Publications by authors named "Donald B Stierle"

18 Publications

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Cryptic Biosynthesis of the Berkeleypenostatins from Coculture of Extremophilic sp.

J Nat Prod 2021 05 6;84(5):1656-1665. Epub 2021 May 6.

Coculture fermentation of and yielded berkeleypenostatins A-G (-) as well as the previously reported berkeleylactones A-H, the known macrolide A26771B, citrinin, and patulin. As was true with the berkeleylactones, there was no evidence of the berkeleypenostatins in either axenic culture. The structures were deduced from analyses of spectral data, and the absolute configuration of berkeleypenostatin A () was determined by single-crystal X-ray crystallography. Berkeleypenostatins A () and E () inhibited migration of human pancreatic carcinoma cells (HPAF-II). Both compounds were tested by the NCI Developmental Therapeutics Program. In the NCI 60 cell five-dose screen, berkeleypenostatin E () was the more active of the two, with 1-10 μM total growth inhibition (TGI) of all leukemia cell lines, as well as the majority of colon, CNS, melanoma, ovarian, prostate, renal, and breast cancer cell lines.
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http://dx.doi.org/10.1021/acs.jnatprod.1c00248DOI Listing
May 2021

The Berkeleylactones, Antibiotic Macrolides from Fungal Coculture.

J Nat Prod 2017 04 22;80(4):1150-1160. Epub 2017 Mar 22.

Center for Biomolecular Sciences, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60607, United States.

A carefully timed coculture fermentation of Penicillium fuscum and P. camembertii/clavigerum yielded eight new 16-membered-ring macrolides, berkeleylactones A-H (1, 4, 6-9, 12, 13), as well as the known antibiotic macrolide A26771B (5), patulin, and citrinin. There was no evidence of the production of the berkeleylactones or A26771B (5) by either fungus when grown as axenic cultures. The structures were deduced from analyses of spectral data, and the absolute configurations of compounds 1 and 9 were determined by single-crystal X-ray crystallography. Berkeleylactone A (1) exhibited the most potent antimicrobial activity of the macrolide series, with low micromolar activity (MIC = 1-2 μg/mL) against four MRSA strains, as well as Bacillus anthracis, Streptococcus pyogenes, Candida albicans, and Candida glabrata. Mode of action studies have shown that, unlike other macrolide antibiotics, berkeleylactone A (1) does not inhibit protein synthesis nor target the ribosome, which suggests a novel mode of action for its antibiotic activity.
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http://dx.doi.org/10.1021/acs.jnatprod.7b00133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467647PMC
April 2017

The Ayurvedic plant Bacopa monnieri inhibits inflammatory pathways in the brain.

J Ethnopharmacol 2017 Feb 26;197:92-100. Epub 2016 Jul 26.

Department of Biomedical and Pharmaceutical Sciences, College of Health Professions and Biomedical Sciences, The University of Montana, Missoula MT 59812, USA. Electronic address:

Ethnopharmacological Relevance: Bacopa monnieri (L) Wettst (common name, bacopa) is a medicinal plant used in Ayurveda, the traditional system of medicine of India, as a nootropic. It is considered to be a "medhya rasayana", an herb that sharpens the mind and the intellect. Bacopa is an important ingredient in many Ayurvedic herbal formulations designed to treat conditions such as memory loss, anxiety, poor cognition and loss of concentration. It has also been used in Ayurveda to treat inflammatory conditions such as arthritis. In modern biomedical studies, bacopa has been shown in animal models to inhibit the release of the pro-inflammatory cytokines TNF-α and IL-6. However, less is known regarding the anti-inflammatory activity of Bacopa in the brain.

Aim Of The Study: The current study examines the ability of Bacopa to inhibit the release of pro-inflammatory cytokines from microglial cells, the immune cells of the brain that participate in inflammation in the CNS. The effect of Bacopa on signaling enzymes associated with CNS inflammatory pathways was also studied.

Materials And Methods: Various extracts of Bacopa were prepared and examined in the N9 microglial cell line in order to determine if they inhibited the release of the proinflammatory cytokines TNF-α and IL-6. Extracts were also tested in cell free assays as inhibitors of caspase-1 and matrix metalloproteinase-3 (enzymes associated with inflammation) and caspase-3, which has been shown to cleave protein Tau, an early event in the development of Alzheimer's disease.

Results: The tea, infusion, and alkaloid extracts of bacopa, as well as Bacoside A significantly inhibited the release of TNF-α and IL-6 from activated N9 microglial cells in vitro. In addition, the tea, infusion, and alkaloid extracts of Bacopa effectively inhibited caspase 1 and 3, and matrix metalloproteinase-3 in the cell free assay.

