Publications (38)235.96 Total impact
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Article: Nahuoic Acid A Produced by a Streptomyces sp. Isolated From a Marine Sediment Is a Selective SAM-Competitive Inhibitor of the Histone Methyltransferase SETD8.
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ABSTRACT: The histone lysine monomethyltransferase SETD8 is an epigenetic regulator of cell cycle progression. Nahuoic acid A (1), a polyketide produced in culture by a Streptomyces sp. obtained from a tropical marine sediment, is the first known selective SAM-competitive inhibitor of SETD8. The structure of nahuoic acid A (1) has been elucidated by chemical transformation and detailed analysis of spectroscopic data.Organic Letters 12/2012; · 5.86 Impact Factor -
Article: Correction of F508del-CFTR Trafficking by the Sponge Alkaloid Latonduine Is Modulated by Interaction with PARP.
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ABSTRACT: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause CF. The most common mutation, F508 deletion, causes CFTR misfolding and endoplasmic reticulum retention, preventing it from trafficking to the cell surface. One approach to CF treatment is to identify compounds that correct the trafficking defect. We screened a marine extract collection and, after extract, deconvolution identified the latonduines as F508del-CFTR trafficking correctors that give functional correction in vivo. Using a biotinylated azido derivative of latonduine, we identified the poly(ADP-ribose) polymerase (PARP) family as latonduine target proteins. We show that latonduine binds to PARPs 1, 2, 3, 4, 5a, and 5b and inhibits PARP activity, especially PARP-3. Thus, latonduine corrects F508del-CFTR trafficking by modulating PARP activity. Latonduines represent pharmacologic agents for F508del-CFTR correction, and PARP-3 is a pathway for the development of CF treatments.Chemistry & biology 10/2012; 19(10):1288-99. · 6.52 Impact Factor -
Article: Hortonones A to C, hydroazulenones from the genus Hortonia.
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ABSTRACT: The new hexahydroazulenones hortonones A (1) to C (3) were isolated from the leaves of three representative species of the endemic Sri Lankan genus Hortonia that belongs to the family Monimiaceae. Hortonones A (1) and B (2) have the unprecedented rearranged hortonane sesquiterpenoid carbon skeleton, and hortonone C (3) has the unprecedented rearranged and degraded 13-norhortonane skeleton. Hortonone C (3) exhibited in vitro cytotoxicity against human breast cancer MCF-7 cells at 5 μg/mL.Journal of Natural Products 05/2012; 75(6):1189-91. · 3.13 Impact Factor -
Article: A daphnane diterpenoid isolated from Wikstroemia polyantha induces an inflammatory response and modulates miRNA activity.
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ABSTRACT: MicroRNAs (miRNAs) are endogenously expressed single-stranded ~21-23 nucleotide RNAs that inhibit gene expression post-transcriptionally by binding imperfectly to elements usually within the 3'untranslated region (3'UTR) of mRNAs. Small interfering RNAs (siRNAs) mediate site-specific cleavage by binding with perfect complementarity to RNA. Here, a cell-based miRNA reporter system was developed to screen for compounds from marine and plant extracts that inhibit miRNA or siRNA activity. The daphnane diterpenoid genkwanine M (GENK) isolated from the plant Wikstroemia polyantha induces an early inflammatory response and can moderately inhibit miR-122 activity in the liver Huh-7 cell line. GENK does not alter miR-122 levels nor does it directly inhibit siRNA activity in an in vitro cleavage assay. Finally, we demonstrate that GENK can inhibit HCV infection in Huh-7 cells. In summary, the development of the cell-based miRNA sensor system should prove useful in identifying compounds that affect miRNA/siRNA activity.PLoS ONE 01/2012; 7(6):e39621. · 4.09 Impact Factor -
Article: Padanamides A and B, highly modified linear tetrapeptides produced in culture by a Streptomyces sp. isolated from a marine sediment.
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ABSTRACT: Two highly modified linear tetrapeptides, padanamides A (1) and B (2), are produced by laboratory cultures of a Streptomyces sp. obtained from a marine sediment. Padanamide B is cytotoxic to Jurkat cells, and a chemical genomics analysis using Saccharomyces cerevisiae deletion mutants suggested that padanamide A inhibits cysteine and methionine biosynthesis or that these amino acids are involved in the yeast's response to the peptide.Organic Letters 08/2011; 13(15):3936-9. · 5.86 Impact Factor -
Article: Turnagainolides A and B, cyclic depsipeptides produced in culture by a Bacillus sp.: isolation, structure elucidation, and synthesis.
