assay. The percentage of apoptotic cells following treatment with the most active extract was determined in a dose- and time-dependent manner by a cytofluorometric double staining technique. Biochemical and morphological changes in the treated and untreated cells were examined by fluorescence and transmission electron microscopy techniques, respectively, to further affirm the induction of apoptosis. RESULTS: The leaves of plants grown at higher elevations and lower air temperatures were more cytotoxic to the D24 melanoma cells than those grown at lower elevations and higher air temperatures, with the leaf extract from Chiang Dao, Chiang Mai, Thailand exhibited the highest cytotoxicity (24 h EC50: 0.95 mg/mL and 72 h EC50: 0.77 mg/mL). This most active crude extract induced apoptotic cell death in the D24 cells in a dose- and time-dependent manner. Typical biochemical and morphological characteristics of apoptosis were also observed in the treated D24 cells. CONCLUSIONS: The results, showing the cytotoxicity of C. nutans and the induction of apoptosis in D24 cells, are significant and useful to facilitate the development of C. nutans as a potential novel chemotherapeutic agent for the management of skin melanoma.

Phytochemical Investigation of the Constituents Derived from the Australian Plant Macropidia fuliginosa.

A phytochemical study of the flowers and bulbs derived from the Australian plant Macropidia fuliginosa, involving hyphenated spectroscopic methodologies (HPLC-NMR and HPLC-MS), together with conventional isolation strategies, resulted in the identification of 16 constituents (1, 2, 4-17) representative of six different structural classes. Six new compounds (12-17) were identified from the bulbs of the plant. The isolated compounds were assessed for antimicrobial activity, and compound 8 was found to be more potent against P. aeruginosa than ampicillin.

HPLC-NMR and HPLC-MS investigation of antimicrobial constituents in Cystophora monilifera and Cystophora subfarcinata.

The crude dichloromethane extracts of the marine brown algae Cystophora monilifera and Cystophora subfarcinata were subjected to phytochemical profiling. This enabled the structures of both new and known phloroglucinols to be dereplicated and proposed using HPLC-NMR and HPLC-MS. Subsequent isolation confirmed the presence of four new and eight previously reported compounds. Five of the isolated phloroglucinols displayed selective antimicrobial activity.

Rapid dereplication and identification of the bioactive constituents from the fungus, Leucocoprinus birnbaumii.

A series of fatty acids were rapidly dereplicated and partially identified from the flowerpot fungus, Leucocoprinus birnbaumii using HPLC-NMR and HPLC-MS. Subsequent off-line isolation unequivocally established the structures, and anti-microbial testing concluded that the fatty acids displayed moderate but selective anti-microbial activity. This represents the first report of these compounds occurring in this particular terrestrial fungus.

Hericium erinaceus (Bull.: Fr) Pers. cultivated under tropical conditions: isolation of hericenones and demonstration of NGF-mediated neurite outgrowth in PC12 cells via MEK/ERK and PI3K-Akt signaling pathways.

Hericium erinaceus (Bull.: Fr.) Pers. is an edible and medicinal mushroom used traditionally to improve memory. In this study, we investigated the neuritogenic effects of hericenones isolated from H. erinaceus and the mechanisms of action involved. H. erinaceus was cultivated and the secondary metabolites were elucidated by high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS), and nuclear magnetic resonance (NMR). The secondary metabolites were tested for neurite outgrowth activity (if any). Rat pheochromocytoma (PC12) cells were employed and the nerve growth factor (NGF) level was also determined. The signaling pathways involved in the mushroom-induced neuritogenesis were investigated using several pharmacological inhibitors. Hericenones B-E (1-4), erinacerin A (5) and isohericerin (6) were isolated from the basidiocarps of H. erinaceus. The hericenones did not promote neurite outgrowth but when induced with a low concentration of NGF (5 ng mL(-1)), the neuritogenic activity was comparable to that of the positive control (50 ng mL(-1) of NGF). Hericenone E was able to stimulate NGF secretion which was two-fold higher than that of the positive control. The neuritogenesis process was partially blocked by the tyrosine kinase receptor (Trk) inhibitor, K252a, suggesting that the neuritogenic effect was not solely due to NGF. Hericenone E also increased the phosphorylation of extracellular-signal regulated kinases (ERKs) and protein kinase B (Akt). Taken together, this study suggests that hericenone E potentiated NGF-induced neuritogenesis in PC12 cells via the MEK/ERK and PI3K/Akt pathways.

Phenylphenalenones and oxabenzochrysenones from the Australian plant Haemodorum simulans.

