Doralyn S. Dalisay
Sex: Female
Education:
Doctor of Philosophy in Microbiology, University of New South Wales, 2004
Master of Science in Biology, University of the Philippines, 1999
Bachelor of Science in Pharmacy, University of San Agustin, 1993
Field of Specialization
Chemistry
Natural Products
Liquid Chromatography-Mass Spectrometry (LC-MS)
Life Sciences and Spectroscopy
Researches:
Article title: Oceanapiside, a Marine Natural Product, Targets the Sphingolipid Pathway of Fluconazole-Resistant Candida glabrata
Authors: Doralyn Dalisay, Evan W. Rogers, Tadeusz F. Molinski
Publication title: Marine Drugs 19(3): 126, February 2021
Abstract:
Oceanapiside (OPS), a marine natural product with a novel bifunctional sphingolipid structure, is fungicidal against fluconazole-resistant Candida glabrata at 10 μg/mL (15.4 μM). The fungicidal effect was observed at 3 to 4 h after exposure to cells. Cytological and morphological studies revealed that OPS affects the budding patterns of treated yeast cells with a significant increase in the number of cells with single small buds. In addition, this budding morphology was found to be sensitive in the presence of OPS. Moreover, the number of cells with single medium-sized buds and cells with single large buds were decreased significantly, indicating that fewer cells were transformed to these budding patterns, suggestive of inhibition of polarized growth. OPS was also observed to disrupt the organized actin assembly in C. glabrata, which correlates with inhibition of budding and polarized growth. It was also demonstrated that phytosphingosine (PHS) reversed the antifungal activity of oceanapiside. We quantified the amount of long chain-bases (LCBs) and phytoceramide from the crude extracts of treated cells using LC-ESI-MS. PHS concentration was elevated in extracts of cells treated with OPS when compared with cells treated with miconazole and amphotericin B. Elevated levels of PHS in OPS-treated cells confirms that OPS affects the pathway at a step downstream of PHS synthesis. These results also demonstrated that OPS has a mechanism of action different to those of miconazole and amphotericin B and interdicts fungal sphingolipid metabolism by specifically inhibiting the step converting PHS to phytoceramide.
Article title: Metabolites from Marine Microorganisms, Micro, and Macroalgae: Immense Scope for Pharmacology
Authors: Noora Barzkar,1,* Saeid Tamadoni Jahromi,2,* Hadi Bolooki Poorsaheli,3,4 and Fabio Vianello
Publication title: Marine Drugs 17(8): 464, August 2019
Abstract:
Marine organisms produce a large array of natural products with relevance in drug discovery. These compounds have biological activities such as antioxidant, antibacterial, antitumor, antivirus, anticoagulant, anti-inflammatory, antihypertensive, antidiabetic, and so forth. Consequently, several of the metabolites have made it to the advanced stages of clinical trials, and a few of them are commercially available. In this review, novel information on natural products isolated from marine microorganisms, microalgae, and macroalgae are presented. Given due research impetus, these marine metabolites might emerge as a new wave of promising drugs.
Article title: Aminorifamycins and Sporalactams Produced in Culture by a Micromonospora sp. Isolated from a Northeastern-Pacific Marine Sediment Are Potent Antibiotics
Authors: David E. Williams, Doralyn Dalisay, Jessie Chen, Elena A. Polishchuck, et al.
Publication title: Organic Letters 19(4), February 2017
Abstract:
The new ansa macrolide antibiotics 1 to 4 have been isolated from cultures of a Micromonospora sp. obtained from a marine sediment. Rifamycins 1 and 2 are the first natural ansa macrolides to have a 3-amino substituent. Sporalactams A (3) and B (4) are comprised of a heterocylic core 5 and a 14-membered ansa bridge that are both unprecedented. Sporalactam B (4) shows selective and potent inhibition of Mycobacterium tuberculosis.
Article title: Structures of Nahuoic Acids B-E Produced in Culture by a Streptomyces sp. Isolated from a Marine Sediment and Evidence for the Inhibition of the Histone Methyl Transferase SETD8 in Human Cancer Cells by Nahuoic Acid A
Authors: David E. Williams, Fanny Izard, Stéphanie Arnould, Doralyn S. Dalisay, et al.
Publication title: Journal of Organic Chemistry 81(4): 1324-32, February 2016
Abstract:
Nahuoic acids A-E (1-5) have been isolated from laboratory cultures of a Streptomyces sp. obtained from a tropical marine sediment. The structures of the new polyketides 2-5 were elucidated by analysis of spectroscopic data of the natural products and the chemical derivatives 6 and 7. Nahuoic acids 1-5 are in vitro inhibitors of the histone methyltransferase SETD8, and nahuoic acid A (1) and its pentaacetate derivative 8 inhibit the proliferation of several cancer cells lines in vitro with modest potency. At the IC50 for cancer cell proliferation, nahuoic acid A (1) showed selective inhibition of SETD8 in U2OS osteosarcoma cells that reflect its selectivity against a panel of pure histone methyl transferases. A cell cycle analysis revealed that the cellular toxicity of nahuoic acid A (1) is likely linked to its ability to inhibit SETD8 activity.
