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Kim, MC, Machado H, Jang KH, Trzoss L, Jensen PR, Fenical W.  2018.  Integration of genomic data with NMR analysis enables assignment of the full stereostructure of Neaumycin B, a potent inhibitor of glioblastoma from a marine-derived micromonospora. Journal of the American Chemical Society. 140:10775-10784.   10.1021/jacs.8b04848   AbstractWebsite

The microbial metabolites known as the macrolides are some of the most successful natural products used to treat infectious and immune diseases. Describing the structures of these complex metabolites, however, is often extremely difficult due to the presence of multiple stereogenic centers inherent in this class of polyketide-derived metabolites. With the availability of genome sequence data and a better understanding of the molecular genetics of natural product biosynthesis, it is now possible to use bioinformatic approaches in tandem with spectroscopic tools to assign the full stereostructures of these complex metabolites. In our quest to discover and develop new agents for the treatment of cancer, we observed the production of a highly cytotoxic macrolide, neaumycin B, by a marine-derived actinomycete bacterium of the genus Micromonospora. Neaumycin B is a complex polycyclic macrolide possessing 19 asymmetric centers, usually requiring selective degradation, crystallization, derivatization, X-ray diffraction analysis, synthesis, or other time-consuming approaches to assign the complete stereostructure. As an alternative approach, we sequenced the genome of the producing strain and identified the neaumycin gene cluster (neu). By integrating the known stereospecificities of biosynthetic enzymes with comprehensive NMR analysis, the full stereostructure of neaumycin B was confidently assigned. This approach exemplifies how mining gene cluster information while integrating NMR-based structure data can achieve rapid, efficient, and accurate stereostructural assignments for complex macrolides.

da Silva, RM, Guaratini T, Jimenez PC, Fenical W, Costa-Lotufo LV, Vessecchi R, Lopes NP.  2018.  Mass spectrometry analysis of protonated marine natural product seriniquinone. Journal of the Brazilian Chemical Society. 29:1162-1166.   10.21577/0103-5053.20180037   AbstractWebsite

Seriniquinone is a natural quinone isolated from a rare marine bacterium of the genus Serinicoccus. This secondary metabolite has been shown to have anticancer properties, which has raised attention of the scientific community. In this short report, we present the first investigation of the gas-phase chemistry fragmentation reactions of seriniquinone in electrospray ionization tandem mass spectrometry (ESI-MS/MS), to be further applied in pharmacokinetics and metabolism studies. All the proposals herein were supported by computational chemistry.

Puyana, M, Fenical W, Pawlik JR.  2003.  Are there activated chemical defenses in sponges of the genus Aplysina from the Caribbean? Marine Ecology-Progress Series. 246:127-135.   10.3354/meps246127   AbstractWebsite

The Mediterranean sponge Aplysina aerophoba has been proposed to rely on damage-induced activation of chemical defenses against pathogens and fish predators. High molecular weight brominated tyrosine derivatives have been suggested to undergo rapid, enzyme-mediated transformations into the metabolites aeroplysinin-1 and dibromocyclohexadienone following tissue damage, a process also called 'biotransformation'. These putative end-products were found to exhibit greater defensive activity compared to their precursors. Because sponges of the genus Aplysina possess similar chemical components worldwide, it has been suggested that the activation of chemical defenses is a common feature in this group. Herein, we report in situ and laboratory experiments conducted with living specimens of 2 species from the Caribbean, Aplysina insularis and A. archeri. Changes in sponge tissue secondary metabolites during time-course experiments were determined using diode-array high performance liquid chromatography coupled with mass spectrometry (LC-MS) analyses of extracts of flash frozen samples. We obtained no evidence of chemical transformation after tissue damage. In short (150 s) and long (30 and 120 min) time-course experiments, conversion of the major high molecular weight brominated constituents into the low molecular weight aeroplysinin-1 or dibromocyclohexadienone was not apparent: there was neither a reduction in the concentration of putative precursor metabolites, nor an increase in end products. Past observations of transformation may be the result of differential tissue extraction efficiency, hydrolysis from insoluble precursors or the heterogeneous distribution of metabolites in sponge tissue.

