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A detailed close phytochemical investigation of the fruits of Ternstroemia cherryi led to the isolation and identification of the minor metabolite, ternstroenol F, which possessed the usual barrigenol-like terpenoid backbone. The notable difference was that this minor metabolite had the 2(E)-4(Z)-6(E)-decatrienoic acid forming an ester bond at C-22 of the oleanane backbone. Ternstroenol F was evaluated for its inhibitory effects on NO inhibition, cell viability and TNF- α release in RAW 264.7 macrophages, displaying an IC50 values of 0.23, 0.81 and 1.84 µM respectively.

Various age-related chronic diseases have been linked to oxidative stress. The cellular antioxidant response pathway is regulated by the transcription factor nuclear erythroid factor 2. Therefore, plant-derived nuclear erythroid factor 2 activators might be useful therapeutics to stimulate the bodyʼs defense mechanisms. Our study focused on the discovery of potent nuclear erythroid factor 2 activators from medicinal plants. Initially, a variety of medicinal plant extracts were screened for nuclear erythroid factor 2 activity using a nuclear erythroid factor 2 luciferase reporter cell line. Among these, Valerian (Valeriana officinalis) root was identified as a potent candidate. Sequential extraction and bioassay-guided fractionation led to the isolation of four nuclear erythroid factor 2-active compounds, which were structurally identified by NMR and LC/HRMS as the known compounds isovaltrate, valtrate, jatamanvaltrate-P, and valerenic acid. These four compounds were then tested in relevant biological assays. Firstly, their effects on the expression of glutathione S-transferase, glutamate–cysteine ligase catalytic subunit, glutathione peroxidase, and heme oxygenase 1 were determined in HepG2 cells. Glutathione S-transferase P1 and glutamate–cysteine ligase catalytic subunit were upregulated by isovaltrate, valtrate, and jatamanvaltrate-P, while heme oxygenase 1 was upregulated by isovaltrate, jatamanvaltrate-P, and valerenic acid. The four compounds also increased the levels of glutathione and its metabolite, CysGly. As glutathione aids in the detoxification of hydrogen peroxide, cytoprotective effects of these four nuclear erythroid factor 2 activators against hydrogen peroxide toxicity were investigated, and indeed, the compounds significantly improved cell survival. This study provides evidence that four valepotriates from the roots of V. officinalis are activators of nuclear erythroid factor 2-mediated antioxidant and detoxification pathways. Our data might expand the medical use of this plant beyond its current application as a sleep aid.

Identification of bioactive natural products from plants starts with the screening of extracts for a desired bioactivity such as antimicrobial, antifungal, anti-cancer, anti-inflammatory, or neuroprotective. When the bioactivity shows sufficient potency, the plant material is subjected to bio-activity-guided fractionation, which involves, e.g., sequential extraction followed by chromatographic separation, including HPLC. The bioactive compounds are then structurally identified by high-resolution mass spectrometry and nuclear magnetic resonance (NMR). One of the questions that come up during the purification process is how much of the bioactivity originally present in the crude extract is preserved during the purification process. If this is the case, it is interesting to investigate if the loss of total bioactivity is caused by the loss of material during purification or by the degradation or evaporation of potent compounds. A further possibility would be the loss of synergy between compounds present in the mixture, which disappears when the compounds are separated. In this publication, a novel formula is introduced that allows researchers to calculate total bioactivity in biological samples using experimental data from our research into the discovery of anti-inflammatory compounds from Backhousia myrtifolia (Grey Myrtle). The results presented show that a raw ethanolic extract retains slightly more bioactivity than the sum of all sequential extracts per gram of starting material and that—despite a large loss of material during HPLC purification—the total bioactivity in all purified fractions is retained, which is indicative of rather an additive than a synergistic principle.

