Publications by authors named "Chris M Ireland"

79 Publications

Topsentinol L Trisulfate, a Marine Natural Product That Targets Basal-like and Claudin-Low Breast Cancers.

Mar Drugs 2021 Jan 18;19(1). Epub 2021 Jan 18.

Department of Pharmacology and Toxicology, University of Utah, Salt Lake, UT 84112, USA.

Patients diagnosed with basal-like breast cancer suffer from poor prognosis and limited treatment options. There is an urgent need to identify new targets that can benefit patients with basal-like and claudin-low (BL-CL) breast cancers. We screened fractions from our Marine Invertebrate Compound Library (MICL) to identify compounds that specifically target BL-CL breast cancers. We identified a previously unreported trisulfated sterol, i.e., topsentinol L trisulfate (TLT), which exhibited increased efficacy against BL-CL breast cancers relative to luminal/HER2+ breast cancer. Biochemical investigation of the effects of TLT on BL-CL cell lines revealed its ability to inhibit activation of AMP-activated protein kinase (AMPK) and checkpoint kinase 1 (CHK1) and to promote activation of p38. The importance of targeting AMPK and CHK1 in BL-CL cell lines was validated by treating a panel of breast cancer cell lines with known small molecule inhibitors of AMPK (dorsomorphin) and CHK1 (Ly2603618) and recording the increased effectiveness against BL-CL breast cancers as compared with luminal/HER2+ breast cancer. Finally, we generated a drug response gene-expression signature and projected it against a human tumor panel of 12 different cancer types to identify other cancer types sensitive to the compound. The TLT sensitivity gene-expression signature identified breast and bladder cancer as the most sensitive to TLT, while glioblastoma multiforme was the least sensitive.
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http://dx.doi.org/10.3390/md19010041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831112PMC
January 2021

Accessing chemical diversity from the uncultivated symbionts of small marine animals.

Nat Chem Biol 2018 02 1;14(2):179-185. Epub 2018 Jan 1.

Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah, USA.

Chemistry drives many biological interactions between the microbiota and host animals, yet it is often challenging to identify the chemicals involved. This poses a problem, as such small molecules are excellent sources of potential pharmaceuticals, pretested by nature for animal compatibility. We discovered anti-HIV compounds from small, marine tunicates from the Eastern Fields of Papua New Guinea. Tunicates are a reservoir for new bioactive chemicals, yet their small size often impedes identification or even detection of the chemicals within. We solved this problem by combining chemistry, metagenomics, and synthetic biology to directly identify and synthesize the natural products. We show that these anti-HIV compounds, the divamides, are a novel family of lanthipeptides produced by symbiotic bacteria living in the tunicate. Neighboring animal colonies contain structurally related divamides that differ starkly in their biological properties, suggesting a role for biosynthetic plasticity in a native context wherein biological interactions take place.
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http://dx.doi.org/10.1038/nchembio.2537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771842PMC
February 2018

Benzotriazoles Reactivate Latent HIV-1 through Inactivation of STAT5 SUMOylation.

Cell Rep 2017 01;18(5):1324-1334

Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA. Electronic address:

The presence of latent HIV-1 in infected individuals represents a major barrier preventing viral eradication. For that reason, reactivation of latent viruses in the presence of antiretroviral regimens has been proposed as a therapeutic strategy to achieve remission. We screened for small molecules and identified several benzotriazole derivatives with the ability to reactivate latent HIV-1. In the presence of IL-2, benzotriazoles reactivated and reduced the latent reservoir in primary cells, and, remarkably, viral reactivation was achieved without inducing cell proliferation, T cell activation, or cytokine release. Mechanistic studies showed that benzotriazoles block SUMOylation of phosphorylated STAT5, increasing STAT5's activity and occupancy of the HIV-1 LTR. Our results identify benzotriazoles as latency reversing agents and STAT5 signaling and SUMOylation as targets for HIV-1 eradication strategies. These compounds represent a different direction in the search for "shock and kill" therapies.
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http://dx.doi.org/10.1016/j.celrep.2017.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461578PMC
January 2017

Total synthesis of dehaloperophoramidine using a highly diastereoselective Hosomi-Sakurai reaction.