Kubanek, J, Hay ME, Brown PJ, Lindquist N, Fenical W.  2001.  Lignoid chemical defenses in the freshwater macrophyte Saururus cernuus. Chemoecology. 11:1-8.   10.1007/pl00001826   AbstractWebsite

Chemical defense against herbivores has rarely been investigated for freshwater plants, possibly due to the common misconception that herbivory on aquatic macrophytes is low and would not select for chemical defenses. In previous work, the freshwater angiosperm Saururus cernuus was shown to be a low preference food for omnivorous crayfish despite its high nutrient value and relatively soft texture. We used feeding by the crayfish Procambarus clarkii to guide fractionation of the deterrent lipid-soluble extract of this plant, leading to the identification of seven deterrent lignoid metabolites, (-)-licarin A, (+)-saucernetin, (-)-dihydroguaiaretic acid, (-)-sauriols A and B, (-)-saucerneol, and (-)-saucerneol methyl ether. Lignans have been implicated in terrestrial plant chemical defenses as insect growth inhibitors, insect toxins, nematocides, antibacterial, and antifungal agents. However, these activities have rarely been demonstrated using ecologically relevant methodologies in terrestrial systems, and never before in freshwater systems. The widespread nature of lignans amongst very distantly related plants, along with their rich diversity of molecular structure, suggests that they could play a large role in mediating plant-herbivore interactions. In addition to the lignoid compounds we identified, there were other compounds present in low concentration or unstable compounds that were deterrent, that did not appear to be lignans, but that we were unable to identify. This plant thus appears to be defended by a complex mixture of natural products.

Kubanek, J, Fenical W, Hay ME, Brown PJ, Lindquist N.  2000.  Two antifeedant lignans from the freshwater macrophyte Saururus cernuus. Phytochemistry. 54:281-287.   10.1016/s0031-9422(00)00076-5   AbstractWebsite

Two diarylbutane derivatives of dihydroguaiaretic acid have been isolated from emergent portions of the southeastern United States freshwater angiosperm Saururus cernuus L. (Saururaceae). Bioassay-guided fractionation of organic extracts of S. cermuus led to the compounds, sauriols A and B, in addition to five previously known lignoids. These metabolites deter feeding by the omnivorous crayfish Procambarus clarkii. The two lignans were identified by analysis of nuclear magnetic resonance and mass spectral data, and by comparison with spectral data of dihydroguaiaretic acid. (C) 2000 Elsevier Science Ltd. All rights reserved.

Bolser, RC, Hay ME, Lindquist N, Fenical W, Wilson D.  1998.  Chemical defenses of freshwater macrophytes against crayfish herbivory. Journal of Chemical Ecology. 24:1639-1658.   10.1023/a:1020816511924   AbstractWebsite

We measured feeding preferences of the crayfish Procambarus clarkii for fresh tissue from four species of freshwater macrophytes (Habenaria repens, Saururus cernuus, Ceratophyllum demersum and Typha angustifolia). We then determined the role of plant chemical defenses in generating these preferences by incorporating crude aqueous and organic extracts from each species into palatable foods and comparing feeding on these foods to feeding on control foods lacking these extracts. Tissue toughness, dry mass and ash-free mass per volume, and percentages of carbon, nitrogen, and phenolics were also measured for each of the four macrophytes. Although it had a low nutritional value, Ceratophyllum was the preferred food when it was offered as fresh tissue; it did not produce a chemically deterrent extract. The lipophilic crude extract from Typha significantly deterred crayfish feeding, but this highly nutritious plant was preferred when offered in an agar-based diet lacking structural defenses. Habenaria and Saururus were low preference foods that did not appear to be structurally defended; each species contained both lipophilic and water-soluble extracts that significantly deterred feeding. Fractionation of the lipophilic crude extract from Saururus indicated the presence of at least three deterrent compounds. From the orchid Habenaria, we isolated and identified a novel bis-p-hydroxybenzyl-2-alkyl-2-hydroxysuccinoate metabolite, habenariol, that appeared to explain most of the feeding deterrent activity present in the lipophilic extract of this species. The concentration of the metabolite in frozen collections of this plant doubled if we allowed the material to thaw before placing it in extraction solvents.