Prof. Dr. Peter Riederer, the former Head of the Neurochemistry Department of the Psychiatry and Psychotherapy Clinic at the University of Würzburg (Germany), has been one of the pioneers of research into oxidative stress in Parkinson's and Alzheimer's disease (AD). This review will outline how his scientific contribution to the field has opened a new direction for AD treatment beyond "plaques and tangles". In the 1990s, Prof. Riederer was one of the first scientists who proposed oxidative stress and neuroinflammation as one of the major contributors to Alzheimer's disease, despite the overwhelming support for the "amyloid-only" hypothesis at the time, which postulated that the sole and only cause of AD is β-amyloid. His group also highlighted the role of advanced glycation end products, sugar and dicarbonyl-derived protein modifications, which crosslink proteins into insoluble aggregates and potent pro-inflammatory activators of microglia. For the treatment of chronic neuroinflammation, he and his group suggested that the most appropriate drug class would be cytokine-suppressive anti-inflammatory drugs (CSAIDs) which have a broader anti-inflammatory action range than conventional non-steroidal anti-inflammatory drugs. One of the most potent CSAIDs is curcumin, but it suffers from a variety of pharmacokinetic disadvantages including low bioavailability, which might have tainted many human clinical trials. Although a variety of oral formulations with increased bioavailability have been developed, curcumin's absorption after oral delivery is too low to reach therapeutic concentrations in the micromolar range in the systemic circulation and the brain. This review will conclude with evidence that rectally applied suppositories might be the best alternatives to oral medications, as this route will be able to evade first-pass metabolism in the liver and achieve high concentrations of curcumin in plasma and tissues, including the brain.

A detailed close phytochemical investigation of the fruits of

Our in-house ethnopharmacological knowledge directed our anti-inflammatory investigation into the leaves of Backhousia mytifolia. Bioassay guided isolation of the Australian indigenous plant Backhousia myrtifolia led to the isolation of six new rare peltogynoid derivatives named myrtinols A–F (1–6) along with three known compounds 4-O-methylcedrusin (7), 7-O-methylcedrusin (8) and 8-demethylsideroxylin (9). The chemical structures of all the compounds were elucidated by detailed spectroscopic data analysis, and absolute configuration was established using X-ray crystallography analysis. All compounds were evaluated for their anti-inflammatory activity by assessing the inhibition of nitric oxide (NO) production and tumor necrosis factor- α (TNF-α) in lipopolysaccharide (LPS) and interferon (IFN)-γ activated RAW 264.7 macrophages. A structure activity relationship was also established between compounds (1–6), noting promising anti-inflammatory potential by compounds 5 and 9 with an IC50 value of 8.51 ± 0.47 and 8.30 ± 0.96 µg/mL for NO inhibition and 17.21 ± 0.22 and 46.79 ± 5.87 µg/mL for TNF-α inhibition, respectively.

Glyoxal (GO) and methylglyoxal (MGO) are two important biomarkers in diabetes. Analytical methods for determination of GO and MGO in serum samples are either HPLC with UV-Vis (low sensitivity) or MS/MS (expensive) detection. These disadvantages have hampered the introduction of these biomarkers as a routine analyte for diabetes diagnostics into the clinical laboratory. In this study, we introduce a UHPLC method with fluorescence detection for the measurement of GO and MGO in serum samples by pre-column derivatization at neutral pH with 5, 6-diamino-2,4-dihydroxypyrimidine sulfate (DDP) to form lumazines. The method was validated as per FDA guidelines. Using this method, we have determined GO and MGO in a variety of animal serum samples, and for example, determined the GO and MGO concentration in adult bovine serum to be 852 ± 27 and 192 ± 10 nmol/L, respectively. In human serum, GO and MGO levels in non-diabetic subjects (n = 14) were determined to be 154 ± 88 and 98 ± 27 nmol/L, and in serum samples from subjects with diabetes (n = 14) 244 ± 137 and 190 ± 68 nmol/L, respectively. In addition, interference studies showed that physiological serum components did not lead to an artificial increase in the levels of GO and MGO.