Chem Commun (Camb) 2016 Sep 10;52(71):10747-50. Epub 2016 Aug 10.

School of Chemistry and Biomedical Sciences Research Complex, University of St. Andrews and EaStCHEM, St. Andrews, Fife, Scotland KY16 9ST, UK.

The synthesis of dehaloperophoramidine, a non-halogenated derivative of the marine natural product perophoramidine, and its biological activity towards HCT116, HT29 and LoVo colorectal carcinoma cells is reported. A [3,3]-Claisen rearrangement and an epoxide opening/allylsilylation reaction installed the contiguous all-carbon quaternary stereocentres with the required relative stereochemistry.
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http://dx.doi.org/10.1039/c6cc05747kDOI Listing
September 2016

Marine natural products as inhibitors of cystathionine beta-synthase activity.

Bioorg Med Chem Lett 2015 Mar 14;25(5):1064-6. Epub 2015 Jan 14.

Department of Medicinal Chemistry, University of Utah, 30 South 2000 East, Salt Lake City, UT 84112, USA. Electronic address:

A library consisting of characterized marine natural products as well as synthetic derivatives was screened for compounds capable of inhibiting the production of hydrogen sulfide (H2S) by cystathionine beta-synthase (CBS). Eight hits were validated and shown to inhibit CBS activity with IC50 values ranging from 83 to 187μM. The majority of hits came from a series of synthetic polyandrocarpamine derivatives. In addition, a modified fluorogenic probe for H2S detection with improved solubility in aqueous solutions is reported.
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http://dx.doi.org/10.1016/j.bmcl.2015.01.013DOI Listing
March 2015

Myristicyclins A and B: antimalarial procyanidins from Horsfieldia spicata from Papua New Guinea.

Org Lett 2014 Jan 19;16(2):346-9. Epub 2013 Dec 19.

Departments of Medicinal Chemistry and ‡Pharmacology and Toxicology, College of Pharmacy and L. S. Skaggs Pharmacy Institute, University of Utah , 30 S 2000 E, Salt Lake City, Utah 84112, United States.

An antimalarial screen for plants collected from Papua New Guinea identified an extract of Horsfieldia spicata as having activity. Isolation of the active constituents led to the identification of two new compounds: myristicyclins A (1) and B (2). Both compounds are procyanidin-like congeners of myristinins lacking a pendant aromatic ring. Myristicyclin A was found to inhibit the ring, trophozoite, and schizont stages of Plasmodium falciparum at similar concentrations in the mid-μM range.
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http://dx.doi.org/10.1021/ol4022639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923365PMC
January 2014

Plakinamine M, a steroidal alkaloid from the marine sponge Corticium sp.

J Nat Prod 2013 Nov 6;76(11):2150-2. Epub 2013 Nov 6.

Department of Medicinal Chemistry, University of Utah , Salt Lake City, Utah 84112, United States.

By means of bioassay-guided fractionation, a new steroidal alkaloid, plakinamine M (1), and the known compound, plakinamine L (2), with a unique acyclic side chain, were isolated from the marine sponge Corticium sp. collected from New Britain, Papua New Guinea. The structures were determined on the basis of extensive 1D and 2D NMR and HRESIMS. The two compounds showed inhibition of Mycobacterium tuberculosis with MIC values of 15.8 and 3.6 μg/mL, respectively.
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http://dx.doi.org/10.1021/np400649eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883566PMC
November 2013

Single-molecule inhibition of human kinesin by adociasulfate-13 and -14 from the sponge Cladocroce aculeata.

Proc Natl Acad Sci U S A 2013 Nov 4;110(47):18880-5. Epub 2013 Nov 4.

Departments of Medicinal Chemistry and Physics and Astronomy and Center for Cell and Genome Science, University of Utah, Salt Lake City, UT 84112.