Article title: Peroxide Natural Products from Plakortis zyggompha and the Sponge Association Plakortis halichondrioides-Xestospongia deweerdtae: Antifungal Activity against Cryptococcus gattii
Authors: Matthew T. Jamison, Doralyn S. Dalisay, Tadeusz F. Molinski
Publication title: Journal of Natural Products 79(3); 555-63, March 2016
Abstract:
Cryptococcus gattii is a human pathogen and causative agent of a pernicious, sometimes fatal, disseminated fungal disease. Investigation of antifungal extracts of the marine sponge association Plakortis halichondrioides-Xestospongia deweerdtae and the sponge Plakortis zyggompha from the Bahamas led to the discovery and isolation of 6-epi-7,8-dihydroplakortide K (1), plakortide AA (2), and three new plakinic acids, N-P (4-6; unstable 1,2-dioxolanes bearing benzyl-substituted conjugated dienes), along with known plakinic acids L, K, and M.5 Chiroptical comparisons and DFT calculations of (13)C NMR chemical shifts were used to assign the absolute stereostructure of 4. The stereospecific base-promoted rearrangement-saponification of 1 to 10 was briefly investigated and showed tight kinetic control and stereospecific formation of the new C-2 stereocenter with inversion at C-3. Plakinic acid M and plakortides 9 and 11 exhibited antifungal activity against C. gattii (MIC90 = 2.4 to 36 μM), but plakinic acids N-P were inactive under the same conditions.
Article title: Dirigent Protein-Mediated Lignan and Cyanogenic Glucoside Formation in Flax Seed: Integrated Omics and MALDI Mass Spectrometry Imaging
Authors: Doralyn S. Dalisay, Kye Won Kim, Choonseok Lee, Hong Yang, et al.
Publication title: Journal of Natural Products 78(6); 1231-42, June 2015
Abstract:
An integrated omics approach using genomics, transcriptomics, metabolomics (MALDI mass spectrometry imaging, MSI), and bioinformatics was employed to study spatiotemporal formation and deposition of health-protecting polymeric lignans and plant defense cyanogenic glucosides. Intact flax (Linum usitatissimum) capsules and seed tissues at different development stages were analyzed. Transcriptome analyses indicated distinct expression patterns of dirigent protein (DP) gene family members encoding (-)- and (+)-pinoresinol-forming DPs and their associated downstream metabolic processes, respectively, with the former expressed at early seed coat development stages. Genes encoding (+)-pinoresinol-forming DPs were, in contrast, expressed at later development stages. Recombinant DP expression and DP assays also unequivocally established their distinct stereoselective biochemical functions. Using MALDI MSI and ion mobility separation analyses, the pinoresinol downstream derivatives, secoisolariciresinol diglucoside (SDG) and SDG hydroxymethylglutaryl ester, were localized and detectable only in early seed coat development stages. SDG derivatives were then converted into higher molecular weight phenolics during seed coat maturation. By contrast, the plant defense cyanogenic glucosides, the monoglucosides linamarin/lotaustralin, were detected throughout the flax capsule, whereas diglucosides linustatin/neolinustatin only accumulated in endosperm and embryo tissues. A putative biosynthetic pathway to the cyanogens is proposed on the basis of transcriptome coexpression data. Localization of all metabolites was at ca. 20 μm resolution, with the web based tool OpenMSI enabling not only resolution enhancement but also an interactive system for real-time searching for any ion in the tissue under analysis.
Article title: Branched dimerization of Tat peptide improves permeability to HeLa and hippocampal neuronal cells
Authors: I. Abrrey Monreal, Qian Liu, Katherine Tyson, Tyler Bland, et al.
Publication title: Chemical Communications 51(25): 5463-5466, February 2015
Abstract:
A dimeric branched peptide TATp-D designed as an analogue of the HIV-Tat protein transduction domain (TATp), a prototypical cell penetrating peptide (CPP), demonstrates significantly enhanced cell uptake at 0.25 to 2.5 μM. Live cell confocal laser scanning microscopy revealed that multivalency dramatically improved the permeation potency of TATp-D to HeLa and primary hippocampal neuronal cells. The observed enhanced ability of TATp-D to translocate through the membrane is highlighted by a non-linear dependence on concentration, exhibiting the greatest uptake at sub-micromolar concentrations as compared to TATp. Multimerization via bis-Fmoc Lysine offered a synthetically straightforward method to investigate the effects of multivalent CPPs while offering orthogonal handles for cargo attachment, increasing the utility of CPPs at significantly lower concentrations.