Three new metabolites, 1-(4′′-Methoxyphenyl)-7-(3′,4′-di-hydroxyphenyl)-(E)-hept-2-ene (1), 1-(4′′-Methoxyphenyl)-7-(3′,4′-di-methoxyphenyl)-(E)-hept-2-ene (2), 1-(4′′-Methoxyphenyl)-7-(4′-methoxyphenyl)-(E)-hept-2-ene (3), and the known diaryl heptanoid (4) were identified following anti-inflammatory activity guided fractionation from the rhizomes of Pleuranthodium racemigerum (Zingiberaceae). These diaryl heptanoids (1 – 4) were evaluated for their inhibitory effects on NO production and downregulation of TNF-α in RAW 264.7 macrophages and N-11 microglial cell lines).

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.

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.

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 (EC

Anti-inflammatory activity guided isolation from Citrus garrawayi (Rutaceae) led to the discovery of five new garracoumarins A – E (1 - 5), and five known (6 – 10) isoprenylated furanocoumarins and the known sterol bourjotinolone A (11). Discussed herein is the anti-inflammatory structure activity relationship of the ten furanocoumarins and a detailed spectroscopic analysis leading to the structure elucidation of the new and known isoprenylated furanocoumarins.

A detailed phytochemical investigation of the leaves of the Australian rainforest tree Eupomatia laurina, led to the discovery of five new neolignans, eupomatenes A – E and eight known compounds, eupomatenoid-2, trans-(2′S)-2-[1′-(4-methoxyphenyl)prop-2′-yl]anethol, chlorogenic acid, chlorogenic acid-methyl ester, tyrosol-1-O-β-xylopyranosyl-1(1 → 6)-O-β-glucopyranoside, leucoside, kaempferol-3-O-neohesperidoside, and pachypodol. The structures of all the compounds were determined by detailed spectroscopic analysis. All compounds were also evaluated for their anti-inflammatory properties by assessing their inhibitory effects on nitric oxide (NO) production and TNF- α release in RAW 264.7 macrophages. Whilst slight anti-inflammatory activity (in terms of inhibition of NO production) was observed with eupomatenes A – E, this was also associated with high levels of cell growth inhibition.

Chemical analysis of an Australian coastal marine sediment-derived fungus, Phomopsis sp. (CMB-M0042F), yielded the known cytochalasins J (1) and H (2), together with five new analogues, cytochalasins J1-J3 (3-5) and H1 and H2 (6 and 7). Structures of 1-7 were assigned on the basis of detailed spectroscopic analysis, chemical interconversion, and biosynthetic and mechanistic considerations. Of note, 1 and 2 proved to be highly sensitive to acid-mediated transformation, with 1 affording 3-5 and 2 affording 6 and 7. Whereas 1, 2, 4, and 5 were detected as natural products in crude culture extracts, 3, 6, and 7 were designated as acid-mediated handling artifacts. We propose novel stereo- and regiospecific intramolecular cycloadditions, under tight functional group control, that facilitate selective conversion of 1 and 2 to the rare 5/6/6/7/5- and 5/6/5/8-fused heterocycles 5 and 7, respectively. Knowledge of acid sensitivity within the cytochalasin family provides a valuable cautionary lesson that has the potential to inform our analysis of past and future investigations into this structure class and inspire novel biomimetic transformations leading to new chemical diversity.

In contrast to ancient Western and Asian cultures, medicinal plants of the Aboriginal and Torres Strait Islanders in Australia have not been as intensively studied for their molecular composition and molecular bioactivity. Syncarpia glomulifera subsp. glomulifera is a species in the plant family Myrtaceae. The resin of the plant has been traditionally used by the D'harawal people of Western Sydney to heal inflamed sores and ulcers. Hence, the anti-inflammatory activity of its leaf extract was investigated in RAW 264.7 macrophage and N11 microglia cell lines to isolate and identify the most active compounds. One new compound, tetragocarbone C, and three known compounds, tetragocarbone B, sideroxylin, and lumaflavanone A showed potent anti-inflammatory activity by downregulating nitric oxide and TNF-α production in LPS and IFN-γ stimulated cells. Except for the less potent tetragocarbone B, all compounds had an IC50 value (for nitric oxide downregulation) of

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.

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.

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.

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.