Two merotriterpenoid hydroquinone sulfates designated adociasulfate-13 (1) and adociasulfate-14 (2) were purified from Cladocroce aculeata (Chalinidae) along with adociasulfate-8. All three compounds were found to inhibit microtubule-stimulated ATPase activity of kinesin at 15 µM by blocking both the binding of microtubules and the processive motion of kinesin along microtubules. These findings directly show that substitution of the 5'-sulfate in 1 for a glycolic acid moiety in 2 maintains kinesin inhibition. Nomarski imaging and bead diffusion assays in the presence of adociasulfates showed no signs of either free-floating or bead-bound adociasulfate aggregates. Single-molecule biophysical experiments also suggest that inhibition of kinesin activity does not involve adociasulfate aggregation. Furthermore, both mitotic and nonmitotic kinesins are inhibited by adociasulfates to a significantly different extent. We also report evidence that microtubule binding of nonkinesin microtubule binding domains may be affected by adociasulfates.
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http://dx.doi.org/10.1073/pnas.1314132110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839781PMC
November 2013

Juxtaposition of chemical and mutation-induced developmental defects in zebrafish reveal a copper-chelating activity for kalihinol F.

Chem Biol 2013 Jun;20(6):753-63

Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.

A major hurdle in using complex systems for drug screening is the difficulty of defining the mechanistic targets of small molecules. The zebrafish provides an excellent model system for juxtaposing developmental phenotypes with mechanism discovery using organism genetics. We carried out a phenotype-based screen of uncharacterized small molecules in zebrafish that produced a variety of chemically induced phenotypes with potential genetic parallels. Specifically, kalihinol F caused an undulated notochord, defects in pigment formation, hematopoiesis, and neural development. These phenotypes were strikingly similar to the zebrafish mutant, calamity, an established model of copper deficiency. Further studies into the mechanism of action of kalihinol F revealed a copper-chelating activity. Our data support this mechanism of action for kalihinol F and the utility of zebrafish as an effective system for identifying therapeutic and target pathways.
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http://dx.doi.org/10.1016/j.chembiol.2013.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715381PMC
June 2013

Investigations of the marine flora and fauna of the Fiji Islands.

Nat Prod Rep 2012 Dec 14;29(12):1424-62. Epub 2012 Sep 14.

Centre for Drug Discovery and Conservation, Institute of Applied Sciences, The University of the South Pacific, Suva, Fiji.

Over the past 30 years, approximately 140 papers have been published on marine natural products chemistry and related research from the Fiji Islands. These came about from studies starting in the early 1980s by the research groups of Crews at the University of California Santa Cruz, Ireland at the University of Utah, Gerwick from the Scripps Institution of Oceanography, the University of California at San Diego and the more recent groups of Hay at the Georgia Institute of Technology (GIT) and Jaspars from the University of Aberdeen. This review covers both known and novel marine-derived natural products and their biological activities. The marine organisms reviewed include invertebrates, plants and microorganisms, highlighting the vast structural diversity of compounds isolated from these organisms. Increasingly during this period, natural products chemists at the University of the South Pacific have been partners in this research, leading in 2006 to the development of a Centre for Drug Discovery and Conservation (CDDC).
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http://dx.doi.org/10.1039/c2np20055dDOI Listing
December 2012

Thiazoline peptides and a tris-phenethyl urea from Didemnum molle with anti-HIV activity.

J Nat Prod 2012 Aug 30;75(8):1436-40. Epub 2012 Jul 30.

Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.

As part of our screening for anti-HIV agents from marine invertebrates, the MeOH extract of Didemnum molle was tested and showed moderate in vitro anti-HIV activity. Bioassay-guided fractionation of a large-scale extract allowed the identification of two new cyclopeptides, mollamides E and F (1 and 2), and one new tris-phenethyl urea, molleurea A (3). The absolute configurations were established using the advanced Marfey's method. The three compounds were evaluated for anti-HIV activity in both an HIV integrase inhibition assay and a cytoprotective cell-based assay. Compound 2 was active in both assays with IC(50) values of 39 and 78 μM, respectively. Compound 3 was active only in the cytoprotective cell-based assay, with an IC(50) value of 60 μM.
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http://dx.doi.org/10.1021/np300270pDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176947PMC
August 2012

New tetromycin derivatives with anti-trypanosomal and protease inhibitory activities.