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ABSTRACT: Two new cyclic depsipeptides, turnagainolides A (1) and B (2), have been isolated from laboratory cultures of a marine isolate of Bacillus sp. The structures of 1 and 2, which are simply epimers at the site of macrolactonization, were elucidated by analysis of NMR data and chemical degradation. A total synthesis of the turnagainolides confirmed their structures. Turnagainolide B (2) showed activity in a SHIP1 activation assay.Journal of Natural Products 05/2011; 74(5):1093-9. · 3.13 Impact Factor -
Article: Dhilirolides A-D, meroterpenoids produced in culture by the fruit-infecting fungus Penicillium purpurogenum collected in Sri Lanka.
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ABSTRACT: Dhilirolides A (1) to D (4), a family of secondary metabolites with a putative meroterpenoid biogenetic origin and the unprecedented dhilirane and isodhilirane carbon skeletons, have been isolated from laboratory cultures of the fruit-infecting fungus Penicillium purpurogenum collected in Sri Lanka. The structures of 1 to 4 were elucidated by interpretation of NMR data and a single crystal X-ray diffraction analysis of 1.Organic Letters 03/2011; 13(5):1174-7. · 5.86 Impact Factor -
Article: Depsides isolated from the Sri Lankan lichen Parmotrema sp. exhibit selective Plk1 inhibitory activity.
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ABSTRACT: Mitotic kinase enzymes regulate critical stages of mitosis and are amenable to pharmacological inhibition. Since natural products have been a rich source of antimitotic inhibitors, we postulated that natural products would also provide effective inhibitors of mitotic kinases. To explore unique marine and terrestrial natural product sources for new anticancer drug leads, we screened our natural product extract library for polo-like kinase-1 (Plk1) kinase inhibitors. Extracts of the lichen Parmotrema sp. (Parmeliaceae) exhibited in vitro inhibitory activity. Bioassay-guided fractionation of the Parmotrema sp. extract led to the isolation of depside inhibitors. A new depside 1 has been isolated from the Sri Lankan lichen Parmotrema sp. along with the known metabolites 2 (β-collatolic acid) and 3 (β-alectoronic acid). The structure of depside 1 was elucidated by spectroscopic analysis. The three depsides 1-3 exhibited moderate inhibition of purified recombinant Plk1 kinase with IC₅₀ of 2.8, 0.7, and 1.7 µM, respectively, at 1 µM ATP. Inhibitory activity was also observed at high concentrations of ATP, suggesting the potential for activity in a cellular environment. The depsides were also tested against a panel of 23 other recombinant kinases and were found to possess up to 30-fold selectivity toward Plk1. These data suggest that the depsides 1-3 may serve as core structures that can be further explored as potential inhibitors of Plk1 and other kinases.Pharmaceutical Biology 03/2011; 49(3):296-301. · 0.88 Impact Factor -
Article: Use of experimental design for the optimization of the production of new secondary metabolites by two Penicillium species.
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ABSTRACT: A fractional factorial design approach has been used to enhance secondary metabolite production by two Penicillium strains. The method was initially used to improve the production of bioactive extracts as a whole and subsequently to optimize the production of particular bioactive metabolites. Enhancements of over 500% in secondary metabolite production were observed for both P. oxalicum and P. citrinum. Two new alkaloids, citrinalins A (5) and B (6), were isolated and identified from P. citrinum cultures optimized for production of minor metabolites.Journal of Natural Products 11/2010; 73(11):1821-32. · 3.13 Impact Factor -
Article: Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor.
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ABSTRACT: Castration-recurrent prostate cancer (CRPC) is suspected to depend on androgen receptor (AR). The AF-1 region in the amino-terminal domain (NTD) of AR contains most, if not all, of the transcriptional activity. Here we identify EPI-001, a small molecule that blocked transactivation of the NTD and was specific for inhibition of AR without attenuating transcriptional activities of related steroid receptors. EPI-001 interacted with the AF-1 region, inhibited protein-protein interactions with AR, and reduced AR interaction with androgen-response elements on target genes. Importantly, EPI-001 blocked androgen-induced proliferation and caused cytoreduction of CRPC in xenografts dependent on AR for growth and survival without causing toxicity.Cancer cell 06/2010; 17(6):535-46. · 25.29 Impact Factor -
Article: Release of membrane-bound vesicles and inhibition of tumor cell adhesion by the peptide Neopetrosiamide A.