Full text available upon request to the author
Article title: Non-host disease resistance response in pea (Pisum sativum) pods: Biochemical function of DRR206 and phytoalexin pathway localization
Authors: Herana Kamal Seneviratne, Doralyn S. Dalisay, Kye-Won Kim, Syed G. A. Moinuddin, et al.
Publication title: Phytochemistry 113: 140-8, May 2015
Abstract:
Continually exposed to potential pathogens, vascular plants have evolved intricate defense mechanisms to recognize encroaching threats and defend themselves. They do so by inducing a set of defense responses that can help defeat and/or limit effects of invading pathogens, of which the non-host disease resistance response is the most common. In this regard, pea (Pisum sativum) pod tissue, when exposed to Fusarium solani f. sp. phaseoli spores, undergoes an inducible transcriptional activation of pathogenesis-related genes, and also produces (+)-pisatin, its major phytoalexin. One of the inducible pathogenesis-related genes is Disease Resistance Response-206 (DRR206), whose role in vivo was unknown. DRR206 is, however, related to the dirigent protein (DP) family. In this study, its biochemical function was investigated in planta, with the metabolite associated with its gene induction being pinoresinol monoglucoside. Interestingly, both pinoresinol monoglucoside and (+)-pisatin were co-localized in pea pod endocarp epidermal cells, as demonstrated using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging. In addition, endocarp epidermal cells are also the site for both chalcone synthase and DRR206 gene expression. Taken together, these data indicate that both (+)-pisatin and pinoresinol monoglucoside function in the overall phytoalexin responses.
Full text available upon request to the author
Article title: A multi-omics strategy resolves the elusive nature of alkaloids in Podophyllum species
Authors: Joaquim V. Marques, Doralyn S. Dalisay, Hong Yang, Choonseok Lee, et al.
Publication title: Molecular Biosystems 10(11): 2838-2849, August 2014
Abstract:
Podophyllum hexandrum and, to a much lesser extent P. peltatum, are sources of podophyllotoxin, extensively used as a chemical scaffold for various anti-cancer drugs. In this study, integrated omics technologies (including advanced mass spectrometry/metabolomics, transcriptome sequencing/gene assemblies, and bioinformatics) gave unequivocal evidence that both plant species possess a hitherto unknown aporphine alkaloid metabolic pathway. Specifically, RNA-seq transcriptome sequencing and bioinformatics guided gene assemblies/analyses in silico suggested presence of transcripts homologous to genes encoding all known steps in aporphine alkaloid biosynthesis. A comprehensive metabolomics analysis, including UPLC-TOF-MS and MALDI-MS imaging in situ, then enabled detection, identification, localization and quantification of the aporphine alkaloids, magnoflorine, corytuberine and muricinine, in the underground and aerial tissues. Interestingly, the purported presence of alkaloids in Podophyllum species has been enigmatic since the 19th century, remaining unresolved until now. The evolutionary and phylogenetic ramifications of this discovery are discussed.
Full text available upon request to the author
Article title: Helvolic acid, an antibacterial nortriterpenoid from a fungal endophyte, Xylaria sp. of orchid Anoectochilus setaceus endemic to Sri Lanka
Authors: Pamoda B. Ratnaweera, David E. Williams, E. Dilip de Silva, Ravi L.C. Wijesundera, et al.
Publication title: Mycology 5(1): 23-28, March 2014
Abstract:
An endophytic fungus was isolated from surface sterilized leaf segments of Anoectochilus setaceus, an orchid endemic to Sri Lanka, and was identified as Xylaria sp. by morphological characters and DNA sequencing. Bioassay-guided chromatographic fractionation of the organic extract of a laboratory culture of this fungus led to the isolation of the known antibacterial helvolic acid. Helvolic acid was active against the Gram-positive bacteria, Bacillus subtilis [minimal inhibitory concentrations (MIC), 2 μg mL−1] and methicillin-resistant Staphylococcus aureus (MIC, 4 μg mL−1).
Article title: Transgenic hybrid poplar for sustainable and scalable production of the commodity/specialty chemical, 2-phenylethanol
Authors: Michael A. Costa, Joaquim V. Marques, Doralyn S. Dalisay, Barrington Herman, et al.
Publication title: PLoS One 8(12): e83169, December 2013
Abstract:
Fast growing hybrid poplar offers the means for sustainable production of specialty and commodity chemicals, in addition to rapid biomass production for lignocellulosic deconstruction. Herein we describe transformation of fast-growing transgenic hybrid poplar lines to produce 2-phenylethanol, this being an important fragrance, flavor, aroma, and commodity chemical. It is also readily converted into styrene or ethyl benzene, the latter being an important commodity aviation fuel component. Introducing this biochemical pathway into hybrid poplars marks the beginnings of developing a platform for a sustainable chemical delivery system to afford this and other valuable specialty/commodity chemicals at the scale and cost needed. These modified plant lines mainly sequester 2-phenylethanol via carbohydrate and other covalently linked derivatives, thereby providing an additional advantage of effective storage until needed. The future potential of this technology is discussed. MALDI metabolite tissue imaging also established localization of these metabolites in the leaf vasculature.