Conclusions: Bacopa inhibits the release of inflammatory cytokines from microglial cells and inhibits enzymes associated with inflammation in the brain. Thus, Bacopa can limit inflammation in the CNS, and offers a promising source of novel therapeutics for the treatment of many CNS disorders.
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http://dx.doi.org/10.1016/j.jep.2016.07.073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5269610PMC
February 2017

Bioactive Secondary Metabolites Produced by the Fungal Endophytes of Conifers.

Nat Prod Commun 2015 Oct;10(10):1671-82

This is a review of bioactive secondary metabolites isolated from conifer-associated endophytic fungi from 1990-2014. This includes compounds with antimicrobial, anti-inflammatory, anti-proliferative and cytotoxic activity towards human cancer cell lines, and activity against either plant pathogens or plant insect pests. Compounds that were originally reported without associated activity were included if other studies ascribed activity to these compounds. Compounds were not included if they were exclusively phytotoxic or if they were isolated from active extracts but were not determined to be the active component of that extract.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5156325PMC
October 2015

Azaphilones from an Acid Mine Extremophile Strain of a Pleurostomophora sp.

J Nat Prod 2015 Dec 7;78(12):2917-23. Epub 2015 Dec 7.

HTS Core Facility, Memorial Sloan-Kettering Cancer Center , New York, New York 10065, United States.

An extremophilic fungus identified as a Pleurostomophora sp. was isolated from the Berkeley Pit, an acid mine waste lake. When grown in liquid culture, the fungus produced berkchaetoazaphilones A-C (1, 2, and 5), the red pigment berkchaetorubramine (6), and the known compound 4-(hydroxymethyl)quinoline. These compounds were evaluated as inhibitors of matrix metalloproteinase-3, caspase-1, and proinflammatory cytokine production in induced THP-1 cells. Berkchaetoazaphilone B (2) inhibited IL-1β, TNFα, and IL-6 production in the induced inflammasome assay and was cytotoxic toward human retinoblastoma cell line Y79 (IC50 = 1.1 μM), leukemia cell lines CCRF-CEM and SR, and the melanoma cell line LOX IMVI (IC50 = 10 μM).
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http://dx.doi.org/10.1021/acs.jnatprod.5b00519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5156323PMC
December 2015

Bioactive secondary metabolites from acid mine waste extremophiles.

Nat Prod Commun 2014 Jul;9(7):1037-44

The extremophilic microbes of the Berkeley Pit Lake are a valuable source of new and interesting secondary metabolites. It is of particular interest that these acidophilic microbes produce small molecule inhibitors of pathways associated with low pH and high Eh. These same small molecules also inhibit molecular pathways induced by reactive oxygen species (ROS) and inflammation in mammalian cells. Low pH is a hallmark of inflammation and high Eh is one of ROS, so the suitability of this collection as a source of bioactive metabolites is actually quite biorational. Compound isolation was guided by inhibition of caspase-1 and matrix metalloproteinase-3, and active compounds were sent to the National Cancer Institute-Developmental Therapeutics Program and Memorial Sloan Kettering Cancer center for evaluation as either antiproliferative or cytotoxic agents.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5156321PMC
July 2014

Phomopsolides and related compounds from the alga-associated fungus, Penicillium clavigerum.

Nat Prod Commun 2014 Jan;9(1):87-90

For the past fifteen years we have studied the secondary metabolites of extremophilic fungi from the Berkeley Pit, an abandoned acid mine waste lake. Fungi associated with an acid-tolerant alga have also been harvested from the Pit. Penicillium clavigerum Demelius was isolated from the green alga Chlorella vulgaris Beyerinck [Beijerinck]. In culture it produced the known compounds phomfuranone (1), patulin (2), dimethylphthalides (3) and (4), phomopsolide A (5), phomopsolide C (6), phomopsolide B (7), phomopsolide E (8), phomopsolide F (9), and phompyrone (10) and the new compound berkbenzofuran thioester (11). Compounds 5 and 6 were potent inhibitors (IC50 < 10 microM) of specific and established human cancer cell lines.
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January 2014

Caspase-1 inhibitors from an extremophilic fungus that target specific leukemia cell lines.

J Nat Prod 2012 Mar 1;75(3):344-50. Epub 2012 Feb 1.

Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, Montana 59812, United States.

