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1.  Myristicyclins A and B: Antimalarial procyanidins from Horsfieldia spicata from Papua New Guinea 
Organic letters  2013;16(2):346-349.
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.
doi:10.1021/ol4022639
PMCID: PMC3923365  PMID: 24350818
2.  Plakinamine M, a Steroidal Alkaloid from the Marine Sponge Corticium sp. 
Journal of natural products  2013;76(11):10.1021/np400649e.
Using 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.
doi:10.1021/np400649e
PMCID: PMC3883566  PMID: 24195491
3.  Thiazoline Peptides and a Tris-Phenethyl Urea from Didemnum molle with Anti-HIV Activity 
Journal of natural products  2012;75(8):1436-1440.
Summary
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 IC50 values of 39 and 78 µM, respectively. Compound 3 was only active in the cytoprotective cell-based assay with an IC50 value of 60 µM.
doi:10.1021/np300270p
PMCID: PMC4176947  PMID: 22845329
4.  Juxtaposition of chemical and mutation- induced developmental defects in zebrafish reveal a novel copper-chelating activity for kalihinol F 
Chemistry & biology  2013;20(6):753-763.
SUMMARY
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 novel copper chelating activity. Our data support a novel mechanism of action for kalihinol F and the utility of zebrafish as an effective system for identifying new therapeutics and target pathways.
doi:10.1016/j.chembiol.2013.05.008
PMCID: PMC3715381  PMID: 23790486
zebrafish; chemical screen; kalihinol F; copper; notochord
5.  3-Bromohomofascaplysin A, a fascaplysin analogue from a Fijian Didemnum sp. ascidian 
Bioorganic & medicinal chemistry  2011;19(22):6604-6607.
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 IC50 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.
doi:10.1016/j.bmc.2011.05.046
PMCID: PMC3205246  PMID: 21696970
Fascaplysin analogues; ascidian; antimalarial; absolute configuration; experimental and theoretically calculated ECD
6.  The challenge of large scale motion for RDC-based analysis of configuration: the case of fibrosterol sulfate A 
Journal of the American Chemical Society  2011;133(37):14629-14636.
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 an RDC-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.
doi:10.1021/ja205295q
PMCID: PMC3173584  PMID: 21776994
bis-steroid; relative configuration; conformational analysis; NMR; residual dipolar coupling; multiple tensor analysis; single tensor analysis
7.  Distinct Pathways Generate Peptides from Defective Ribosomal Products for CD8+ T Cell Immunosurveillance 
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.
doi:10.4049/jimmunol.1003096
PMCID: PMC3408966  PMID: 21228349
8.  Araiosamines A–D: Tris-bromoindole Cyclic Guanidine Alkaloids from the Marine Sponge Clathria (Thalysias) araiosa 
The Journal of organic chemistry  2011;76(14):5515-5523.
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.
doi:10.1021/jo200327d
PMCID: PMC3188435  PMID: 21462976
9.  Mirabamides E-H, HIV-Inhibitory Depsipeptides from the Sponge Stelletta clavosa 
Journal of natural products  2011;74(2):185-193.
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 IC50 values of 121, 62, 68 and 41 nM, respectively.
doi:10.1021/np100613p
PMCID: PMC3072293  PMID: 21280591
10.  Two Ring-A-Aromatized Bile Acids from the Marine Sponge Sollasella moretonensis 
Natural product communications  2010;5(10):1571-1574.
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.
PMCID: PMC3050653  PMID: 21121250
marine natural product; sponge; Sollasella moretonensis; ring-A-aromatized bile acids
11.  New Tetromycin Derivatives with Anti-Trypanosomal and Protease Inhibitory Activities † 
Marine Drugs  2011;9(10):1682-1697.
Four new tetromycin derivatives, tetromycins 1–4 and a previously known one, tetromycin B (5) were isolated from Streptomyces axinellae Pol001T 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 Mpro, and PLpro. The compounds showed antiparasitic activities against T. brucei and time-dependent inhibition of cathepsin L-like proteases with Ki values in the low micromolar range.
doi:10.3390/md9101682
PMCID: PMC3210601  PMID: 22072992
tetromycin; anti-trypanosomal; protease inhibition; Streptomyces axinellae; marine sponge
12.  Carteriosulfonic Acids A-C, GSK-3β Inhibitors from a Carteriospongia sp 
Journal of natural products  2009;72(9):1651-1656.
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-3β, which inhibits Wnt signaling through phosphorylation of β-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 MS3 spectra.
doi:10.1021/np900336f
PMCID: PMC2754322  PMID: 19778090
14.  Biologically active components of a Papua New Guinea analgesic and anti-inflammatory lichen preparation 
Fitoterapia  2009;80(5):270-273.
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 Parmotrema 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.
doi:10.1016/j.fitote.2009.03.003
PMCID: PMC2793093  PMID: 19289158
Parmotrema saccatilobum; lichen; atranorin; chloroatranorin; COX inhibition
15.  Psammaplin A as a general activator of cell based signaling assays via HDAC inhibition and studies on some bromotyrosine derivatives 
Bioorganic & medicinal chemistry  2008;17(6):2189-2198.
The Wnt signaling pathway regulates cell growth and development in metazoans, and is therefore of interest for drug discovery. By screening a library of 5,808 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.
doi:10.1016/j.bmc.2008.10.077
PMCID: PMC2670876  PMID: 19022675
16.  Isolation, Structure Elucidation and Synthesis of Eudistomides A and B, Lipopeptides from a Fijian Ascidian Eudistoma sp. 
The Journal of organic chemistry  2009;74(3):1156-1162.