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ABSTRACT: Neopetrosiamide A (NeoA) is a 28-amino acid tricyclic peptide originally isolated from a marine sponge as a tumor cell invasion inhibitor whose mechanism of action is unknown. We show that NeoA reversibly inhibits tumor cell adhesion, disassembles focal adhesions in pre-attached cells, and decreases the level of beta1 integrin subunits on the cell surface. NeoA also induces the formation of dynamic, membrane-bound protrusions on the surface of treated cells and the release of membrane-bound vesicles into the culture medium. Proteomic analysis indicates that the vesicles contain EGF and transferrin receptors as well as a number of proteins involved in adhesion and migration including: beta1 integrin and numerous alpha integrin subunits; actin and actin-binding proteins such as cofilin, moesin and myosin 1C; and membrane modulating eps15 homology domain (EHD) proteins. Surface labeling, trafficking inhibition, and real-time imaging experiments all suggest that beta1 integrin-containing vesicles are released directly from NeoA-induced cell surface protrusions rather than from vesicles generated intracellularly. The biological activity of NeoA is dependent on its disulfide bond pattern and NMR spectroscopy indicates that the peptide is globular with a continuous ridge of hydrophobic groups flanked by charged amino acid residues that could facilitate a simultaneous interaction with lipids and proteins in the membrane. NeoA is an anti-adhesive peptide that decreases cell surface integrin levels through a novel, yet to be elucidated, mechanism that involves the release of adhesion molecule-containing vesicles from the cell surface.PLoS ONE 01/2010; 5(5):e10836. · 4.09 Impact Factor -
Article: A multi-parameter, high-content, high-throughput screening platform to identify natural compounds that modulate insulin and Pdx1 expression.
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ABSTRACT: Diabetes is a devastating disease that is ultimately caused by the malfunction or loss of insulin-producing pancreatic beta-cells. Drugs capable of inducing the development of new beta-cells or improving the function or survival of existing beta-cells could conceivably cure this disease. We report a novel high-throughput screening platform that exploits multi-parameter high-content analysis to determine the effect of compounds on beta-cell survival, as well as the promoter activity of two key beta-cell genes, insulin and pdx1. Dispersed human pancreatic islets and MIN6 beta-cells were infected with a dual reporter lentivirus containing both eGFP driven by the insulin promoter and mRFP driven by the pdx1 promoter. B-score statistical transformation was used to correct systemic row and column biases. Using this approach and 5 replicate screens, we identified 7 extracts that reproducibly changed insulin and/or pdx1 promoter activity from a library of 1319 marine invertebrate extracts. The ability of compounds purified from these extracts to significantly modulate insulin mRNA levels was confirmed with real-time PCR. Insulin secretion was analyzed by RIA. Follow-up studies focused on two lead compounds, one that stimulates insulin gene expression and one that inhibits insulin gene expression. Thus, we demonstrate that multi-parameter, high-content screening can identify novel regulators of beta-cell gene expression, such as bivittoside D. This work represents an important step towards the development of drugs to increase insulin expression in diabetes and during in vitro differentiation of beta-cell replacements.PLoS ONE 01/2010; 5(9):e12958. · 4.09 Impact Factor -
Article: Bafilomycins produced in culture by Streptomyces spp. isolated from marine habitats are potent inhibitors of autophagy.
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ABSTRACT: Five new bafilomycins, F (1) to J (5), have been isolated from laboratory cultures of two Streptomyces spp. obtained from marine sediments collected in British Columbia, and their structures have been elucidated by detailed analysis of spectroscopic data and the synthesis of model compounds. The new bafilomycins F (1), G (2), H (3), and J (5) along with several co-occurring known analogues showed potent inhibition of autophagy in microscopy and biochemical assays. The thiomorpholinone fragment present in bafilomycin F (1) has not previously been found in a natural product.Journal of Natural Products 12/2009; 73(3):422-7. · 3.13 Impact Factor -
Article: Pyrodysinoic acid derivatives from the marine sponge Dysidea robusta.
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ABSTRACT: Three new nitrogen-containing terpenes related to pyrodysinoic acid (1) have been isolated from the sponge Dysidea robusta collected in Brazil. Isopyrodysinoic acid (2), 13-hydroxyisopyrodysinoic acid (3), and pyrodysinoic acid B (4) were obtained from the crude extract of D. robusta and identified by analysis of spectroscopic data. Pyrodysinoic acid B (4) is the first furodysin or furodysinin sesquiterpene derivative with a trans junction between the two six-membered rings of the 1,2,3,4,4a,7,8,8a-octahydro-1,1,6-trimethylnaphthalene moiety.Journal of Natural Products 10/2009; 72(9):1691-4. · 3.13 Impact Factor -
Article: Rolloamides A and B, cytotoxic cyclic heptapeptides isolated from the Caribbean marine sponge Eurypon laughlini.
