Publications by authors named "Ritesh Raju"

33 Publications

Eupomatenes A - E: Neolignans isolated from the leaves of Australian rainforest plant Eupomatia laurina.

Fitoterapia 2021 Sep 18;153:104972. Epub 2021 Jun 18.

Department of Pharmacology, Western Sydney University, Campbelltown Campus, Sydney, Australia.

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.
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http://dx.doi.org/10.1016/j.fitote.2021.104972DOI Listing
September 2021

Identification of tetragocarbone C and sideroxylin as the most potent anti-inflammatory components of Syncarpia glomulifera.

Fitoterapia 2021 Apr 1;150:104843. Epub 2021 Feb 1.

Pharmacology Unit, School of Medicine, Western Sydney University, Building 30, Campbelltown, NSW, Australia; NICM Health Research Institute, Western Sydney University, Sydney, NSW, Australia. Electronic address:

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 IC value (for nitric oxide downregulation) of <10 μg/mL and moderate cytotoxicity in both cell lines. The molecular targets along pro-inflammatory signaling pathways were further investigated in RAW 264.7 cells. All four compounds suppressed phosphorylation of ERK, c-Jun, and limited the phosphorylation of STAT-1 and STAT-3 in response to LPS and IFN-γ activation. The four compounds also suppressed NF-κB activation by preventing the translocation of the p65 subunit into the nucleus. Collectively, these findings suggest that the compounds isolated from Syncarpia glomulifera, especially tetragocarbone C and sideroxylin are promising anti-inflammatory agents, and could be further investigated for the treatment of diseases characterized by chronic inflammation.
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http://dx.doi.org/10.1016/j.fitote.2021.104843DOI Listing
April 2021

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

Neurochem Int 2021 01 10;142:104897. Epub 2020 Nov 10.

Department of Pharmacology, Western Sydney University, Campbelltown Campus, Sydney, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.neuint.2020.104897DOI Listing
January 2021

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

Phytochemistry 2020 Aug 9;176:112426. Epub 2020 Jun 9.

Department of Pharmacology, Western Sydney University, Campbelltown Campus, Sydney, Australia. Electronic address:

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 IC 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.
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http://dx.doi.org/10.1016/j.phytochem.2020.112426DOI Listing
August 2020

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

Fitoterapia 2020 Jun 22;143:104595. Epub 2020 Apr 22.

Department of Pharmacology, Western Sydney University, Campbelltown Campus, Sydney, Australia.

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 (IC) 42-55 μM. The structures of the new compounds were assigned based on a detailed spectroscopic interpretation.
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http://dx.doi.org/10.1016/j.fitote.2020.104595DOI Listing
June 2020

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

Fitoterapia 2020 Jun 21;143:104598. Epub 2020 Apr 21.

Pharmacology Unit, School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia; NICM Health Research Institute, Western Sydney University, Sydney, Campbelltown, NSW 2560, Australia. Electronic address:

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), 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 EC 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 EC value, and the most potent compound is the one with the lowest EC. 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 (EDV)" as the reciprocal of the EC (1/EC). We show how the EDV 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 EDV to point out the most potent compounds. We hope that the EDV 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.
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http://dx.doi.org/10.1016/j.fitote.2020.104598DOI Listing
June 2020

Hydrogen peroxide mediates pro-inflammatory cell-to-cell signaling: a new therapeutic target for inflammation?

Neural Regen Res 2019 Aug;14(8):1430-1437

Department of Pharmacology, School of Medicine, Western Sydney University, Penrith, NSW, Australia.

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.
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http://dx.doi.org/10.4103/1673-5374.253529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524506PMC
August 2019

Determination of glyoxal and methylglyoxal in serum by UHPLC coupled with fluorescence detection.

Anal Biochem 2019 05 20;573:51-66. Epub 2019 Feb 20.