Berkeley Pit Lake, Butte, Montana, is a 540 m deep abandoned open-pit copper mine filled with over 140 billion liters of acidic, metal-sulfate-contaminated water. This harsh environment has yielded several microorganisms that produce interesting biologically active compounds. Several polyketide metabolites including the new berkazaphilones A (1) and B (2) and octadienoic acid derivatives berkedienoic acid (13) and berkedienolactone (15), as well as previously reported azaphilone 4, vermistatin (6), dihydrovermistatin (7), penisimplicissin (8), aldehyde 9, and methylparaconic acid (11), were isolated from a culture broth of Penicillium rubrum taken from a depth of 270 m. The structures of these compounds were deduced by interpretation of spectroscopic data. The compounds were isolated either for their inhibition of the signal transduction enzyme caspase-1 or because of their structural similarity to these inhibitors. Selected compounds were further evaluated for their ability to inhibit interleukin-1β production by inflammasomes in induced THP-1 cells. Berkazaphilones B (2) and C (4) and vermistatin analogue penisimplicissin (8) exhibited selective activity against leukemia cancer cell lines in the National Cancer Institute 60 human cell line assay.
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http://dx.doi.org/10.1021/np200414cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3330824PMC
March 2012

Caspase-1 and -3 inhibiting drimane sesquiterpenoids from the extremophilic fungus Penicillium solitum.

J Nat Prod 2012 Feb 25;75(2):262-6. Epub 2012 Jan 25.

Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, Montana 59812, USA.

Two new drimane sesquiterpene lactones and one new tricarboxylic acid derivative were isolated from the Berkeley Pit extremophilic fungus Penicillium solitum. The structures of these compounds were deduced by spectroscopic analysis. Berkedrimanes A and B inhibited the signal transduction enzymes caspase-1 and caspase-3 and mitigated the production of interleukin 1-β in the induced THP-1 (pro-monocytic leukemia cell line) assay.
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http://dx.doi.org/10.1021/np200528nDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3330828PMC
February 2012

Berkeleyones and related meroterpenes from a deep water acid mine waste fungus that inhibit the production of interleukin 1-β from induced inflammasomes.

J Nat Prod 2011 Oct 14;74(10):2273-7. Epub 2011 Sep 14.

Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, Montana 59812, United States.

The Berkeley Pit, an acid mine waste lake, is a source of extremophilic microorganisms that produce interesting bioactive compounds. We have previously reported the isolation of berkeleydione (1), berkeleytrione (2), the berkeleyacetals, and the berkeleyamides from the Pit Lake fungus Penicillium rubrum. In this paper we report the isolation and characterization of berkeleyones A-C (4, 5, and 7) as well as previously described preaustinoid A (3) and A1(6) from this same fungus. These compounds were evaluated as inhibitors of the signaling enzyme caspase-1 and as potential inhibitors of interleukin 1-β production by inflammasomes in induced THP-1 cell line assays.
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http://dx.doi.org/10.1021/np2003066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3214658PMC
October 2011

The berkeleyamides, amides from the acid lake fungus Penicillum rubrum.

J Nat Prod 2008 May 11;71(5):856-60. Epub 2008 Mar 11.

Department of Chemistry and Geochemistry, Montana Tech of the University of Montana, Butte, MT 59701, USA.

We previously reported several novel bioactive hybrid polyketide-terpenoid metabolites from a deep water Penicillium rubrum isolated from Berkeley Pit Lake, Butte, Montana. In this paper we report the structures of four new amides, berkeleyamides A-D (1, 4, 5, 7), isolated from extracts of this fungus. The structures of these compounds were deduced by analysis of NMR data, chemical derivatization, and comparison of their spectroscopic data to those of known compounds.
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http://dx.doi.org/10.1021/np0705054DOI Listing
May 2008

The berkeleyacetals, three meroterpenes from a deep water acid mine waste Penicillium.

J Nat Prod 2007 Nov 31;70(11):1820-3. Epub 2007 Oct 31.

Department of Chemistry, Montana Tech of University of Montana, Butte, Montana 59701, USA.

Berkeley Pit Lake is a 1500 ft deep abandoned open-pit copper mine filled with over 1140 billion liters of acidic, metal-sulfate-contaminated water. This harsh environment is proving to be a source of unusual microorganisms that produce novel bioactive compounds. We recently reported the structures of berkeleydione (1) and berkeleytrione (2), two novel hybrid polyketide-terpenoid metabolites isolated from a deep water Penicillium sp. growing in Berkeley Pit Lake. In this paper we report the structures of three new compounds, berkeleyacetals A-C ( 3-5) isolated from extracts of this fungus. The structures of these compounds were deduced by comparison of mass spectral and NMR data to that of berkeleydione (1).
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http://dx.doi.org/10.1021/np070329zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562172PMC
November 2007

Berkelic acid, a novel spiroketal with selective anticancer activity from an acid mine waste fungal extremophile.

J Org Chem 2006 Jul;71(14):5357-60

Department of Chemistry, Montana Tech of University of Montana, Butte, MT 59701, USA.