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.
doi:10.1021/jo8022582
PMCID: PMC2670194  PMID: 19053188
17.  Tetrahdroxysqualene from Rhus taitensis Shows Antimycobacterial Activity Against Mycobacterium tuberculosis 
Journal of natural products  2008;71(9):1623-1624.
Tuberculosis has become a major health problem, in particular with the emergence of extremely drug resistant tuberculosis (XDRTB). In our search for new therapeutic leads against TB, we isolated a new triterpene (1) from the plant Rhus taitensis collected in Papua New Guinea. Tetrahydroxysqualene (1) was isolated using bioassay-guided fractionation of the methanolic extract of R. taitensis leaves and twigs. The structure of tetrahydroxysqualene (1) was elucidated on the basis of HRESIMS and 1D and 2D NMR spectra. Tetrahydroxysqualene (1) exhibited anti–tuberculosis activity with an MIC of 10.0 μg/mL while showing only modest cytotoxicity.
doi:10.1021/np800082e
PMCID: PMC2807728  PMID: 18710283
18.  Anti-Parasitic Compounds from Streptomyces sp. Strains Isolated from Mediterranean Sponges 
Marine Drugs  2010;8(2):373-380.
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 IC50 < 0.11 μM; staurosporine IC50 5.30 μM) and Trypanosoma brucei brucei (valinomycin IC50 0.0032 μM; staurosporine IC50 0.022 μM; butenolide IC50 31.77 μM). 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.
doi:10.3390/md8020373
PMCID: PMC2852844  PMID: 20390111
marine sponges; Streptomyces; valinomycin; staurosporine; butenolide; anti-parasitic
19.  Evaluation of Pyridoacridine Alkaloids in a Zebrafish Phenotypic Assay 
Marine Drugs  2010;8(6):1769-1778.
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 μM. No phenotype other than death was observed for compounds 1–3, 5, 6.
doi:10.3390/md8061769
PMCID: PMC2901824  PMID: 20631869
pyridoacridine alkaloids; Xestospongia cf. carbonaria; zebrafish
20.  Deoxyamphimedine, a Pyridoacridine Alkaloid, Damages DNA via the Production of Reactive Oxygen Species 
Marine Drugs  2009;7(2):196-209.
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.
doi:10.3390/md7020196
PMCID: PMC2707043  PMID: 19597581
deoxyamphimedine; neoamphimedine; amphimedine; pyridoacridine; reactive oxygen species
21.  Spheciosterol Sulfates, PKCζ Inhibitors from a Philippine Sponge Spheciospongia sp 
Journal of natural products  2008;71(7):1213-1217.
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 PKCζ with IC50 values of 1.59, 0.53, 0.11 and 1.21 μM, respectively. In a cell based assay, 1–4 also inhibited NF-κB activation with EC50 values between 12–64 μM.
doi:10.1021/np8001628
PMCID: PMC2593898  PMID: 18558742
22.  Spheciosterol Sulfates, PKCζ Inhibitors from a Philippine Sponge Spheciospongia sp. 
Journal of Natural Products  2008;71(7):1213-1217.
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 PKCζ with IC50 values of 1.59, 0.53, 0.11, and 1.21 μM, respectively. In a cell-based assay, 1−4 also inhibited NF-κB activation with EC50 values of 12−64 μM.
doi:10.1021/np8001628
PMCID: PMC2593898  PMID: 18558742
23.  The Total Synthesis of Neoamphimedine 
The Journal of organic chemistry  2007;72(22):8501-8505.
Neoamphimedine, a Pyridoacridine alkaloid from Xestospongia sp., is a potent antitumor agent both in vitro and in vivo. Neoamphimedine can efficiently induce topoisomerase II mediated catenation of plasmid DNA in vitro, and is the only member of more than one hundred pyridoacridines thus far to have this mechanism of action. Herein we report the first total synthesis of Neoamphimedine.
doi:10.1021/jo7017813
PMCID: PMC2547140  PMID: 17900144
24.  Theopapuamide: a Cyclic Depsipeptide from a Papua New Guinea Lithistid Sponge Theonella swinhoei 
Journal of natural products  2006;69(11):1582-1586.
Theopapuamide (1), a new cytotoxic peptide has been isolated from the lithistid sponge Theonella swinhoei from Papua New Guinea. The structure was established by analysis of NMR, mass spectrometry and chemical methods. The undecapeptide (1) contains several unusual amino acid residues, of which the occurrence of β-methoxyasparagine and 4-amino-5-methyl-2,3,5-trihydroxy-hexanoic acid (Amtha) is unprecedented in natural peptides. Compound 1 also contains a amide linked fatty acid moiety, 3-hydroxy-2,4,6-trimethyl-octanoic acid (Htoa). Theopapuamide (1) was cytotoxic against CEM-TART and HCT-116 cell lines with EC50 values of 0.5 μM and 0.9 μM respectively.
doi:10.1021/np060229d
PMCID: PMC2566935  PMID: 17125225
25.  Halogenated Cyclic Peptides Isolated From the Sponge Corticium sp 
Journal of natural products  2007;70(5):741-746.
Fractionation of two Fijian specimens of the sponge Corticium sp., led to the isolation of the known active alkaloid steroid plakinamine A and two new halogenated cyclic peptides, corticiamide A (1) and cyclocinamide B (2). Structural elucidation of 1 and 2 was achieved by an extensive combination of high field NMR and HRFT MS/MS experiments, and the absolute stereochemistry of 2 was determined by acid hydrolysis and Marfey’s analysis. Corticiamide A (1) and cyclocinamide B (2) represent the first peptides to be described from the genus Corticium.
doi:10.1021/np060489v
PMCID: PMC2533844  PMID: 17391049

Results 1-25 (32)