Montanari, AM, Fenical W, Lindquist N, Lee AY, Clardy J.  1996.  Volutamides A-E, halogenated alkaloids with antifeedant properties from the Atlantic bryozoan Amathia convoluta. Tetrahedron. 52:5371-5380.   10.1016/0040-4020(96)00188-3   AbstractWebsite

Volutamides A-E (1-5), halogenated alkaloids of amino acid origin, have been isolated from the temperate Atlantic bryozoan Amathia convoluta Lamouroux. The structures of the new compounds were determined by spectral and chemical methods. The absolute stereochemistries of volutamides B and C were established by CD measurements, while the absolute stereochemistries of volutamides D and E could not be established with confidence. Several of the volutamides deterred feeding by potential predators and were toxic toward larvae of a co-occurring hydroid, suggesting that these metabolites form the basis of an effective chemical defense. Copyright (C) 1996 Elsevier Science Ltd

Cronin, G, Hay ME, Fenical W, Lindquist N.  1995.  Distribution, density, and sequestration of host chemical defenses by the specialist nudibranch Tritonia hamnerorum found at high densities on the sea fan Gorgonia ventalina. Marine Ecology-Progress Series. 119:177-189.   10.3354/meps119177   AbstractWebsite

The dendronotid nudibranch Trotonia hamnerorum was observed on some reefs in the Florida Keys, USA, at very high densities during the summer of 1992. T. hamnerorum specializes on the sea fan Gorgonia rentalina and sequesters the furano-germacrene julieannafuran from its host; this compound effectively protects the nudibranch from consumption by the common predatory reef fish Thalassoma bifasciatum. T. hamnerorum densities were extremely high at some locations, with as many as 1700 nudibranchs found on a single G. ventalina colony. At high densities, nudibranch feeding killed large areas on some sea fan colonies by stripping all tissue from portions of the sea fan and allowing filamentous algae and other epibionts to colonize. The density of T. hamnerorum on G. ventalina varied greatly on scales of centimeters, meters and kilometers. High density patches of nudibranchs on individual sea fans were usually composed of equivalent-sized nudibranchs. These observations suggest that pelagic veligers have an incredible capability to find and settle synchronously on one portion of a sea fan or that the larvae or juveniles hatch from egg masses and develop without leaving the sea fan. This study adds to a growing number of marine examples suggesting that feeding specialization occurs primarily among small, sedentary consumers that deter or escape predators by associating with defended hosts.

Cronin, G, Lindquist N, Hay ME, Fenical W.  1995.  Effects of storage and extraction procedures on yields of lipophilic metabolites from the brown seaweeds Dictyota ciliolata and D. menstrualis. Marine Ecology-Progress Series. 119:265-273.   10.3354/meps119265   AbstractWebsite

Investigations focused on the ecological roles of marine secondary metabolites have become common, but marine ecologists have rarely assessed how methodologies used in sample preparation affect the extractability and stability of secondary metabolites and, thus, measurements of intraspecific and interspecific compound variance. We assessed various procedures for storing, drying, and extracting samples of 2 chemically defended brown seaweeds Dictyota ciliolata and D. menstrualis. These plants contain the diterpenoid alcohols pachydictyol A, dictyol B acetate, and dictyol E that are relatively stable under all test conditions. In contrast, the related diterpenoid dialdehyde, dictyodial, decomposed when plant tissues or crude extracts were stored at -25 degrees C for 13 to 27 wk or when tissues or extracts were freeze-dried or subjected to high vacuum (<0.01 torr), methods that are commonly used in studies of marine chemical ecology. The stability of dictyodial was species-specific, degrading more in D. ciliolata than in D. menstrualis. During a few extractions, dictyodial reacted with methanol (MeOH) to yield an artifact resulting from the addition of 2 molecules of MeOH per molecule of dictyodial. A mixture of 2:1 dichloromethane (DCM) and MeOH tended to extract the lipophilic secondary metabolites better than MeOH or DCM alone. Metabolites were also afforded some protection against degradation when fresh tissue was submerged in 2:1 DCM:MeOH during storage at -25 degrees C. Results of this investigation indicate that storage, extraction, and quantification methods need to be optimized for analyses of individual compounds and that even identical compounds can behave differently when they occur in different species.

Jensen, PR, Fenical W.  1994.  Strategies for the discovery of secondary metabolites from marine bacteria: ecological perspectives. Annual Review of Microbiology. 48:559-584.   10.1146/annurev.mi.48.100194.003015   AbstractWebsite

Marine-microorganisms have become an important point of study in the search for novel microbial products. Today, both academic and industrial interest in marine microorganisms is on the rise, in part-because of the growing number of unique, biologically active secondary metabolites reported from marine bacteria. Our ability to assess the biosynthetic potential of marine bacteria, however, is inevitably coupled to our basic understanding of their biology. This review summarizes the chemical discoveries and biological activities reported from marine bacteria and focuses upon several microbiological topics as they relate to natural product discovery, including the distributions, diversity, and culturability of marine bacteria, as well as the role of symbiotic bacteria in the production of substances previously ascribed to other sources.