Publications by authors named "Mary Kay Harper"

46 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

Development of a novel and rapid phenotype-based screening method to assess rice seedling growth.

Plant Methods 2020 15;16:139. Epub 2020 Oct 15.

Present Address: Department of Plant Biotechnology and Bioinformatics, Ghent University, 9052 Ghent, Belgium.

Background: Rice () is one of the most important model crops in plant research. Despite its considerable advantages, (phenotypic) bioassays for rice are not as well developed as for . Here, we present a phenotype-based screening method to study shoot-related parameters of rice seedlings via an automated computer analysis.

Results: The phenotype-based screening method was validated by testing several compounds in pharmacological experiments that interfered with hormone homeostasis, confirming that the assay was consistent with regard to the anticipated plant growth regulation and revealing the robustness of the set-up in terms of reproducibility. Moreover, abiotic stress tests using NaCl and DCMU, an electron transport blocker during the light dependent reactions of photosynthesis, confirmed the validity of the new method for a wide range of applications. Next, this method was used to screen the impact of semi-purified fractions of marine invertebrates on the initial stages of rice seedling growth. Certain fractions clearly stimulated growth, whereas others inhibited it, especially in the root, illustrating the possible applications of this novel, robust, and fast phenotype-based screening method for rice.

Conclusions: The validated phenotype-based and cost-efficient screening method allows a quick and proper analysis of shoot growth and requires only small volumes of compounds and media. As a result, this method could potentially be used for a whole range of applications, ranging from discovery of novel biostimulants, plant growth regulators, and plant growth-promoting bacteria to analysis of CRISPR knockouts, molecular plant breeding, genome-wide association, and phytotoxicity studies. The assay system described here can contribute to a better understanding of plant development in general.
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http://dx.doi.org/10.1186/s13007-020-00682-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560306PMC
October 2020

Myrmenaphthol A, Isolated from a Hawaiian Sponge of the Genus .

J Nat Prod 2019 09 28;82(9):2668-2671. Epub 2019 Aug 28.

Department of Chemistry , University of Hawaii at Manoa , Honolulu , Hawaii 96822 , United States.

Four compounds (-) were isolated from a Hawaiian sponge of the genus . Myrmenaphthol A () incorporates two unusual elements into an oxidized steroidal core: a naphthyl AB-ring system and a hydroxy group at C-2. A comparison of the experimental and predicted electronic circular dichroism (ECD) spectra of assigned an configuration to the lone stereocenter (Δ = 0.75; similarity factor 0.8137). Known compounds, cinanthrenol A (), 3,4-dihydroxypregna-5,17-diene-10,2-carbolactone (), and 3,4-dihydroxypregna-5,20-diene-10,2-carbolactone (), were also isolated. Despite literature reports of competitive inhibition at nanomolar levels for , neither nor the structurally related showed any activity against estrogen receptors at the concentrations tested.
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http://dx.doi.org/10.1021/acs.jnatprod.9b00665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919962PMC
September 2019

Madurastatin D1 and D2, Oxazoline Containing Siderophores Isolated from an

Org Lett 2019 08 5;21(16):6275-6279. Epub 2019 Aug 5.

Pharmaceutical Sciences Division , University of Wisconsin-Madison , 777 Highland Avenue , Madison , Wisconsin 53705 , United States.

Two new siderophores, madurastatin D1 and D2, together with (-)-madurastatin C1, the enantiomer of a known compound, were isolated from marine-derived sp. The presence of an unusual 4-imidazolidinone ring in madurastatins D1 and D2 inspired us to sequence the sp. genome and to identify the biosynthetic gene cluster, knowledge of which enables us to now propose a biosynthetic pathway. Madurastatin D1 and D2 are moderately active in antimicrobial assays with .
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http://dx.doi.org/10.1021/acs.orglett.9b02159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941472PMC
August 2019

Cytotoxic Sesquiterpenoid Quinones and Quinols, and an 11-Membered Heterocycle, Kauamide, from the Hawaiian Marine Sponge .

Mar Drugs 2019 Jul 19;17(7). Epub 2019 Jul 19.

Department of Chemistry, University of Hawaii at Manoa, Honolulu, HI 96822, USA.