Mar Drugs 2011 26;9(10):1682-97. Epub 2011 Sep 26.

Julius-von-Sachs Institute for Biological Sciences, University of Würzburg, Julius-von-Sachs-Platz 3, Würzburg 97082, Germany.

Four new tetromycin derivatives, tetromycins 1-4 and a previously known one, tetromycin B (5) were isolated from Streptomyces axinellae Pol001(T) cultivated from the Mediterranean sponge Axinella polypoides. Structures were assigned using extensive 1D and 2D NMR spectroscopy as well as HRESIMS analysis. The compounds were tested for antiparasitic activities against Leishmania major and Trypanosoma brucei, and for protease inhibition against several cysteine proteases such as falcipain, rhodesain, cathepsin L, cathepsin B, and viral proteases SARS-CoV M(pro), and PL(pro). The compounds showed antiparasitic activities against T. brucei and time-dependent inhibition of cathepsin L-like proteases with K(i) values in the low micromolar range.
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http://dx.doi.org/10.3390/md9101682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210601PMC
February 2013

Strongylophorine-8, a pro-electrophilic compound from the marine sponge Petrosia (Strongylophora) corticata, provides neuroprotection through Nrf2/ARE pathway.

Biochem Biophys Res Commun 2011 Nov 1;415(1):6-10. Epub 2011 Oct 1.

Department of Welfare Engineering, Faculty of Engineering, Iwate University, Morioka, Iwate 020-8551, Japan.

Green plant-origin electrophilic compounds are a newly-recognized class of neuroprotective compounds that provide neuroprotection through activation of the Nrf2/ARE pathway. Electrophilic hydroquinones are of particular interest due to their ability to become electrophilic quinones upon auto-oxidation. Although marine organisms frequently produce a variety of electrophilic compounds, the detailed mechanisms of action of these compounds remain unknown. Here, we focused on the neuroprotective effects of strongylophorine-8 (STR8), a para-hydroquinone-type pro-electrophilic compound from the sponge Petrosia (Strongylophora) corticata. STR8 activated the Nrf2/ARE pathway, induced phase 2 enzymes, and increased glutathione, thus protecting neuronal cells from oxidative stress. Microarray analysis indicated that STR8 induced a large number of phase 2 genes, the regulation of which is controlled by the Nrf2/ARE pathway. STR8 is the first example of a neuroprotective pro-electrophilic compound from marine organisms.
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http://dx.doi.org/10.1016/j.bbrc.2011.09.114DOI Listing
November 2011

Challenge of large-scale motion for residual dipolar coupling based analysis of configuration: the case of fibrosterol sulfate A.

J Am Chem Soc 2011 Sep 23;133(37):14629-36. Epub 2011 Aug 23.

Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.

Fibrosterol sulfate A is a polysulfated bis-steroid with an atypical side chain. Due to the flexibility of the linker, large-scale motions that change dramatically the shape of the entire molecule are expected. Such motions pose major challenges to the structure elucidation and the correct determination of configuration. In this study, we will describe the determination of the relative configuration of fibrosterol sulfate A through a residual dipolar coupling based multiple alignment tensor analysis complemented by molecular dynamics. For completeness, we applied also the single tensor approach which is unreliable due to the large-scale motions and compare the results.
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http://dx.doi.org/10.1021/ja205295qDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173584PMC
September 2011

3-bromohomofascaplysin A, a fascaplysin analogue from a Fijian Didemnum sp. ascidian.

Bioorg Med Chem 2011 Nov 1;19(22):6604-7. Epub 2011 Jun 1.

Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.