Chronic inflammation is a contributing factor in many age-related diseases. In a previous study, we have shown that Sri Lankan cinnamon (C. zeylanicum) was one of the most potent anti-inflammatory foods out of 115 foods tested. However, knowledge about the exact nature of the anti-inflammatory compounds and their distribution in the two major cinnamon species used for human consumption is limited. The aim of this investigation was to determine the anti-inflammatory activity of C. zeylanicum and C. cassia and elucidate their main phytochemical compounds. When extracts were tested in LPS and IFN-γ activated RAW 264.7 macrophages, most of the anti-inflammatory activity, measured by down-regulation of nitric oxide and TNF-α production, was observed in the organic extracts. The most abundant compounds in these extracts were E-cinnamaldehyde and o-methoxycinnamaldehyde. The highest concentration of E-cinnamaldehyde was found in the DCM extract of C. zeylanicum or C. cassia (31 and 34 mg g(-1) of cinnamon, respectively). When these and other constituents were tested for their anti-inflammatory activity in RAW 264.7 and J774A.1 macrophages, the most potent compounds were E-cinnamaldehyde and o-methoxycinnamaldehyde, which exhibited IC₅₀ values for NO with RAW 264.7 cells of 55 ± 9 μM (7.3 ± 1.2 μg mL(-1)) and 35 ± 9 μM (5.7 ± 1.5 μg mL(-1)), respectively; and IC₅₀ values for TNF-α of 63 ± 9 μM (8.3 ± 1.2 μg mL(-1)) and 78 ± 16 μM (12.6 ± 2.6 μg mL(-1)), respectively. If therapeutic concentrations can be achieved in target tissues, cinnamon and its components may be useful in the treatment of age-related inflammatory conditions.

Die Entwicklung neuer Antibiotika befindet sich in einer ernsthaften Krise, die unter anderem dadurch begrundet ist, dass kaum innovative chemische Grundstrukturen mit Aktivitat gegen Gram-negative und multiresistente Bakterien gefunden werden. Hier berichten wir uber die Entdeckung neuer hochwirksamer Antibiotika aus Myxobakterien, den Cystobactamiden 1–3, die aus Cystobacter sp. isoliert wurden und minimale Hemmkonzentrationen im niedrigen μg mL−1-Bereich aufweisen. Wir beschreiben die Aufreinigung und Strukturaufklarung von drei Derivaten und die Identifizierung und Annotation des dazugehorigen Biosynthesegenclusters. Die molekularen Zielstrukturen der Cystobactamide konnten uber die Analyse des Eigenresistenzmechanismus des Produzentenstammes als bakterielle Typ-IIa-Topoisomerasen identifiziert werden. Da die Optimierungsmoglichkeiten von Chinolonen als Basis fur neue Inhibitoren der Typ-II-Topoisomerasen weitgehend ausgereizt sind, erscheinen die Cystobactamide als hochinteressante Alternativen, die durch Medizinalchemie und biosynthetisches Engineering der Entwicklung neuartiger Antibiotika dienen konnen.

In the search for new secondary metabolites from myxobacteria, a strain from the genus Pyxidicoccus was investigated. This led to the identification of a new class of natural products showing structural novelty and interesting biological activity. Isolation and structure elucidation of two analogues led to the identification of pyxipyrrolone A and B, harboring the novel 3-methylene-2,3,4,5,6,7,8,9-octahydro-1H-benzo[e]isoindol-1-one scaffold. Mosher's ester analysis combined with NMR studies allowed the determination of all stereocenters but one. Genome sequencing of the producer strain led to the identification of a putative biosynthetic gene cluster for the pyxipyrrolones. The compounds showed activity against several cancer cell lines (μm range) with pyxipyrrolone B having 2- to 11-fold higher activity than A, although they differ only by one methylene group.