Berkeley Pit Lake is an abandoned open-pit copper mine filled with 30 billion gallons of acidic, metal-contaminated water. This harsh environment is proving to be a source of unusual microorganisms that produce novel bioactive metabolites. Bioassay-guided fractionation using signal transduction enzyme assays led to the isolation of the novel spiroketal, berkelic acid 1, and of the known gamma-pyrone, spiciferone A 4. Berkelic acid has shown selective, nanomolar activity against OVCAR-3, an ovarian cancer cell line in the National Cancer Institute cell line screen. The isolation and characterization of these compounds are reported here.
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http://dx.doi.org/10.1021/jo060018dDOI Listing
July 2006

Novel sesquiterpenoid matrix metalloproteinase-3 inhibitors from an acid mine waste extremophile.

J Nat Prod 2004 Aug;67(8):1392-5

Department of Chemistry, Montana Tech of The University of Montana, Butte, Montana 59701, USA.

Berkeley Pit Lake is a 1500 ft deep abandoned open-pit copper mine filled with 30 billion gallons of acidic, metal-contaminated water. This harsh environment is proving to be a source of unusual, biologically active microorganisms. Bioassay-guided fractionation using signal transduction enzyme assays led to the isolation of three novel bisabolane sesquiterpenes and a novel coumarin. The isolation and characterization of these compounds are reported here.
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http://dx.doi.org/10.1021/np049975dDOI Listing
August 2004

Berkeleydione and berkeleytrione, new bioactive metabolites from an acid mine organism.

Org Lett 2004 Mar;6(6):1049-52

Department of Chemistry, Montana Tech of the University of Montana, Butte, Montana 59701, USA.

[structure: see text] Two novel hybrid polyketide-terpenoid metabolites were isolated from a Penicillium sp. growing in the Berkeley Pit Lake of Butte, Montana. Their structures were deduced by spectroscopic analysis and confirmed by single-crystal X-ray analysis on berkeleydione (1). Both compounds inhibited matrix metalloproteinase-3 and caspase-1, and berkeleydione showed activity toward non-small-cell lung cancer in NCI's human cell line antitumor screen.
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http://dx.doi.org/10.1021/ol049852kDOI Listing
March 2004

A novel 5-HT receptor ligand and related cytotoxic compounds from an acid mine waste extremophile.

J Nat Prod 2003 Aug;66(8):1097-100

Department of Chemistry, Montana Tech of The University of Montana, Butte, Montana 59701, USA.

Berkeley Pit Lake in Butte, Montana, is an acid mine waste reservoir rich in toxic metals. A Pithomycessp. isolated from the Pit Lake yielded three tyrosine derivatives (1-3), one of which acts as a 5-HT((2a)) receptor ligand. This type of activity has been associated with migraine preventative and antihypertensive drugs. The isolation and characterization of compounds 1-3 and three sesquiterpenes (5-7) that have been isolated previously from higher plants are reported here.
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http://dx.doi.org/10.1021/np030044wDOI Listing
August 2003

Sequoiamonascins a-d: novel anticancer metabolites isolated from a redwood endophyte.

J Org Chem 2003 Jun;68(12):4966-9

Department of Chemistry and Geochemistry, Montana Tech of the University of Montana, Butte, MT 59701, USA.

Aspergillus parasiticus, a fungal isolate from the bark of a redwood tree (Sequoia sempervirens), has been shown to produce the antitumor metabolites sequoiatones A and B and more recently the sequoiatones C-F. We have also isolated another series of compounds with a new carbon skeleton, the sequoiamonascins. The structures of sequoiamonascins A-D were deduced by interpretation of their spectral data and that of some reaction products. The sequoiamonascins were isolated by brine shrimp lethality-guided fractionation and were submitted to the NCI for anticancer evaluation.
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http://dx.doi.org/10.1021/jo0340253DOI Listing
June 2003

Sequoiatones A and B: Novel Antitumor Metabolites Isolated from a Redwood Endophyte.

J Org Chem 1999 Jul;64(15):5479-5484

Department of Chemistry and Geochemistry, Montana Tech of the University of Montana,Butte, Montana 59701.

Sequoiatones A and B were isolated from the fungus Aspergillus parasiticus, an endophytic fungus of the coast redwood, Sequoia sempervirens. The compounds were isolated from the methanol extract of the mycelial mat of the fungus when grown in liquid culture for 21 days. The compounds were isolated because of their brine shrimp lethality, which served as an excellent guide for chromatographic purification. Full details of the isolation and characterization of sequoiatones A and B are provided herein, along with the test results from the NCI human tumor 60 cell-line screen.
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http://dx.doi.org/10.1021/jo990277lDOI Listing
July 1999