Article title: Marine Sediment-Derived Streptomyces Bacteria from British Columbia, Canada Are a Promising Microbiota Resource for the Discovery of Antimicrobial Natural Products
Authors: Doralyn S. Dalisay, David E. Williams, Xiao Ling Wang, Ryan Centko, et al.
Publication title: PLoS One 8(10): e77078, October 2013
Abstract:
Representatives of the genus Streptomyces from terrestrial sources have been the focus of intensive research for the last four decades because of their prolific production of chemically diverse and biologically important compounds. However, metabolite research from this ecological niche had declined significantly in the past years because of the rediscovery of the same bioactive compounds and redundancy of the sample strains. More recently, a new picture has begun to emerge in which marine-derived Streptomyces bacteria have become the latest hot spot as new source for unique and biologically active compounds. Here, we investigated the marine sediments collected in the temperate cold waters from British Columbia, Canada as a valuable source for new groups of marine-derived Streptomyces with antimicrobial activities. We performed culture dependent isolation from 49 marine sediments samples and obtained 186 Streptomyces isolates, 47 of which exhibited antimicrobial activities. Phylogenetic analyses of the active isolates resulted in the identification of four different clusters of bioactive Streptomyces including a cluster with isolates that appear to represent novel species. Moreover, we explored whether these marine-derived Streptomyces produce new secondary metabolites with antimicrobial properties. Chemical analyses revealed structurally diverse secondary metabolites, including four new antibacterial novobiocin analogues. We conducted structure-activity relationships (SAR) studies of these novobiocin analogues against methicillin-resistant Staphylococcus aureus (MRSA). In this study, we revealed the importance of carbamoyl and OMe moieties at positions 3" and 4" of novobiose as well as the hydrogen substituent at position 5 of hydroxybenzoate ring for the anti-MRSA activity. Changes in the substituents at these positions dramatically impede or completely eliminate the inhibitory activity of novobiocins against MRSA.
Article title: N-Carbamoylation of 2,4-Diaminobutyrate Reroutes the Outcome in Padanamide Biosynthesis
Authors: Yi-Ling Du, Doralyn S. Dalisay, Raymond J. Andersen, Katherine S. Ryan
Publication title: Chemistry & Biology 20(8): 1002-1011, August 2013
Abstract:
Padanamides are linear tetrapeptides notable for the absence of proteinogenic amino acids in their structures. In particular, two unusual heterocycles, (S)-3-amino-2-oxopyrrolidine-1-carboxamide (S-Aopc) and (S)-3-aminopiperidine-2,6-dione (S-Apd), are found at the C-termini of padanamides A and B, respectively. Here we identify the padanamide biosynthetic gene cluster and carry out systematic gene inactivation studies. Our results show that padanamides are synthesized by highly dissociated hybrid nonribosomal peptide synthetase/polyketide synthase machinery. We further demonstrate that carbamoyltransferase gene padQ is critical to the formation of padanamide A but dispensable for biosynthesis of padanamide B. Biochemical investigations show that PadQ carbamoylates the rare biosynthetic precursor l-2,4-diaminobutyrate, generating l-2-amino-4-ureidobutyrate, the presumed precursor to the C-terminal residue of padanamide A. By contrast, the C-terminal residue of padanamide B may derive from glutamine. An unusual thioesterase-catalyzed cyclization is proposed to generate the S-Aopc/S-Apd heterocycles.
Article title: Nahuoic Acid A Produced by a Streptomyces sp Isolated From a Marine Sediment Is a Selective SAM-Competitive Inhibitor of the Histone Methyltransferase SETD8
Authors: David E. Williams, Doralyn S. Dalisay, Fengling Li, James Amphlett, et al.
Publication title: Organic Letters 15(2): 414-417, January 2013
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.
Article title: Tyrocidine a from a haliclona sponge derived Vibrio sp
Authors: J. Noro, John A Kalaitzis, De Williams, Doralyn S. Dalisay, et al.