Chemical analysis of an Australian marine sediment-derived Aspergillus sp. (CMB-M081F) yielded the new diketomorpholine (DKM) shornephine A (1) together with two known and one new diketopiperazine (DKP), 15b-β-hydroxy-5-N-acetyladreemin (2), 5-N-acetyladreemin (3), and 15b-β-methoxy-5-N-acetyladreemin (4), respectively. Structure elucidation of 1–4 was achieved by detailed spectroscopic analysis, supported by chemical degradation and derivatization, and biosynthetic considerations. The DKM (1) underwent a facile (auto) acid-mediated methanolysis to yield seco-shornephine A methyl ester (1a). Our mechanistic explanation of this transformation prompted us to demonstrate that the acid-labile and solvolytically unstable DKM scaffold can be stabilized by N-alkylation. Furthermore, we demonstrate that at 20 μM shornephine A (1) is a noncytotoxic inhibitor of P-glycoprotein-mediated drug efflux in multidrug-resistant human colon cancer cells.

A marine-derived Streptomyces sp. (CMB-M0244) isolated from a sediment collected off South Molle Island, Queensland, produced mollemycin A (1) as a new first in class glyco-hexadepsipeptide-polyketide. The structure of 1 was assigned by detailed spectroscopic analysis, supported by chemical derivatization and degradation, and C3 Marfey's analysis. Mollemycin A (1) exhibits exceptionally potent and selective growth inhibitory activity against Gram-positive and Gram-negative bacteria (IC50 10-50 nM) and drug-sensitive (3D7; IC50 7 nM) and multidrug-resistant (Dd2; IC50 9 nM) clones of the malaria parasite Plasmodium falciparum.

Nitric oxide is now universally recognized as an extracellular signaling molecule. Nitric oxide, produced in one cell, diffuses across the extracellular space and acts with targets in an adjoining cell. In this study, we present proof that hydrogen peroxide – like nitric oxide – acts as a true first (intercellular) messenger for a multitude of pro-inflammatory ligands. RAW 264.7 macrophages were activated with three different ligands, lipopolysaccharide, interferon-gamma or advanced glycation end products in the presence of increasing concentrations of (hydrogen peroxide scavenging) catalase. As inflammatory readouts, nitric oxide and tumor necrosis factor were determined. We hypothesize that hydrogen peroxide travels between cells propagating the signal, then a certain percentage of the readout should be inhibited by catalase in a concentration-dependent manner. The experiment showed concentration-dependent inhibition of nitric oxide and tumor necrosis factor-α production in response to all three ligands/ligand combinations (interferon-gamma, lipopolysaccharide, and chicken egg albumin-derived advanced glycation end product) in the presence of increasing concentration of catalase. For example, catalase inhibited 100% of nitric oxide and 40% of tumor necrosis factor-α production at its highest concentration. Our results suggest that hydrogen peroxide travels through cell membranes into the extracellular space and enters and activates adjacent cells. Like nitric oxide, we suggest that it is a ubiquitous first messenger, able to transmit cell-to-cell pro-inflammatory signals such as nitric oxide and tumor necrosis factor-α. In a therapeutic setting, our data suggest that compounds acting as hydrogen peroxide scavengers might not even need to enter the cell to act as anti-inflammatory drugs.

A Nocardiopsis sp. (CMB-M0232) recovered from marine sediment collected off the coast of South Molle Island, Queensland, Australia, yielded two new examples of rare prolinyl-macrolactam polyketides, nocardiopsins C (1) and D (2), a new highly substituted α-pyrone polyketide, nocardiopyrone A (3), and the previously reported macrolide polyketides nocardiopsins A (4) and B (5). Structures were assigned on the basis of detailed spectroscopic analysis, degradation, and chemical derivatization. PCR amplification of CMB-M0232 genomic DNA revealed the presence of type I and type II polyketide synthase and non-ribosomal peptide synthase domains.

Disorazol, a macrocyclic polykitide produced by the myxobacterium Sorangium cellulosum So ce12 and it is reported to have potential cytotoxic activity towards several cancer cell lines, including multi-drug resistant cells. The disorazol biosynthetic gene cluster (dis) from Sorangium cellulosum (So ce12) was identified by transposon mutagenesis and cloned in a bacterial artificial chromosome (BAC) library. The 58-kb dis core gene cluster was reconstituted from BACs via Red/ET recombineering and expressed in Myxococcus xanthus DK1622. For the first time ever, a myxobacterial trans-AT polyketide synthase has been expressed heterologously in this study. Expression in M. xanthus allowed us to optimize the yield of several biosynthetic products using promoter engineering. The insertion of an artificial synthetic promoter upstream of the disD gene encoding a discrete acyl transferase (AT), together with an oxidoreductase (Or), resulted in 7-fold increase in disorazol production. The successful reconstitution and expression of the genetic sequences encoding for these promising cytotoxic compounds will allow combinatorial biosynthesis to generate novel disorazol derivatives for further bioactivity evaluation.