Department of Pharmacology, School of Medicine, Western Sydney University, Locked Bag 1797, Penrith, NSW, 2751, Australia; NICM Health Research Institute, Western Sydney University, Locked Bag 1797, Penrith, NSW, 2751, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ab.2019.02.014DOI Listing
May 2019

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

Fitoterapia 2019 Mar 14;133:171-174. Epub 2019 Jan 14.

Department of Pharmacology, Western Sydney University, Campbelltown Campus, Sydney, Australia.

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.
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http://dx.doi.org/10.1016/j.fitote.2019.01.004DOI Listing
March 2019

Cytochalasins from an Australian Marine Sediment-Derived Phomopsis sp. (CMB-M0042F): Acid-Mediated Intramolecular Cycloadditions Enhance Chemical Diversity.

J Org Chem 2017 09 31;82(18):9704-9709. Epub 2017 Aug 31.

Institute for Molecular Bioscience, The University of Queensland , St. Lucia, Queensland 4072, Australia.

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 J-J (3-5) and H and H (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.
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http://dx.doi.org/10.1021/acs.joc.7b01793DOI Listing
September 2017

Pyxipyrrolones: Structure Elucidation and Biosynthesis of Cytotoxic Myxobacterial Metabolites.

Angew Chem Int Ed Engl 2017 08 5;56(32):9614-9618. Epub 2017 Jul 5.

Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University, building E8.1, 66123, Saarbrücken, Germany.

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.
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http://dx.doi.org/10.1002/anie.201704790DOI Listing
August 2017

Medicinal Plants of the Australian Aboriginal Dharawal People Exhibiting Anti-Inflammatory Activity.

Evid Based Complement Alternat Med 2016 27;2016:2935403. Epub 2016 Dec 27.

Department of Pharmacology, School of Medicine, Western Sydney University, Sydney, NSW, Australia.

Chronic inflammation contributes to multiple ageing-related musculoskeletal and neurodegenerative diseases, cardiovascular diseases, asthma, rheumatoid arthritis, and inflammatory bowel disease. More recently, chronic neuroinflammation has been attributed to Parkinson's and Alzheimer's disease and autism-spectrum and obsessive-compulsive disorders. To date, pharmacotherapy of inflammatory conditions is based mainly on nonsteroidal anti-inflammatory drugs which in contrast to cytokine-suppressive anti-inflammatory drugs do not influence the production of cytokines such as tumour necrosis factor- or nitric oxide. However, their prolonged use can cause gastrointestinal toxicity and promote adverse events such as high blood pressure, congestive heart failure, and thrombosis. Hence, there is a critical need to develop novel and safer nonsteroidal anti-inflammatory drugs possessing alternate mechanism of action. In this study, plants used by the Dharawal Aboriginal people in Australia for the treatment of inflammatory conditions, for example, asthma, arthritis, rheumatism, fever, oedema, eye inflammation, and inflammation of bladder and related inflammatory diseases, were evaluated for their anti-inflammatory activity in vitro. Ethanolic extracts from 17 spp. (Myrtaceae) were assessed for their capacity to inhibit nitric oxide and tumor necrosis factor- production in RAW 264.7 macrophages. showed the most potent nitric oxide inhibitory effect (IC  5.57 ± 1.4 g/mL), whilst exhibited nitric oxide inhibition values between 7.58 and 19.77 g/mL.
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http://dx.doi.org/10.1155/2016/2935403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223016PMC
December 2016

Anti-Inflammatory Chemical Profiling of the Australian Rainforest Tree Alphitonia petriei (Rhamnaceae).

Molecules 2016 Nov 11;21(11). Epub 2016 Nov 11.

School of Medicine, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia.

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 led to the isolation of the known plant sterols emmolic acid (), alphitolic acid (), and -coumaroyl esters of alphitolic acid ( and ) and betulinic acid (). A detailed spectroscopic analysis led to the structure elucidation of the alphitolic acid derivatives (-), and the semi-synthetic emmolic acid acetate (). When tested in LPS (Lipopolysaccharides) + IFN-γ (Interferon gamma) activated RAW 264.7 macrophages, all compounds except () exhibited potent anti-inflammatory activity (IC values as low as 1.7 μM) in terms of downregulation of NO and TNF-α production, but also demonstrated some considerable cytotoxicity.
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http://dx.doi.org/10.3390/molecules21111521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273140PMC
November 2016

Genetic engineering and heterologous expression of the disorazol biosynthetic gene cluster via Red/ET recombineering.