Publication title: Planta Medica 78(11): 174, July 2012
Abstract:
Taxonomically diverse, sponge-associated microbial communities represent a rich source of potentially novel and bioactive natural products. In our search for bioactive compounds from sponge-associated microbes we isolated and identified a Vibrio sp. from a sample of Haliclona collected from Milne Bay, Papua New Guinea. The Vibrio strain was selected for further investigation on the basis of testing positive for the presence of non-ribosomal peptide synthetase (NRPS) coding genes in our PCR-based screen. Chemical investigation of this Vibrio sp. resulted in the isolation and identification of the NRPS product tyrocidine A, and its decapeptide structure was confirmed by 1D and 2D NMR. Tyrocidine A displayed moderate activity against methicillin resistant S. aureus, E. coli and P. aeruginosa. The discovery of tyrocidine A from a marine Vibrio sp is intriguing from a microbiological viewpoint as it has long been known to be a product of the Gram-positive, soil-dwelling and spore forming Bacillus spp. Aspects of this, and the notion that the marine environment is a largely untapped source of bioactive natural products will be presented.
Full text available upon request to the author
Article title: Liposomal circular dichroism. Assignment of remote stereocenters in plakinic acids K and L from a Plakortis-Xestospongia sponge association
Authors: Doralyn S. Dalisay, Tim Quach, Tadeusz F. Molinski
Publication title: Organic Letters 12(7): 1524-27, April 2010
Abstract:
Two new omega-phenyl polyketide peroxides, plakinic acids K and L, were isolated from a two-sponge association of Plakortis halichondroides and Xestospongia deweerdtae. The absolute configurations of the remote dimethyl-branched stereocenters in plakinic acid K were assigned by degradation of plakinic acid K to a long-chain naphthamide and analysis by liposomal circular dichroism (L-CD) and comparison with synthetic standards.
Article title: Padanamides A and B, Highly Modified Linear Tetrapeptides Produced in Culture by a Streptomyces sp Isolated from a Marine Sediment
Authors: David. E. Williams, Doralyn S. Dalisay, Brian O. Patrick, Teatulohi Matainaho, et al.
Publication title: Organic Letters 13(15): 3936-3939, August 2011
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.
Article title: Ptilomycalin A inhibits laccase and melanization in Cryptococcus neoformans
Authors: Doralyn S. Dalisay, Jonel P. Saludes, Tadeusz F. Molinski
Publication title: Bioorganic & Medicinal Chemistry 19(22): 6654-57, November 2011
Abstract:
The antifungal spirocyclic guanidine alkaloid, ptilomycalin A, from marine sponge Monanchora arbuscula, inhibits melanogenesis of Cryptococcus neoformans in vitro through inhibition of biosynthesis of laccase in the melanin biosynthetic pathway with an IC(50) of 7.3 μM.
Article title: Use of Experimental Design for the Optimization of the Production of New Secondary Metabolites by Two Penicillium Species
Authors: Eli F. Pimenta, Aline M. Vita-Marques, Aristeu Tininis, Mirna H. R. Seleghim, et al.
Publication title: Journal of Natural Products 73(11): 1821-32, November 2010
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.
Article title: Synthesis and Chain-Dependent Antifungal Activity of Long-Chain 2H-Azirine-Carboxylate Esters Related to Dysidazirine
Authors: Colin K. Skepper, Doralyn S. Dalisay, Tadeusz F. Molinski
Publication title: Bioorganic & Medicinal Chemistry 20(6): 2029-32, March 2010
Abstract:
Analogues of the antifungal marine natural product (E)-dysidazirine were prepared and evaluated in broth ro-dilution assays against a panel of fungal pathogens. A simple structure-activity relationship was developed which provides insight into the mechanism of action of long-chain 2H-azirine carboxylates.
Article title: Structure Elucidation at the Nanomole Scale. 3. Phorbasides G-I from Phorbas sp.
Authors: Doralyn S. Dalisay and Tadeusz F. Molinski
Publication title: Journal of Natural Products 73(4): 679-682, April 2010
Abstract:
Three new phorbasides (G-I), chlorocyclopropyl ene-yne macrolide glycosides, were isolated from the sponge Phorbas sp. in yields of 7-9.5 mug and fully characterized by MS, CD, and microcryoprobe NMR. The structures of the new compounds differ only in the nature of the sugar residues. The absolute configurations of the new compounds were correlated by ROESY and CD with the parent compounds phorbasides A and B.
Article title: Zwittermicin A: Synthesis of Analogs and Structure-Activity Studies
Authors: Evan W. Rogers, Doralyn S. Dalisay, Tadeusz F. Molinski
Publication title: Bioorganic & Medicinal Chemistry 20(7): 2183-85, April 2010
Abstract:
Analogs and diastereomers of the natural product zwittermicin A were prepared. SAR studies of these compounds reveal the antifungal activity to be dependent singularly upon the natural constitution and configuration.
Article title: Hemi-phorboxazole a: structure confirmation, analogue design and biological evaluation
Authors: Amos B. Smith III, Zhuqing Liu, Anne-Marie L Hogan, Doralyn S. Dalisay, et al.