Several known sesquiterpenoid quinones and quinols (-), and kauamide (), a new polyketide-peptide containing an 11-membered heterocycle, were isolated from the extracts of the Hawaiian marine sponge . The planar structure of was determined from spectroscopic analyses, and its relative and absolute configurations were established from density functional theory (DFT) calculations of the GIAO NMR shielding tensors, and advanced Marfey's analysis of the -MeLeu residue, respectively. Compounds and showed moderate inhibition of β-secretase 1 (BACE1), whereas - exhibited moderate to potent inhibition of growth of human glioma (U251) cells. Compounds - and - were also active against human pancreatic carcinoma (Panc-1) cells.
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http://dx.doi.org/10.3390/md17070423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669564PMC
July 2019

The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research.

Nat Prod Rep 2019 01 13;36(1):35-107. Epub 2018 Jul 13.

Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA.

Covering: up to 2018With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.
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http://dx.doi.org/10.1039/c7np00064bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350634PMC
January 2019

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

Brackish habitat dictates cultivable Actinobacterial diversity from marine sponges.

PLoS One 2017 10;12(7):e0176968. Epub 2017 Jul 10.

Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

Bacterial communities associated with marine invertebrates such as sponges and ascidians have demonstrated potential as sources of bio-medically relevant small molecules. Metagenomic analysis has shown that many of these invertebrates harbor populations of Actinobacteria, many of which are cultivable. While some populations within invertebrates are transmitted vertically, others are obtained from the environment. We hypothesized that cultivable diversity from sponges living in brackish mangrove habitats have associations with Actinobacterial populations that differ from those found in clear tropical waters. In this study, we analyzed the cultivable Actinobacterial populations from sponges found in these two distinct habitats with the aim of understanding the secondary metabolite potential. Importantly, we wanted to broadly evaluate the potential differences among these groups to guide future Actinobacterial collection strategies for the purposes of drug discovery.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176968PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503172PMC
September 2017

Puupehenol, a potent antioxidant antimicrobial meroterpenoid from a Hawaiian deep-water Dactylospongia sp. sponge.

J Nat Prod 2015 Feb 10;78(2):325-9. Epub 2015 Feb 10.

DKI College of Pharmacy, University of Hawaii at Hilo , Hilo, Hawaii 96720, United States.

From the organic extract of a deep-water Hawaiian sponge Dactylospongia sp., a new potent antioxidant and antimicrobial meroterpenoid, puupehenol (1), was isolated. The structure of 1 was determined using spectroscopic techniques ((1)H and (13)C NMR, MS, IR, UV, [α]D). The known compound puupehenone (2) was also isolated and suggested as a probable artifact of the isolation procedures. Complete unambiguous (1)H and (13)C NMR data are provided for compounds 1 and 2. Bioassays performed with 1 and 2 showed them both to be very effective antioxidants and to have antimicrobial properties.
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http://dx.doi.org/10.1021/np500793gDOI Listing
February 2015

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

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

Isolation of steroidal glycosides from the Caribbean sponge Pandaros acanthifolium.

J Nat Prod 2012 Dec 17;75(12):2094-100. Epub 2012 Dec 17.

Department of Chemistry, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI C1A 4P3, Canada.

Four new steroidal glycosides, acanthifoliosides G-J (1-4), were isolated as minor constituents from the Caribbean marine sponge Pandaros acanthifolium. These metabolites are characterized by a highly oxygenated D ring and the presence of a disaccharide rhamnose-glucose residue and a rhamnose at positions C-3 and C-15, respectively. Their structures were established on the basis of extensive interpretation of 1D and 2D NMR data and HRESIMS analyses. The absolute configurations of the glucose and rhamnose sugars were determined by preparing aldose o-tolylthiocarbamate derivatives and comparison to authentic standards by LC/HRESIMS. Acanthifolioside G (1) exhibited antioxidant and cytoprotective activities.
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http://dx.doi.org/10.1021/np300520wDOI Listing
December 2012

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

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

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

3D models of epithelial-mesenchymal transition in breast cancer metastasis: high-throughput screening assay development, validation, and pilot screen.

J Biomol Screen 2011 Feb;16(2):141-54

Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver Anschutz Medial Center, Aurora, CO 80045, USA.