Sci Rep 2016 Feb 15;6:21066. Epub 2016 Feb 15.

Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany.

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.
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http://dx.doi.org/10.1038/srep21066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753468PMC
February 2016

Plant polyphenols as inhibitors of NF-κB induced cytokine production-a potential anti-inflammatory treatment for Alzheimer's disease?

Front Mol Neurosci 2015 16;8:24. Epub 2015 Jun 16.

School of Medicine, University of Western Sydney Penrith, NSW, Australia ; National Institute of Complementary Medicine, University of Western Sydney Penrith, NSW, Australia ; Molecular Medicine Research Group, University of Western Sydney Penrith, NSW, Australia.

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http://dx.doi.org/10.3389/fnmol.2015.00024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468843PMC
July 2015

Aranciamycins I and J, Antimycobacterial Anthracyclines from an Australian Marine-Derived Streptomyces sp.

J Nat Prod 2015 Apr 19;78(4):949-52. Epub 2015 Mar 19.

†Institute for Molecular Bioscience, ⊥Diamantina Institute, and ∥Australian Infectious Diseases Research Centre, The University of Queensland, St Lucia, QLD 4072, Australia.

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-Guérin.
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http://dx.doi.org/10.1021/acs.jnatprod.5b00095DOI Listing
April 2015

Cystodienoic acid: a new diterpene isolated from the myxobacterium Cystobacter sp.

J Antibiot (Tokyo) 2015 Jul 18;68(7):473-5. Epub 2015 Feb 18.

German Centre for Infection Research Association, Braunschweig, Germany.

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http://dx.doi.org/10.1038/ja.2015.8DOI Listing
July 2015

Anti-inflammatory activity of cinnamon (C. zeylanicum and C. cassia) extracts - identification of E-cinnamaldehyde and o-methoxy cinnamaldehyde as the most potent bioactive compounds.

Food Funct 2015 Mar;6(3):910-9

School of Medicine, University of Western Sydney, Locked Bag 1797, Penrith, NSW 2751, Australia.

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.
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http://dx.doi.org/10.1039/c4fo00680aDOI Listing
March 2015

Cystobactamids: myxobacterial topoisomerase inhibitors exhibiting potent antibacterial activity.

Angew Chem Int Ed Engl 2014 Dec 15;53(52):14605-9. Epub 2014 Dec 15.

Abteilung Mikrobielle Naturstoffe, Helmholtz Institut für Pharmazeutische Forschung Saarland, Helmholtz Zentrum für Infektionsforschung, Universität des Saarlandes, Campus C2.3, 66123 Saarbrücken (Germany); Deutsches Zentrum für Infektionsforschung (DZIF), Standort Hannover-Braunschweig (Germany).

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.
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http://dx.doi.org/10.1002/anie.201409964DOI Listing
December 2014

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

J Antibiot (Tokyo) 2015 Apr 1;68(4):286-8. Epub 2014 Oct 1.

German Centre for Infection Research Association, Braunshweig, Germany.

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http://dx.doi.org/10.1038/ja.2014.138DOI Listing
April 2015

Shornephine A: structure, chemical stability, and P-glycoprotein inhibitory properties of a rare diketomorpholine from an Australian marine-derived Aspergillus sp.

J Org Chem 2014 Sep 2;79(18):8700-5. Epub 2014 Sep 2.

Institute for Molecular Bioscience, The University of Queensland , St. Lucia, QLD 4072, Australia.

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.
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http://dx.doi.org/10.1021/jo501501zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4168782PMC
September 2014

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

J Antibiot (Tokyo) 2014 Oct 7;67(10):725-6. Epub 2014 May 7.