Publication title: Organic Letters 11(16): 3766-9, August 2009
Abstract:
A synthesis providing totally synthetic (+)-hemi-phorboxazole A (1), proceeding in two steps (85% yield) from known vinyl iodide precursor (+)-2, has been achieved in conjunction with the design, synthesis, and biological evaluation of two hemi-phorboxazole analogues [(+)-3 and (-)-4] featuring ring replacements inscribed within the macrolide. Although hemi-phorboxazole A (1) displayed no activity when tested against Candida albicans and two human cancer cell lines, analogue (-)-4 exhibited significant tumor cell growth inhibitory activity in the nanomolar range against HCT-116 (colon) and SK-BR-3 (breast), while (+)-3 displayed promising antifungal activity against C. albicans.
Article title: Isorhizochalin: a Minor Unprecedented Bipolar Sphingolipid of Stereodivergent Biogenesis from the Rhizochalina incrustata
Authors: Tatyana N. Makarieva, Alexander M. Zakharenko, Pavel S. Dmitrenok, Alla G. Guzii, et al.
Publication title: Lipids 44(12): 1152-62, December 2009
Abstract:
Isorhizochalin (1) was isolated as its peracetate from the EtOH extract of the sponge Rhizochalina incrustata. Its structure and absolute stereochemistry were elucidated as (2S,3R,26R,27R)-2,27-diamino-3-O-beta-D: -galactopyranosyl-oxy-26-hydroxyoctacosan-18-one by extensive NMR, MS studies, chemical transformations, including micromolar-scale Baeyer-Villiger oxidation, and by analysis of CD spectra of isorhizochalinin perbenzoate (2b). Isorhizochalin is an unprecedented C-2 epimer of rhizochalin having an erythro configuration at the glycosylated 2-amino-3-alkanol alpha-terminus in contrast with a canonical threo configuration for other representatives of this structural group. Probable biogenesis of 1 is discussed in the context of known sphingolipid biosynthesis beginning with condensation of alanine with a fatty acyl CoA thioester. The aglycone, isorhizochalinin (2a), shows cytotoxicity against human leukemia HL-60 and THP-1 cells with IC(50) values of 2.90 and 2.20 microM, respectively.
Full text available upon request to the author
Article title: Structure elucidation at the nanomole scale. 2. Hemi-phorboxazole A from Phorbas sp
Authors: Doralyn S. Dalisay and Tadeusz F. Molinski
Publication title: Organic Letters 11(9): 1969-70, May 2009
Abstract:
Hemi-phorboxazole A, a minor truncated analogue of phorboxazole A from the marine sponge Phorbas sp., was isolated in a total yield of 16.5 microg (28 nmol). The structure was elucidated by application of integrated nanomole-scale natural product techniques, including cryomicroprobe NMR, (1)H-coupled HSQC, and circular dichroism (CD).
Article title: Synthesis and Structure-Activity Relationships of Bengazole A Analogs
Authors: Roger J. Mulderc, Cynthia M. Shaferc, Doralyn S. Dalisay, Tadeusz F. Molinski
Publication title: Bioorganic & Medicinal Chemistry 19(11): 1928-2930, June 2009
Abstract:
Analogs of the potent antifungal agent, bengazole A, were prepared and evaluated against Candida spp. in both microbroth dilution and disk diffusion assays.
Full text available upon request to the author
Article title: Amplification of the Cotton effect of a single chromophore through liposomal ordering-stereochemical assignment of plakinic acids I and J
Authors: Doralyn S. Dalisay, Tim Quach, Gillian N. Nicholas, Tadeusz F. Molinski
Publication title: Angewandte Chemie (International ed. in English) 48(24): 4367-71, 2009
Abstract:
A dramatic effect is observed when acyclic N-(2-naphthamides) of medium-chain 1-amino-2-methylalkanes are partially ordered with the help of liposomes: the Cotton effect arising from pi-pi* transitions of the terminal naphthamide chromophor is enormously enhanced. This effect was exploited to assign the configuration of new polyketide peroxides such as 1 from the sponge Plakortis halichondroides.
Article title: A Tetrachloro Polyketide Hexahydro-1H-isoindolone, Muironolide A, from the Marine Sponge Phorbas sp Natural Products at the Nanomole Scale
Authors: Doralyn S. Dalisay, Brandon I. Morinaka, Colin K. Skepper, Tadeusz F. Molinski
Publication title: Journal of the American Chemical Society 131(22): 7552-3, June 2009
Abstract:
Muironolide A, a new chemical entity with an unprecedented chlorinated hexahydro-1H-isoindolone skeleton, was isolated in only 90 microg yield from the same marine sponge, Phorbas sp. that also provided phorboxazoles A and B. The structure was solved by interpretation of NMR data obtained at 600 MHz with a 1.7 mm cryo-microprobe in combination with FTMS, exciton coupled CD, and stereochemical correlation with authentic standards prepared by Reformatsky reaction of (-)-(1R,2S)-2-chloro-1-cyclopropanecarboxaldehyde. The absolute configuration of the chlorocyclopropane ring in 1 is opposite to that of co-occurring phorbasides A-F. Muironolide A is the first described macrolide bearing an esterified trichloromethyl carbinol, and may be produced by a cyanobacterium that also makes phorbasides.