Chemical investigation of the Australian plant Haemodorum simulans (Haemodoraceae) resulted in the isolation of two new phenylphenalenones, haemoxiphidone and haemodordioxolane from the bulbs together with the first report of an oxabenzochrysenone glycoside, haemodoroxychrysenose from the aerial parts of the plant. Also isolated were two previously described phenylphenalenones 5,6-dimethoxy-7-phenyl-1H,3H-naphtho[1,8-cd]pyran-1,3-dione and haemodorone and two oxabenzochrysenones 5-hydroxyl-2-methoxy-1H-naphtho[2,1,8-mna]xanthen-1-one and 5-methoxy-1H-naphtho[2,1,8-mna]xanthen-1-one. The X-ray structure of the phenylphenalenone 5,6-dimethoxy-7-phenyl-1H,3H-naphtho[1,8-cd]pyran-1,3-dione was secured for the first time. All compounds were deduced by detailed spectroscopic analyses. HPLC-NMR chemical profiling of an enriched fraction containing a mixture of haemodordioxolane and 5,6-dimethoxy-7-phenyl-1H,3H-naphtho[1,8-cd]pyran-1,3-dione facilitated the partial identification of these secondary metabolites. The structure previously assigned as xiphidone in our initial studies of this plant was re-assigned as the new isomer haemoxiphidone.

Application of HPLC-NMR in the identification of plocamenone and isoplocamenone from the marine red alga Plocamium angustum.

A combination of on-line HPLC-NMR and off-line chemical investigations has resulted in the identification of the previously reported polyhalogenated monoterpene plocamenone, together with the new structural analogue isoplocamenone from the crude extract of the marine alga Plocamium angustum. On-flow and stop-flow HPLC-NMR analyses (including the acquisition of WET 2D NMR spectra) rapidly assisted in the identification of the major component plocamenone and in the partial identification of its unstable double bond isomer isoplocamenone. Conventional off-line isolation and structural characterization techniques were employed to unequivocally confirm both structures, leading to a structural revision for plocamenone, as well as to obtain sufficient quantities for biological testing.

On-line (HPLC-NMR) and off-line phytochemical profiling of the Australian plant, Lasiopetalum macrophyllum.

On-line (HPLC-NMR) and off-line (HPLC, NMR and MS) methodologies were used to profile the constituents present in the crude extract of Lasiopetalum macrophyllum. On-flow and stop-flow HPLC-NMR supported the presence of trans-tiliroside and permitted partial identification of cis-tiliroside and 4'-methoxy-trans-tiliroside. Off-line isolation led to the unequivocal identification of four flavanoid glycosides including a new structural derivative, 4'-methoxycis-tiliroside. This is the first report of flavonoid glycosides occurring in this plant genus. In addition, a number of structure revisions have been proposed for previously reported flavonoid glycosides that were incorrectly assigned.

Phytochemical studies of the southern Australian marine alga, Laurencia elata.

Chemical profiling of the southern Australian marine alga Laurencia elata (Rhodomelaceae) employing on-flow and stop-flow HPLC-NMR methodology followed by off-line chemical investigations resulted in the isolation of two C16 chamigrenes, cycloelatanene A and B together with three previously reported sesquiterpenes, (3Z)-chlorofucin, pacifenol and elatenyne. The chemical structures were elucidated via detailed spectroscopic analyses.

On-line (HPLC-NMR) and off-line phytochemical profiling of the Australian plant, Lasiopetalum macrophyllum.

On-line (HPLC-NMR) and off-line (HPLC, NMR and MS) methodologies were used to profile the constituents present in the crude extract of Lasiopetalum macrophyllum. On-flow and stop-flow HPLC-NMR supported the presence of trans-tiliroside and permitted partial identification of cis-tiliroside and 4'-methoxy-trans-tiliroside. Off-line isolation led to the unequivocal identification of four flavanoid glycosides including a new structural derivative, 4'-methoxy-cis-tiliroside. This is the first report of flavonoid glycosides occurring in this plant genus. In addition, a number of structure revisions have been proposed for previously reported flavonoid glycosides that were incorrectly assigned.

Phytochemical investigation of the Australian lichens Ramalina glaucescens and Xanthoria parietina.

Phytochemical investigation of the Australian lichen, Ramalina glaucescens resulted in the isolation of a new halogenated depside, 5-chlorosekikaic acid 5, together with (+)-usnic acid 1, sekikaic acid 2, atranorin 6 and parietin 7, the latter of which was isolated from the associated (co-occurring) lichen, X. parietina. Compound 5 is suspected to be an artifact of the isolation procedure. All structures were assigned using spectroscopic methods and mass spectrometry. In addition to the full characterization of 5, this report represents the first application of 2D NMR spectroscopy to complete the unequivocal chemical shift assignment for compounds 2 and 7. Compounds 1-2 and 5-7 all displayed varying degrees of antitumor activity (ranging from an IC50 of 15 microM to >44 microM) with compounds 1, 2 and 5 also displaying antibacterial properties. Of these, (+)-usnic acid 1 displayed the most significant antitumor and antibacterial activities.