A new fascaplysin analogue, 3-bromohomofascaplysin A (1), along with two known analogues, homofascaplysin A (2) and fascaplysin (3), were isolated from a Fijian Didemnum sp. ascidian. The absolute configurations of 3-bromohomofascaplysin A (1) and homofascaplysin A (2) were determined via experimental and theoretically calculated ECD spectra. The differential activities of 1-3 against different blood-borne life stages of the malaria pathogen Plasmodium falciparum were assessed. Homofascaplysin A (2) displayed an IC(50) of 0.55±0.11 nM against ring stage parasites and 105±38 nM against all live parasites. Given the stronger resistance of ring stage parasites against most current antimalarials relative to the other blood stages, homofascaplysin A (2) represents a promising agent for treatment of drug resistant malaria.
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http://dx.doi.org/10.1016/j.bmc.2011.05.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205246PMC
November 2011

Araiosamines A-D: tris-bromoindole cyclic guanidine alkaloids from the marine sponge Clathria (Thalysias) araiosa.

J Org Chem 2011 Jul 11;76(14):5515-23. Epub 2011 Apr 11.

Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112, United States.

Four new tris-bromoindole cyclic guanidine alkaloids, araiosamines A-D, were isolated from the methanol extract of a marine sponge, Clathria (Thalysias) araiosa, collected from Vanuatu. Their carbon skeletons delineate a new class of indole alkaloids apparently derived from a linear polymerization process involving a carbon-carbon bond formation. Comparison of the structures including the relative configurations suggests a common intermediate containing a dihydroaminopyrimidine moiety capable of undergoing various modalities of conjugate addition to yield unprecedented ring systems.
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http://dx.doi.org/10.1021/jo200327dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188435PMC
July 2011

Mirabamides E-H, HIV-inhibitory depsipeptides from the sponge Stelletta clavosa.

J Nat Prod 2011 Feb 31;74(2):185-93. Epub 2011 Jan 31.

Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112, USA.

Four new depsipeptides, mirabamides E-H (1-4), and the known depsipeptide mirabamide C (5) have been isolated from the sponge Stelletta clavosa, collected from the Torres Strait. The planar structures were determined on the basis of extensive 1D and 2D NMR and HRESIMS. The absolute configurations were established by the advanced Marfey's method, NMR, and GC-MS. The four new compounds all showed strong inhibition of HIV-1 in a neutralization assay with IC(50) values of 121, 62, 68, and 41 nM, respectively.
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http://dx.doi.org/10.1021/np100613pDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072293PMC
February 2011

Distinct pathways generate peptides from defective ribosomal products for CD8+ T cell immunosurveillance.

J Immunol 2011 Feb 12;186(4):2065-72. Epub 2011 Jan 12.

Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

To understand better the endogenous sources of MHC class I peptide ligands, we generated an antigenic reporter protein whose degradation is rapidly and reversibly controlled with Shield-1, a cell-permeant drug. Using this system, we demonstrate that defective ribosomal products (DRiPs) represent a major and highly efficient source of peptides and are completely resistant to our attempts to stabilize the protein. Although peptides also derive from nascent Shield-1-sensitive proteins and "retirees" created by Shield-1 withdrawal, these are much less efficient sources on a molar basis. We use this system to identify two drugs--each known to inhibit polyubiquitin chain disassembly--that selectively inhibit presentation of Shield-1-resistant DRiPs. These findings provide the initial evidence for distinct biochemical pathways for presentation of DRiPs versus retirees and implicate polyubiquitin chain disassembly or the actions of deubiquitylating enzymes as playing an important role in DRiP presentation.
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http://dx.doi.org/10.4049/jimmunol.1003096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408966PMC
February 2011

Two ring-A-aromatized bile acids from the marine sponge Sollasella moretonensis.

Nat Prod Commun 2010 Oct;5(10):1571-4

Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112, USA.

Two ring-A-aromatized bile acids, 1 and 2, were isolated from the sponge Sollasella moretonensis, collected from the seabed of northern Queensland. Structures were assigned on the basis of extensive 1D and 2D NMR studies, as well as analysis by HRESIMS. Compound 2 has previously been produced synthetically, though this marks its first isolation from a natural source.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3050653PMC
October 2010

WLS-dependent secretion of WNT3A requires Ser209 acylation and vacuolar acidification.