Article title: NMR Quantitation of Natural Products at the Nanomole Scale
Authors: Doralyn S. Dalisay and Tadeusz F. Molinski
Publication title: Journal of Natural Products 72(4): 739-44, April 2009
Abstract:
We describe a simple and accurate method for quantitation by solvent 13C-satellites (QSCS) of very small amounts of natural products using microprobe NMR spectroscopy. The method takes advantage of integration of 13C satellite peaks of deuterated solvents, in particular CDCl3, that have favorable intensities for measurements of samples in NMR microcoils and microprobe tubes in the 1-200 nanomole range.
Article title: Structure Elucidation at the Nanomole Scale. 1. Trisoxazole Macrolides and Thiazole-Containing Cyclic Peptides from the Nudibranch Hexabranchus sanguineus
Authors: Doralyn S. Dalisay, Evan W. Rogers, Arthur S. Edison, Tadeusz F. Molinski
Publication title: Journal of Natural Products 72(4): 732-8, April 2009
Abstract:
A single specimen of Hexabranchus sanguineus, a nudibranch from the Indo-Pacific that is known to sequester kabiramides B and C and other trisoxazole macrolides, yielded new kabiramide analogues, 9-desmethylkbiramide B and 33-methyltetrahydrohalichondramide, and two new unexpected thiazole-containing cyclic peptides in submicromolar amounts. The structures of these cyclic peptides were determined by analyses of 1D and 2D NMR spectra recorded with a state-of-the-art 1 mm (1)H NMR high-temperature superconducting microcryoprobe, together with mass spectra. In addition to two proline residues, each peptide contains a thiazole- or oxazole-modified amino acid residue, together with conventional amino acid residues. All of the amino acid residues were l, as determined by Marfey's analysis of the acid hydrolysates of the peptides. This is the first report of cyclic thiazole peptides from H. sanguineus. Since thiazole-oxazole-modified peptides are typically associated with cyanobacteria and tunicates, the finding may imply a dietary component of the H. sanguineus that was previously overlooked.
Article title: Absolute configuration of the alpha,omega-bifunctionalized sphingolipid leucettamol A from Leucetta microrhaphis by deconvoluted exciton coupled CD
Authors: Doralyn S. Dalisay, Sachiko Tsukamoto, Tadeusz F. Molinski
Publication title: Journal of Natural Products 72(3): 353-9, March 2009
Abstract:
The configuration of leucettamol A (1), a known long-chain "two-headed" sphingolipid (dimeric sphingolipid) from the marine sponge Leucetta microrhaphis, was determined by conversion to an N,N',O,O'-tetrabenzoyl derivative, measurement of the exciton coupled circular dichroism spectrum (ECCD), and quantitative analysis by deconvolution of superposed exciton couplets. Contrary to the earlier assignment that claimed leucettamol A (1) was racemic, the CD approach unambiguously reveals the natural product is chiral and optically active and displays pseudo-C(2) symmetry. The configuration of each end of the chain has erythro stereochemistry with an absolute configuration of 2R,3S,28S,29R. We show that deconvolution ECCD reliably predicts erythro versus threo vicinal amino alcohols in all cases with greater sensitivity (<5 nmol) compared to (1)H NMR J-based methods and provides verification of optical purity and unequivocal elucidation of absolute configuration in this difficult class of natural products.
Article title: (+)-Zwittermicin A: assignment of its complete configuration by total synthesis of the enantiomer and implication of D-serine in its biosynthesis
Authors: Evan W. Rogers, Doralyn S. Dalisay, Tadeusz F. Molinski
Publication title: Angewandte Chemie (International ed. in English) 47(42): 8086-9, 2008
Abstract:
No abstract available
Article title: Drug development from marine natural products
Authors: Tadeusz F. Molinski, Doralyn S. Dalisay, Sarah L. Lievens, Jonel P. Saludes
Publication title: Nature reviews. Drug discovery 8(1): 69-85, January 2009
Abstract:
Drug discovery from marine natural products has enjoyed a renaissance in the past few years. Ziconotide (Prialt; Elan Pharmaceuticals), a peptide originally discovered in a tropical cone snail, was the first marine-derived compound to be approved in the United States in December 2004 for the treatment of pain. Then, in October 2007, trabectedin (Yondelis; PharmaMar) became the first marine anticancer drug to be approved in the European Union. Here, we review the history of drug discovery from marine natural products, and by describing selected examples, we examine the factors that contribute to new discoveries and the difficulties associated with translating marine-derived compounds into clinical trials. Providing an outlook into the future, we also examine the advances that may further expand the promise of drugs from the sea.