Despite advancements in therapies developed for the treatment of cancer, patient prognosis and mortality rates have improved minimally, and metastasis remains the primary cause of cancer mortality worldwide. An underlying mechanism promoting metastasis in many types of cancer is epithelial-mesenchymal transition (EMT). Here the authors report a novel 3D model of EMT and metastatic breast cancer suitable for high-throughput screening (HTS) drug discovery. The primary assay incorporates the expression of the prognostic biomarker vimentin, as a luciferase reporter of EMT, in basil-like/triple-negative MDA-MB-231 breast carcinoma spheroids. Using this model, the authors developed a number of known antitumor agents as control modulators of EMT. U0126, PKC412, PF2341066, dasatinib, and axitinib downregulated vimentin expression by 70% to 90% as compared to untreated spheroids. Counterassays were developed to measure spheroid viability and the invasive potential of MDA-MB-231 spheroids after small-molecule treatment and used to confirm hits from primary screening. Finally, the authors conducted a pilot screen to validate this model for HTS using a purified library of marine secondary metabolites. From 230 compounds screened, they obtained a Z' score of 0.64, indicative of an excellent assay, and confirmed 4 hits, including isonaamidine B, papuamine, mycalolide E, and jaspamide. This HTS model demonstrates the potential to identify small-molecule modulators of EMT that could be used to discover novel antimetastatic agents for the treatment of cancer.
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http://dx.doi.org/10.1177/1087057110392995DOI Listing
February 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

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

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

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

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

Psammaplin A as a general activator of cell-based signaling assays via HDAC inhibition and studies on some bromotyrosine derivatives.

Bioorg Med Chem 2009 Mar 5;17(6):2189-98. Epub 2008 Nov 5.

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

The Wnt signaling pathway regulates cell growth and development in metazoans, and is therefore of interest for drug discovery. By screening a library of 5808 pre-fractionated marine extracts in a cell-based Wnt signaling assay, several signaling activators and inhibitors were observed. LCMS-based fractionation rapidly identified an active compound from Pseudoceratina purpurea as psammaplin A, a known HDAC inhibitor. Other HDAC inhibitors similarly activated signaling in this assay, indicating HDAC inhibitors will be identified through many cell-based reporter assays. In a large scale analysis of P. purpurea, three previously undescribed bromotyrosine based natural products were identified; the structure of one of these was confirmed by synthesis. Additionally, three other derivatives of psammaplin A were prepared: a mixed disulfide and two sulfinate esters. Finally, evidence to support a structural reassignment of psammaplin I from a sulfone to the isomeric sulfinate ester is presented.
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http://dx.doi.org/10.1016/j.bmc.2008.10.077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670876PMC
March 2009

Fractionated marine invertebrate extract libraries for drug discovery.

Molecules 2008 Jun 19;13(6):1372-83. Epub 2008 Jun 19.

Department of Medicinal Chemistry, University of Utah, 30 S. 2000 E. RM 307, Salt Lake City, UT 84112, USA.

The high-throughput screening and drug discovery paradigm has necessitated a change in preparation of natural product samples for screening programs. In an attempt to improve the quality of marine natural products samples for screening, several fractionation strategies were investigated. The final method used HP20SS as a solid support to effectively desalt extracts and fractionate the organic components. Additionally, methods to integrate an automated LCMS fractionation approach to shorten discovery time lines have been implemented.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2505051PMC
http://dx.doi.org/10.3390/molecules13061372DOI Listing
June 2008

Spheciosterol sulfates, PKCzeta inhibitors from a philippine sponge Spheciospongia sp.

J Nat Prod 2008 Jul 18;71(7):1213-7. Epub 2008 Jun 18.

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

Three new sterol sulfates, spheciosterol sulfates A-C (1-3), and the known sterol sulfate topsentiasterol sulfate E (4) have been isolated from the sponge Spheciospongia sp., collected in the Philippines. Structures were assigned on the basis of extensive 1D and 2D NMR studies as well as analysis by HRESIMS. Compounds 1-4 inhibited PKCzeta with IC50 values of 1.59, 0.53, 0.11, and 1.21 microM, respectively. In a cell-based assay, 1-4 also inhibited NF-kappaB activation with EC50 values of 12-64 microM.
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http://dx.doi.org/10.1021/np8001628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2593898PMC
July 2008
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