J Cell Sci 2010 Oct 7;123(Pt 19):3357-67. Epub 2010 Sep 7.

Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, 169857, Singapore.

Wnt proteins are secreted post-translationally modified proteins that signal locally to regulate development and proliferation. The production of bioactive Wnts requires a number of dedicated factors in the secreting cell whose coordinated functions are not fully understood. A screen for small molecules identified inhibitors of vacuolar acidification as potent inhibitors of Wnt secretion. Inhibition of the V-ATPase or disruption of vacuolar pH gradients by diverse drugs potently inhibited Wnt/β-catenin signaling both in cultured human cells and in vivo, and impaired Wnt-regulated convergent extension movements in Xenopus embryos. WNT secretion requires its binding to the carrier protein wntless (WLS); we find that WLS is ER-resident in human cells and WNT3A binding to WLS requires PORCN-dependent lipid modification of WNT3A at serine 209. Inhibition of vacuolar acidification results in accumulation of the WNT3A-WLS complex both in cells and at the plasma membrane. Modeling predictions suggest that WLS has a lipid-binding β-barrel that is similar to the lipocalin-family fold. We propose that WLS binds Wnts in part through a lipid-binding domain, and that vacuolar acidification is required to release palmitoylated WNT3A from WLS in secretory vesicles, possibly to facilitate transfer of WNT3A to a soluble carrier protein.
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http://dx.doi.org/10.1242/jcs.072132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939803PMC
October 2010

Evaluation of pyridoacridine alkaloids in a zebrafish phenotypic assay.

Mar Drugs 2010 Jun 2;8(6):1769-78. Epub 2010 Jun 2.

Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.

Three new minor components, the pyridoacridine alkaloids 1-hydroxy-deoxyamphimedine (1), 3-hydroxy-deoxyamphimedine (2), debromopetrosamine (3), and three known compounds, amphimedine (4), neoamphimedine (5) and deoxyamphimedine (6), have been isolated from the sponge Xestospongia cf. carbonaria, collected in Palau. Structures were assigned on the basis of extensive 1D and 2D NMR studies as well as analysis by HRESIMS. Compounds 1-6 were evaluated in a zebrafish phenotype-based assay. Amphimedine (4) was the only compound that caused a phenotype in zebrafish embryos at 30 muM. No phenotype other than death was observed for compounds 1-3, 5, 6.
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http://dx.doi.org/10.3390/md8061769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901824PMC
June 2010

Fibrosterol sulfates from the Philippine sponge Lissodendoryx (Acanthodoryx) fibrosa: sterol dimers that inhibit PKCzeta.

J Org Chem 2009 Aug;74(16):5902-8

Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112, USA.

Three new sulfated sterol dimers, fibrosterol sulfates A-C (1-3), have been isolated from the sponge Lissodendoryx (Acanthodoryx) fibrosa, collected in the Philippines. The structures were assigned on the basis of extensive 1D and 2D NMR studies as well as analysis by HRESIMS. Compounds 1 and 2 inhibited PKCzeta with IC(50) values of 16.4 and 5.6 microM, respectively.
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http://dx.doi.org/10.1021/jo900844rDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2889921PMC
August 2009

Exocarpic acid inhibits mycolic acid biosynthesis in Mycobacterium tuberculosis.

Planta Med 2010 Oct 26;76(15):1678-82. Epub 2010 May 26.

Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112, USA.

Exocarpic acid (13 E-octadecene-9,11-diynoic acid) from Exocarpos latifolius R.Br. (Santalaceae) was previously shown to have specific antimycobacterial activity. Microarray data suggested inhibition of fatty acid metabolism as a potential mode of action. Experiments designed to elucidate the mechanism of action showed that exocarpic acid was effective at inhibition of mycolic acid biosynthesis and did not act by dissipating the proton gradient in treated M. tuberculosis. Amide derivatives of exocarpic acid displayed similar properties to exocarpic acid, while other polyacetylenic fatty acids varied in their effects on mycolic acid biosynthesis.
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http://dx.doi.org/10.1055/s-0030-1249939DOI Listing
October 2010

Anti-parasitic compounds from Streptomyces sp. strains isolated from Mediterranean sponges.