Full text available upon request to the author
Article title: Synthesis and Antifungal Activity of (-)-(Z)-Dysidazirine
Authors: Colin K. Skepper, Doralyn S. Dalisay, Tadeusz F. Molinski
Publication title: Organic Letters 10(22): 5269-71, November 2008
Abstract:
A short, flexible synthesis of the marine natural product (2 R)-(Z)-dysidazirine (-)-1 has been completed. (-)-1 shows significant antifungal activity across a panel of seven human pathogens, whereas the structural analogue (-)-2, featuring a terminal tert-butyl group, is essentially inactive.
Article title: Analysis of the Pseudoalteromonas tunicata Genome Reveals Properties of a Surface-Associated Life Style in the Marine Environment
Authors: Torsten Thomas, Flavia F Evans, David Schleheck, Anne Mai-Prochnow, et al.
Publication title: PLoS One 3(9): e3252, September 2008
Abstract:
Colonisation of sessile eukaryotic host surfaces (e.g. invertebrates and seaweeds) by bacteria is common in the marine environment and is expected to create significant inter-species competition and other interactions. The bacterium Pseudoalteromonas tunicata is a successful competitor on marine surfaces owing primarily to its ability to produce a number of inhibitory molecules. As such P. tunicata has become a model organism for the studies into processes of surface colonisation and eukaryotic host-bacteria interactions.
Article title: A mannose-sensitive haemagglutinin (MSHA)-like pilus promotes attachment of Pseudoalteromonas tunicata cells to the surface of the green alga Ulva australis
Authors: Doralyn S. Dalisay, Jeremy S. Webb, André Scheffel, Charles Svenson, et al.
Publication title: Microbiology (Reading) 152(10): 2875-2883, October 2006
Abstract:
This study demonstrates that attachment of the marine bacterium Pseudoalteromonas tunicata to the cellulose-containing surface of the green alga Ulva australis is mediated by a mannose-sensitive haemagglutinin (MSHA-like) pilus. We have identified an MSHA pilus biogenesis gene locus in P. tunicata, termed msh/1/2JKLMNEGFBACDOPQ, which shows significant homology, with respect to its genetic characteristics and organization, to the MSHA pilus biogenesis gene locus of Vibrio cholerae. Electron microscopy studies revealed that P. tunicata wild-type cells express flexible pili peritrichously arranged on the cell surface. A P. tunicata mutant (SM5) with a transposon insertion in the mshJ region displayed a non-piliated phenotype. Using SM5, it has been demonstrated that the MSHA pilus promotes attachment of P. tunicata wild-type cells in polystyrene microtitre plates, as well as to microcrystalline cellulose and to the living surface of U. australis. P. tunicata also demonstrated increased pilus production in response to cellulose and its monomer constituent cellobiose. The MSHA pilus thus functions as a determinant of attachment in P. tunicata, and it is proposed that an understanding of surface sensing mechanisms displayed by P. tunicata will provide insight into specific ecological interactions that occur between this bacterium and higher marine organisms.
Full text available upon request to the author
Article title: Biofilm Development and Cell Death in the Marine Bacterium Pseudoalteromonas tunicata
Authors: Anne Mai-Prochnow, Flavia Evans, Doralyn S. Dalisay, Sacha Stelzer, et al.
Publication title: Applied and Environmental Microbiology 70(6): 3232-8, June 2004
Abstract:
The newly described green-pigmented bacterium Pseudoalteromonas tunicata (D2) produces target-specific inhibitory compounds against bacteria, algae, fungi, and invertebrate larvae and is frequently found in association with living surfaces in the marine environment. As part of our studies on the ecology of P. tunicata and its interaction with marine surfaces, we examined the ability of P. tunicata to form biofilms under continuous culture conditions within the laboratory. P. tunicata biofilms exhibited a characteristic architecture consisting of differentiated microcolonies surrounded by water channels. Remarkably, we observed a repeatable pattern of cell death during biofilm development of P. tunicata, similar to that recently reported for biofilms of Pseudomonas aeruginosa (J. S. Webb et al., J. Bacteriol. 185:4585-4595, 2003). Killing and lysis occurred inside microcolonies, apparently resulting in the formation of voids within these structures. A subpopulation of viable cells was always observed within the regions of killing in the biofilm. Moreover, extensive killing in mature biofilms appeared to result in detachment of the biofilm from the substratum. A novel 190-kDa autotoxic protein produced by P. tunicata, designated AlpP, was found to be involved in this biofilm killing and detachment. A Delta alpP mutant derivative of P. tunicata was generated, and this mutant did not show cell death during biofilm development. We propose that AlpP-mediated cell death plays an important role in the multicellular biofilm development of P. tunicata and subsequent dispersal of surviving cells within the marine environment.