Chemical constituents of the lichen, Candelaria concolor: a complete NMR and chemical degradative investigation.

A detailed chemical and spectroscopic investigation of the terrestrial lichen Candelaria concolor has yielded several lichenic metabolites belonging to the pulvinic acid series, as well as several depside derivatives including pulvinic dilactone (1), vulpinic acid (4) and calycin (5). The chemical transformation of 1 to pulvinic acid (3) is reported for the first time, as is the conversion of atranorin (6) to 5-chloroatranorin (7) and then finally to 5,5'-dichloroatranorin (8) under very mild conditions. Also presented is the complete 1D and 2D NMR assignment for compounds 1, 3, 4, 5 and 8, including partial NMR chemical shift assignments for the unstable depside (7). Previously, these metabolites had only been partially assigned by NMR spectroscopy.

Multiple component isolation in preparative multidimensional gas chromatography with characterisation by mass spectrometry and nuclear magnetic resonance spectroscopy.

The preparative scale isolation of multiple components from an essential oil matrix is described using multidimensional gas chromatography (prep-MDGC) which allows their further characterisation by mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. Menthol, linalyl acetate, carvone and geraniol were isolated individually, and were also collected in various combinations. It was demonstrated to be possible to collect multiple selected components from numerous repeat injections of the sample, to permit increased mass recovery from an external cryotrap collection device. Peak retention times remained reproducible (<0.3s) over the repeated injections and switching events. This methodology may be utilised to confirm peak identity or to produce unique mixed-component reference standards, for instance to allow their identification in other samples using GC/MS, or identify them in comprehensive two-dimensional gas chromatography (GCxGC) analysis.

Phenylphenalenones from the Australian plant Haemodorum simplex.

Chemical investigation of the Australian plant Haemodorum simplex resulted in the isolation of three new phenylphenalenones, haemodorone (10), haemodorol (11), and haemodorose (12), together with the previously reported compounds 5, dilatrin (6), and xiphidone (8). The first complete 2D NMR characterization for all of the compounds isolated, including several chemical shift reassignments for dilatrin (6), is reported. In addition this is one of the few reports to discuss the isolation of new phenylphenalenones from an Australian medicinal plant. The crude extract of both the bulbaceous and aerial components of the plant exhibited varying degrees of antibacterial, antifungal, and antiviral activity, and only the bulbs displayed potent cytotoxic activity.

HPLC and NMR studies of phenoxazone alkaloids from Pycnoporus cinnabarinus.

Crude extracts of the red-orange, bracket fungus Pycnoporus cinnabarinus, collected from five distinct Australian localities were subjected to a chemical and biological profiling study. Subsequent detailed investigation of two of these specimens resulted in the isolation of the new phenoxazone alkaloid, pycnoporin (8), together with cinnabarin (1), tramesanguin (2), and cinnabarinic acid (3). Ergosterol peroxide (11) was also identified from one of the specimens studied. Compounds 1-3 and 8 were elucidated by detailed spectroscopic analyzes, which included the application of elevated temperature-controlled NMR experiments. In addition to the isolation and characterization of 8, this study describes the first successful HPLC purification strategy and complete 2D NMR spectroscopic characterization of compounds 1-3. Also reported are the antioxidant and antiinflammatory activities of the crude extracts of one of the P. cinnabarinus specimens. Compounds 1-3, 8 and 11 displayed varying degrees of antitumor activity while ergosterol peroxide (11) also showed slight antimicrobial and antiviral activities. This is the first report documenting the significant antitumor activity of cinnabarin (1).

Naphthalene aglycones and glycosides from the Australian medicinal plant, Dianella callicarpa.

The crude extract of the roots from the Australian medicinal plant Dianella callicarpa (Liliaceae) displayed significant antimicrobial and antiviral activities. This prompted a chemical investigation, resulting in the isolation of the new naphthalene glycoside, dianellose (10), together with dianellin (1), dianellidin (2), dianellinone (3), stellalderol (9) and 5-hydroxydianellin (11). The structures for compounds 1, 9 and 10 were secured by detailed spectroscopic analyses, while compounds 2, 3 and 11 were identified on the basis of comparisons to literature data. Whilst the chemistry of the genus Dianella has previously been investigated, we report the first isolation of stellalderol (9) from this genus, together with the chemical and biological evaluation of the callicarpa species. Biological evaluation of the isolated compounds established that 2 showed antiviral and mild antimicrobial properties and that compounds 1, 9 and 10 displayed moderate antitumour activities.