A new linear polyketide, juniperolide A (1), was produced by the terrestrial actinomycete (Lv1-48) isolated from the rhizosphere of the plant Juniperus excelsa. The juniperolide A (1) structure contains a THP unit and a 3-amino-2,3,6-trideoxyhexose as the glycosidic moiety. Mosher's analysis was used for absolute stereochemistry determinations at C-2, C-8, C-20, and C-4', while the relative stereochemistry assignments of the remaining stereocenters were based on ROESY correlations and J-based coupling.

An Australian marine sediment-derived isolate, Nocardiopsis sp. (CMB-M0232), yielded a new class of prenylated diketopiperazine, indicative of the action of a uniquely regioselective diketopiperazine indole prenyltransferase. The bridged scaffold of nocardioazine A proved to be a noncytotoxic inhibitor of the membrane protein efflux pump P-glycoprotein, reversing doxorubicin resistance in a multidrug resistant colon cancer cell.

Chemical analysis of the ethanolic extract of the Australian rainforest plant Elaeocarpus eumundi yielded a new phenolic monosaccharide (1) and the known dihydropieceid (2). The structures of both compounds were elucidated based on the spectroscopic methods including UV, HR-ESIMS and 1D, 2D NMR data. Compounds 1 and 2 exhibited good anti-inflammatory activity in LPS and IFN-γ activated RAW 264.7 macrophage cells.

Chemical analysis of a Streptomyces sp. (CMB-MQ030) isolated from a Fijian marine sediment yielded two new diketopiperazines, naseseazines A and B (1, 2), featuring a new dimeric framework. Structures were determined by detailed spectroscopic analysis and C(3) Marfey's analysis.

Chemical analysis of an Australian marine-derived Streptomyces sp. (CMB-M0150) yielded two new anthracycline antibiotics, aranciamycins I (1) and J (2), as well as the previously reported aranciamycin A (3) and aranciamycin (4). The aranciamycins 1-4, identified by detailed spectroscopic analysis, were noncytotoxic when tested against selected Gram-negative bacteria and fungi (IC50 >30 μM) and exhibited moderate and selective cytotoxicity against Gram-positive bacteria (IC50 >1.1 μM) and a panel of human cancer cell lines (IC50 > 7.5 μM). Significantly, 1-4 were cytotoxic (IC50 0.7-1.7 μM) against the Mycobacterium tuberculosis surrogate M. bovis bacille Calmette-Guerin.

Lorneic acids C and D, new trialkyl-substituted aromatic acids isolated from a terrestrial Streptomyces sp.

Chemical analysis of a terrestrial actinomycete (Lv-6-8) isolated from the root zone of Yucca aloiofolia yielded a new anthraquinone possessing a 3-furanone ring system, rubimycinone A ( 1 ). The structure of 1 was elucidated based on spectroscopic methods including UV, HR-ESIMS and 1D, and 2D NMR data. Rubimycinone A ( 1 ) displayed modest to good antibacterial and cytotoxic activity against a panel of Gram positive strains and various cancer cell lines.

Chemical analysis of a marine-derived Vibrio sp. (Q-459) isolated from a depth of 10 m near Okinawa prefecture Japan, yielded a new cyclic acyldepsipeptide, kailuin F (1) together with the known kailuins B (3) and E (6). The structure of 1 was elucidated based on spectroscopic methods including UV, HR-ESIMS, chemical derivatizations and 1D, 2D NMR data. Kailuin B (3) exhibited a strong antimicroalgal activity against the dinoflagellate Prorocentrum micans.