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ABSTRACT: Two cyclic heptapeptides, rolloamides A (1) and B (2), have been isolated from the Dominican marine sponge Eurypon laughlini. The structures of 1 and 2 were elucidated by a combination of spectroscopic analyses and chemical degradation. Rolloamide A (1), which was found to exist as two distinct conformers in C(5)D(5)N, exhibits growth suppressive activity against a panel of histologically diverse cancer cell lines.Journal of Natural Products 08/2009; 72(7):1253-7. · 3.13 Impact Factor -
Article: Scalarane-based sesterterpenoid RCE-protease inhibitors isolated from the Indonesian marine sponge Carteriospongia foliascens.
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ABSTRACT: Two new 20,24-bishomo-25-norscalaranes, compounds 1 and 2, and two new and two known 20,24-bishomoscalaranes, compounds 3-6, have been isolated from the Indonesian marine sponge Carteriospongia foliascens. The structures of 1-6 were determined by spectroscopic analysis. Compounds 1 and 3-6 inhibit RCE-protease activity.Journal of Natural Products 07/2009; 72(6):1106-9. · 3.13 Impact Factor -
Article: Cladoniamides A-G, tryptophan-derived alkaloids produced in culture by Streptomyces uncialis.
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ABSTRACT: Cladoniamides A-G (3- 9) have been isolated from cultures of Streptomyces uncialis, and their structures have been elucidated by a combination of spectroscopic analysis and an X-ray diffraction analysis of cladoniamide A (3). The cladoniamides have unprecedented rearranged and degraded alkaloid skeletons with putative biogenetic origins from indolocarbazole precursors. Cladoniamide G (9) is cytotoxic to MCF-7 cells in vitro at 10 microg/mL.Organic Letters 08/2008; 10(16):3501-4. · 5.86 Impact Factor -
Article: Spirastrellolides C to G: macrolides obtained from the marine sponge Spirastrella coccinea.
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ABSTRACT: Five new macrolides, spirastrellolides C (3) to G (7), have been isolated from extracts of the marine sponge Spirastrella coccinea collected in Dominica. Their structures have been elucidated by a combination of spectroscopic analysis and chemical transformations.The Journal of Organic Chemistry 01/2008; 72(25):9842-5. · 4.45 Impact Factor -
Article: Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells.
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ABSTRACT: Because phosphoinositide 3-kinase (PI3K) plays a central role in cellular activation, proliferation, and survival, pharmacologic inhibitors targeting components of the PI3K pathway are actively being developed as therapeutics for the treatment of inflammatory disorders and cancer. These targeted drugs inhibit the activity of either PI3K itself or downstream protein kinases. However, a previously unexplored, alternate strategy is to activate the negative regulatory phosphatases in this pathway. The SH2-containing inositol-5'-phosphatase SHIP1 is a normal physiologic counter-regulator of PI3K in immune/hematopoietic cells that hydrolyzes the PI3K product phosphatidylinositiol-3,4,5-trisphosphate (PIP(3)). We now describe the identification and characterization of potent and specific small-molecule activators of SHIP1. These compounds represent the first small-molecule activators of a phosphatase, and are able to activate recombinant SHIP1 enzyme in vitro and stimulate SHIP1 activity in intact macrophage and mast cells. Mechanism of activation studies with these compounds suggest that they bind a previously undescribed, allosteric activation domain within SHIP1. Furthermore, in vivo administration of these compounds was protective in mouse models of endotoxemia and acute cutaneous anaphylaxis, suggesting that SHIP1 agonists could be used therapeutically to inhibit the PI3K pathway.Blood 10/2007; 110(6):1942-9. · 9.90 Impact Factor -
Article: Nigricanosides A and B, antimitotic glycolipids isolated from the green alga Avrainvillea nigricans collected in Dominica.
Journal of the American Chemical Society 06/2007; 129(18):5822-3. · 9.91 Impact Factor
Top co-authors
Top Journals
Institutions
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2012
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University of Toronto
Toronto, Ontario, Canada
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2011
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University of Colombo
- Department of Chemistry
Colombo, Western Province, Sri Lanka
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2003–2011
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University of British Columbia - Vancouver
- • Department of Chemistry
- • Department of Biochemistry and Molecular Biology
Vancouver, British Columbia, Canada
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2009
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Universidade de São Paulo
- Instituto de Química de São Carlos (IQSC)
São Paulo, Estado de Sao Paulo, Brazil
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