Mar Drugs 2010 Feb 23;8(2):373-80. Epub 2010 Feb 23.

Julius-von-Sachs Institute for Biological Sciences, University of Würzburg, Würzburg, Germany.

Actinomycetes are prolific producers of pharmacologically important compounds accounting for about 70% of the naturally derived antibiotics that are currently in clinical use. In this study, we report on the isolation of Streptomyces sp. strains from Mediterranean sponges, on their secondary metabolite production and on their screening for anti-infective activities. Bioassay-guided isolation and purification yielded three previously known compounds namely, cyclic depsipeptide valinomycin, indolocarbazole alkaloid staurosporine and butenolide. This is the first report of the isolation of valinomycin from a marine source. These compounds exhibited novel anti-parasitic activities specifically against Leishmania major (valinomycin IC(50) < 0.11 microM; staurosporine IC(50) 5.30 microM) and Trypanosoma brucei brucei (valinomycin IC(50) 0.0032 microM; staurosporine IC(50) 0.022 microM; butenolide IC(50) 31.77 microM). These results underscore the potential of marine actinomycetes to produce bioactive compounds as well as the re-evaluation of previously known compounds for novel anti-infective activities.
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http://dx.doi.org/10.3390/md8020373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852844PMC
February 2010

Carteriosulfonic acids A-C, GSK-3beta inhibitors from a Carteriospongia sp.

J Nat Prod 2009 Sep;72(9):1651-6

Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, USA.

Modulators of Wnt signaling have therapeutic potential in a number of human diseases. A fractionated library from marine invertebrates was screened in a luciferase assay designed to identify modulators of Wnt signaling. A fraction from a Carteriospongia sp. sponge activated Wnt signaling and was subsequently shown to inhibit GSK-3beta, which inhibits Wnt signaling through phosphorylation of beta-catenin. Three novel natural products, carteriosulfonic acids A (1), B (2), and C (3), were identified as active constituents. The carteriosulfonic acids contain unprecedented 4,6,7,9-tetrahydroxylated decanoic acid subunits. Their structures were elucidated through analysis of NMR data and a detailed analysis of pseudo MS(3) spectra.
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http://dx.doi.org/10.1021/np900336fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754322PMC
September 2009

Deoxyamphimedine, a pyridoacridine alkaloid, damages DNA via the production of reactive oxygen species.

Mar Drugs 2009 May 25;7(2):196-209. Epub 2009 May 25.

Department of Pharmacology and Toxicology, University of Utah, 30 South 2000 East Rm. 201, Salt Lake City, Utah 84112, USA.

Marine pyridoacridines are a class of aromatic chemicals that share an 11H-pyrido[4,3,2-mn]acridine skeleton. Pyridoacridine alkaloids display diverse biological activities including cytotoxicity, fungicidal and bactericidal properties, production of reactive oxygen species (ROS) and topoisomerase inhibition. These activities are often dependent on slight modifications to the pyridoacridine skeleton. Here we demonstrate that while structurally similar to neoamphimedine and amphimedine, the biological activity of deoxyamphimedine differs greatly. Deoxyamphimedine damages DNA in vitro independent of topoisomerase enzymes through the generation of reactive oxygen species. Its activity was decreased in low oxygen, with the removal of a reducing agent and in the presence of anti-oxidants. Deoxyamphimedine also showed enhanced toxicity in cells sensitive to single or double strand DNA breaks, consistent with the in vitro activity.
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http://dx.doi.org/10.3390/md7020196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707043PMC
May 2009

Antimycobacterial activity of Exocarpos latifolius is due to exocarpic acid.

Planta Med 2009 Oct 14;75(12):1326-30. Epub 2009 May 14.

Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112, USA.