German Centre for Infection Research Association, Braunshweig, Germany.

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http://dx.doi.org/10.1038/ja.2014.55DOI Listing
October 2014

Mollemycin A: an antimalarial and antibacterial glyco-hexadepsipeptide-polyketide from an Australian marine-derived Streptomyces sp. (CMB-M0244).

Org Lett 2014 Mar 11;16(6):1716-9. Epub 2014 Mar 11.

Institute for Molecular Bioscience, The University of Queensland , St. Lucia, QLD 4072, Australia.

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.
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http://dx.doi.org/10.1021/ol5003913DOI Listing
March 2014

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

J Antibiot (Tokyo) 2014 Apr 22;67(4):339-43. Epub 2014 Jan 22.

1] Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research (HZI), Saarland University, Saarbrücken, Germany [2] Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany.

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http://dx.doi.org/10.1038/ja.2014.1DOI Listing
April 2014

Oleaceran: a novel spiro[isobenzofuran-1,2'-naptho[1,8-bc]furan] isolated from a terrestrial Streptomyces sp.

Org Lett 2013 Jul 26;15(14):3487-9. Epub 2013 Jun 26.

Department of Microbial Natural Products, Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Pharmaceutical Biotechnology, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany.

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.
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http://dx.doi.org/10.1021/ol401490uDOI Listing
July 2013

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

J Antibiot (Tokyo) 2013 Jun 3;66(6):347-9. Epub 2013 Apr 3.

Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland HIPS, Helmholtz Centre for Infection Research HZI, Saarland University, Saarbrücken, Germany.

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http://dx.doi.org/10.1038/ja.2013.18DOI Listing
June 2013

Juniperolide A: a new polyketide isolated from a terrestrial actinomycete, Streptomyces sp.

Org Lett 2012 Dec 21;14(23):5860-3. Epub 2012 Nov 21.

Department of Microbial Natural Products, Helmholtz-Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Pharmaceutical Biotechnology, Saarland University, Campus C2 3, 66123 Saarbrücken, Germany.

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.
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http://dx.doi.org/10.1021/ol302766zDOI Listing
December 2012

Fijimycins A-C, three antibacterial etamycin-class depsipeptides from a marine-derived Streptomyces sp.

Bioorg Med Chem 2011 Nov 26;19(22):6557-62. Epub 2011 Jun 26.

Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093-0204, USA.

Three new depsipeptides, fijimycins A-C (1-3), together with the known etamycin A (4), were isolated and identified from the fermentation broth of strain CNS-575, a Streptomyces sp. cultured from a marine sediment sample collected off Nasese, Fiji. The planar structures of the new fijimycins were assigned by combined interpretation of NMR and MS/MS spectroscopic data. These assignments were complicated by the fact that 1-3 occurred as complex amide conformational mixtures. The absolute configurations of the component amino acids were established using the Marfey's method. Fijimycins A-C, and etamycin A, were shown to possess significant in vitro antibacterial activity against three methicillin-resistant Staphylococcus aureus (MRSA) strains with MIC(100) values between 4 and 16 μg mL(-1).
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http://dx.doi.org/10.1016/j.bmc.2011.06.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205191PMC
November 2011

Nocardioazines: a novel bridged diketopiperazine scaffold from a marine-derived bacterium inhibits P-glycoprotein.

Org Lett 2011 May 22;13(10):2770-3. Epub 2011 Apr 22.

Institute for Molecular Bioscience, The University of Queensland , St. Lucia, Queensland 4072, Australia.

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.
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http://dx.doi.org/10.1021/ol200904vDOI Listing
May 2011

Heronapyrroles A-C: farnesylated 2-nitropyrroles from an Australian marine-derived Streptomyces sp.

Org Lett 2010 Nov 15;12(22):5158-61. Epub 2010 Oct 15.

Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.

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.
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http://dx.doi.org/10.1021/ol102162dDOI Listing
November 2010
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