A Streptomyces sp. Lv3-13, isolated from the rhizosphere soil of the plant Mespilus germanica , has yielded three new pimprinine derivatives, named pimprinols A–C ( 1 – 3 ) and the unknown (2-aminophenyl)(2-ethyloxazol-5-yl) methanone ( 4 ) along with the known compounds 2-ethyl oxazole pimprinine and 2-propyl oxazole pimprinine. The structures of the compounds were elucidated based on spectroscopic methods including UV, HR-ESIMS and 1D, 2D NMR data. Compounds 1 – 4 were screened for antimicrobial and cytotoxic activities.

Chemical analysis of a marine-derived Streptomyces sp. (CMB-M0392) isolated from sediment collected off Heron Island, Queensland, Australia, yielded a new benzothiazine ansamycin, heronamycin A. The absolute stereostructure of heronamycin A was determined by detailed spectroscopic analysis and Xray crystallography. Heronamycin A exhibited modest antimicrobial activity against Bacillus subtilis strains ATCC 6051 and 6633 (IC50 = 18 and 14 mu M, respectively). (C) 2011 Elsevier Ltd. All rights reserved.

The development of new antibiotics faces a severe crisis inter alia owing to a lack of innovative chemical scaffolds with activities against Gram-negative and multiresistant pathogens. Herein, we report highly potent novel antibacterial compounds, the myxobacteria-derived cystobactamids 1-3, which were isolated from Cystobacter sp. and show minimum inhibitory concentrations in the low μg mL(-1) range. We describe the isolation and structure elucidation of three congeners as well as the identification and annotation of their biosynthetic gene cluster. By studying the self-resistance mechanism in the natural producer organism, the molecular targets were identified as bacterial type IIa topoisomerases. As quinolones are largely exhausted as a template for new type II topoisomerase inhibitors, the cystobactamids offer exciting alternatives to generate novel antibiotics using medicinal chemistry and biosynthetic engineering.

Albaflavenol B, a new sesquiterpene isolated from the terrestrial actinomycete, Streptomyces sp.

Angiolactone, a new Butyrolactone isolated from the terrestrial myxobacterium, Angiococcus sp.

Oleamycins A and B: new antibacterial cyclic hexadepsipeptides isolated from a terrestrial Streptomyces sp.

Chemical analysis of a terrestrial-derived Streptomyces sp. Lv20–195 cultivated from the root zone of Olea europea yielded oleaceran, 1, possessing a novel spiro[isobenzofuran-1,2′-naptho[1,8-b,c]furan] carbon skeleton. The structure of 1 was determined by detailed spectroscopic analysis.

Chronic inflammation is an important pathological condition in many human diseases, and due to the side effects of the currently used non-steroidal anti-inflammatory drugs, discovery of novel anti-inflammatory drugs is of general interest. Anti-inflammatory activity guided compound isolation from the plant Alphitonia petriei led to the isolation of the known plant sterols emmolic acid (1), alphitolic acid (2), trans- and cis-coumaroyl esters of alphitolic acid (3 and 4) and betulinic acid (5). A detailed spectroscopic analysis led to the structure elucidation of the alphitolic acid derivatives (1–5), and the semi-synthetic emmolic acid acetate (6). When tested in LPS (Lipopolysaccharides) + IFN-γ (Interferon gamma) activated RAW 264.7 macrophages, all compounds except (1) exhibited potent anti-inflammatory activity (IC50 values as low as 1.7 μM) in terms of downregulation of NO and TNF-α production, but also demonstrated some considerable cytotoxicity.

Investigations for cytotoxicity and antimicrobial activity reveal only modest effects against Bacillus subtilis strains.

Chemical analysis of a marine-derived Streptomyces sp. (CMB-M0423) isolated from beach sand off Heron Island, Australia, yielded three new members of the rare pyrroloterpene biosynthetic structure class. Identified by detailed spectroscopic analysis as the first reported examples of naturally occurring 2-nitropyrroles, heronapyrroles A-C (1-3) displayed promising biological activity-with low to submicromolar IC(50) activity against Gram-positive bacteria but no cytotoxicity toward mammalian cell lines.