Lipophilic fractions of stem extracts from Exocarpos latifolius, native to Papua New Guinea, showed significant activity against Mycobacterium tuberculosis H37Ra. Bioactivity-guided fractionation yielded exocarpic acid (E-octadeca-13-ene-9,11-diynoic-acid) as the major active component. Several new exocarpic acid analogs were also shown to be active. Exocarpic acid has previously been reported active against gram-positive, but not gram-negative bacteria. Work presented here demonstrates the selective activity of exocarpic acid against Mycobacterium tuberculosis H37Ra.
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http://dx.doi.org/10.1055/s-0029-1185687DOI Listing
October 2009

The marine alkaloid naamidine A promotes caspase-dependent apoptosis in tumor cells.

Anticancer Drugs 2009 Jul;20(6):425-36

Department of Medicinal Chemistry University of Utah, Salt Lake City, UT 84112, USA.

Apoptosis is important for normal development and removal of damaged cells. Evasion of apoptosis by cancer cells is one of the key characteristics of many tumor types. Thus, discovering agents that promote apoptosis in tumor cells could have great therapeutic value. Marine natural products have demonstrated great potential as anticancer agents, and the proapoptotic activity of some of these products is emerging as a potentially useful property for cancer treatments. Using a tumor xenograft assay in rodents, we previously found that the marine alkaloid naamidine A is a potent antitumor agent. In this study, we further characterize the mechanism of action of naamidine A. In cultured tumor cells, we find that naamidine A induces cell death, which is accompanied with annexin V staining, disruption of the mitochondrial membrane potential, and cleavage and activation of caspases 3, 8, and 9, all of which are hallmarks of apoptosis. Furthermore, naamidine A-induced cell death is caspase dependent. We also find that under conditions where naamidine A inhibits tumor xenograft growth, it induces activation of caspase 3, suggesting that apoptosis is part of its antitumorigenic activity in vivo. Apoptosis is not dependent on extracellular signal-regulated kinase 1/2, previously characterized molecular targets of naamidine A, nor does it require functional p53. Our studies support the continued study of naamidine A and its target(s) for the potential development of better clinical treatments for cancer.
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http://dx.doi.org/10.1097/CAD.0b013e32832ae55fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992254PMC
July 2009

Biologically active components of a Papua New Guinea analgesic and anti-inflammatory lichen preparation.

Fitoterapia 2009 Jul 14;80(5):270-3. Epub 2009 Mar 14.

Department of Medicinal Chemistry, University of Utah, UT 84112, USA.

A traditional preparation of Parmotrema saccatilobum (Taylor) Hale (Family: Parmeliaceae) is being considered for inclusion into the PNG national drug formulary by the Ministry of Health Taskforce on Traditional Medicines. The lichen preparation is traditionally used in the Milne Bay province of Papua New Guinea for analgesic and anti-inflammatory activities. A hexane extract of P. saccatilobum yielded the principle components atranorin and chloroatranorin. Atranorin and chloroatranorin were tested in a COX-1 and -2 enzyme inhibition assay, which showed that atranorin inhibited COX-1 in a dose dependent manner and suggests partial inhibition by atranorin and chloroatranorin of COX-2 and COX-1, respectively.
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http://dx.doi.org/10.1016/j.fitote.2009.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2793093PMC
July 2009

Isolation, structure elucidation, and synthesis of eudistomides A and B, lipopeptides from a Fijian ascidian Eudistoma sp.

J Org Chem 2009 Feb;74(3):1156-62

Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112, USA.

Eudistomides A (1) and B (2), two new cyclic peptides, were isolated from a Fijian ascidian Eudistoma sp. These five-residue cystine-linked cyclic peptides are flanked by a C-terminal methyl ester and a 12-oxo- or 12-hydroxy-tetradecanoyl moiety. The complete structures of the eudistomides were determined using a combination of spectroscopic and chemical methods. Chiral HPLC analysis revealed that all five amino acid residues in 1 and 2 had the L-configuration. Total synthesis of eudistomides A (1) and B (2) confirmed the proposed structures. Enantioselective lipase-catalyzed hydrolysis of a mixture of C-35 acetoxy epimers indicated a 35R absolute configuration for 2.
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http://dx.doi.org/10.1021/jo8022582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670194PMC
February 2009