A Novel 5-HT Receptor Ligand and Related Cytotoxic Compounds from an Acid Mine Waste Extremophile

Stierle, Andrea A.; Stierle, Donald B.; Goldstein, Eric; Parker, Keith K.; Bugni, Tim S.; Baarson, Chad; Gress, Julie; Blake, Danielle M.

doi:10.1021/np030044w

Cited by 36 publications

(34 citation statements)

References 8 publications

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“…Several interesting compounds have been isolated from these microbes based on their activities in different bioassay guided fractionation schemes. [2][3][4][5][6] One of the first microbes to be studied from this environment was isolated from a depth of 885 feet and was subsequently identified as Penicillium rubrum Stoll based on rRNA sequencing alignment data (300 base pairs). 3 The fungus was grown in acidified potato dextrose broth (pH 2.7, still) for 21 days.…”

Section: Introductionmentioning

confidence: 99%

“…At harvest time the fungus was killed by the addition of MeOH, the mycelia removed by gravity filtration and the filtrate extracted with CHCl 3 . The CHCl 3 extract inhibited both MMP-3 and caspase-1 in assay systems so it was fractionated by LH-20 column chromatography followed by HPLC to yield berkeleydione (1) and berkeleytrione (2). 3 The 1 H NMR spectra from all of the column fractions were examined for evidence of related analogs.…”

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The Berkeleyacetals, Three Meroterpenes from a Deep Water Acid Mine Waste Penicillium

2007

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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, 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.The Berkeley Pit Lake System is part of the largest EPA Superfund site in North America. Berkeley Pit Lake contains roughly 1140 billion liters of acidic (pH 2.5), metal-sulfate rich water that sits poised at the head of the Columbia River ecosystem. 1 We are studying the secondary metabolism of the culturable microbes isolated from Pit water and sediment samples. Several interesting compounds have been isolated from these microbes based on their activities in different bioassay guided fractionation schemes. [2][3][4][5][6] One of the first microbes to be studied from this environment was isolated from a depth of 885 feet and was subsequently identified as Penicillium rubrum Stoll based on rRNA sequencing alignment data (300 base pairs). 3 The fungus was grown in acidified potato dextrose broth (pH 2.7, still) for 21 days. At harvest time the fungus was killed by the addition of MeOH, the mycelia removed by gravity filtration and the filtrate extracted with CHCl 3 . The CHCl 3 extract inhibited both MMP-3 and caspase-1 in assay systems so it was fractionated by LH-20 column chromatography followed by HPLC to yield berkeleydione (1) and berkeleytrione (2). 3 The 1 H NMR spectra from all of the column fractions were examined for evidence of related analogs. Promising candidates were purified and tested for activity. The three new berkeleyacetals 3-5 were isolated based on this "NMR guided" fractionation as well as their activity in both enzyme bioassays. We report here the isolation and characterization of berkeleyacetals A-C, (3-5). The structures were established based upon extensive spectroscopic data and a single crystal X-ray structure for 1.We are exploring the possibility of isolating compounds with anticancer potential using in vitro signal transduction bioassay systems. Two enzyme inhibition schemes have shown promising correlation to the National Cancer Institutes Developmental Therapeutics Program human cancer cell line assay. To date, compounds isolated in our lab based on these assays have shown activity against non-small cell lung cancer 3 and ovarian cancer 4 . Matrix metalloproteinases (MMP) hydrolyze the extracellular matrix of connective tissues and basement membranes. 7, 8 MMP-3 is up-regulated in many tumors 9, 10 and can induce *To whom correspondence should be addressed. Tel: (406) Casp...

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Section: Introductionmentioning

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The Berkeleyacetals, Three Meroterpenes from a Deep Water Acid Mine Waste Penicillium

2007

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“…Studies suggest that 5-HT2A (serotonin) receptor antagonists might act as migraine preventatives [56], or as antihypertensive agents [57]. In this assay, we assessed the ability of a compound to displace radiolabeled ketanserin from rat 5-HT2A receptor’s ligand binding site [15]. Since 100% of the ketanserin is bound in the control setting, smaller numbers indicated stronger displacement of ketanserin.…”

Section: Extremophilic Fungal Secondary Metabolites Isolated By Bioasmentioning

confidence: 99%

Bioactive Secondary Metabolites from Acid Mine Waste Extremophiles

Stierle

2014

Natural Product Communications

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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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“…The known sesquiterpenoids isolated from the woody-note fraction of the essential oil of L. pterodonta were identified as bisabolol oxide B (2) [12], ylangenol (3) [13], (4) [14], guai-11-en-10-ol (5) [15], spathulenol (6) [16], aromadendran-10-ol (7) [17], caryophyllenol (8) [18], 5a,7a-eudesm-11(13)-en-4a-ol (9) [19], g-costic acid (10) [20], and eudesma-4(15),11(13)-dien-12,5b-olide (11) [21] by comparision of their NMR and MS data with those reported in literature.…”

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Fragrant Volatile Sesquiterpenoids Isolated from the Essential Oil of Laggera pterodonta by Using Olfactory‐Guided Fractionation

Gu¹,

Z²,

Zhang³

et al. 2014

Chemistry & Biodiversity

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Chemical composition of the essential oil from Laggera pterodonta (Compositae) was inverstigated. GC/MS Analyses led to the identification of 68 components, representing more than 96% of the total oil. By focusing on the woody note fraction of the essential oil, one new bisabolane‐type sesquiterpenoid, bisabola‐2,7(14),11‐trien‐10‐ol (1), together with ten known compounds, bisabolol oxide B (2), ylangenol (3), copaborneol (4), guai‐11‐en‐10‐ol (5), spathulenol (6), aromadendran‐10‐ol (7), caryophyllenol (8), 5α,7α‐eudesm‐11(13)‐en‐4α‐ol (9), γ‐costic acid (10), and eudesma‐4(15),11(13)‐diene‐12,5β‐olide (11), were isolated by using olfactory‐guided fractionation. The structures of the eleven compounds were determined by NMR and MS analyses. All the volatile compounds reported here were isolated for the first time from this plant. On the basis of preliminary odor assessment, the odor of the woody‐note fractions of the essential oil was assumed to be due to these isolated sesquiterpenoids.

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A Novel 5-HT Receptor Ligand and Related Cytotoxic Compounds from an Acid Mine Waste Extremophile

Cited by 36 publications

References 8 publications

The Berkeleyacetals, Three Meroterpenes from a Deep Water Acid Mine Waste Penicillium

The Berkeleyacetals, Three Meroterpenes from a Deep Water Acid Mine Waste Penicillium

Bioactive Secondary Metabolites from Acid Mine Waste Extremophiles

Fragrant Volatile Sesquiterpenoids Isolated from the Essential Oil of Laggera pterodonta by Using Olfactory‐Guided Fractionation

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