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Castro-Falcon, G, Millan-Aguinaga N, Roullier C, Jensen PR, Hughes CC.  2018.  Nitrosopyridine probe to detect polyketide natural products with conjugated alkenes: Discovery of novodaryamide and nocarditriene. Acs Chemical Biology. 13:3097-3106.   10.1021/acschembio.8b00598   AbstractWebsite

An optimized nitroso-based probe that facilitates the discovery of conjugated alkene-containing natural products in unprocessed extracts was developed. It chemoselectively reacts with conjugated olefins via a nitroso-Diels-Alder cyclization to yield derivatives with a distinct chromophore and an isotopically unique bromine atom that can be rapidly identified using liquid chromatography/mass spectrometry and a bioinformatics tool called MeHaloCoA (Marine Halogenated Compound Analysis). The probe is ideally employed when genome-mining techniques identify strains containing polyketide gene clusters with two or more repeating KS-AT-DH-KR-ACP domain sequences, which are required for the biosynthesis of conjugated alkenes. Comparing the reactivity and spectral properties of five brominated arylnitroso reagents with model compounds spiramycin, bufalin, rapamycin, and rifampicin led to the identification of 5-bromo-2-nitrosopyridine as the most suitable probe structure. The utility of the dienophile probe was then demonstrated in bacterial extracts. Tylactone, novodaryamide and daryamide A, piperazimycin A, and the saccharamonopyrones A and B were cleanly labeled in extracts from their respective bacterial producers, in high regioselectivity but with varying degrees of diastereoselectivity. Further application of the method led to the discovery of a new natural product called nocarditriene, containing an unprecedented epoxy-2,3,4,5-tetrahydropyridine structure, from marine-derived Nocardiopsis strain CNY-503.

Cheng, XC, Jensen PR, Fenical W.  1999.  Luisols A and B, new aromatic tetraols produced by an estuarine marine bacterium of the genus Streptomyces (Actinomycetales). Journal of Natural Products. 62:608-610.   10.1021/np980415m   AbstractWebsite

Luisols A (1) and B (2), two new aromatic tetraols, have been isolated from the cultivation broth of an estuarine marine actinomycete of the genus Streptomyces (strain #CNH-370). The structures of luisols A and B were assigned by combined spectroscopic methods, including extensive 2D NMR experiments. Luisol A appears related to the anthraquinone antibiotics of the granaticin class, while the structure of luisol B contains the rare epoxynaphtho[2,3c]furan, a structural feature found in only one natural product, the fungal metabolite anthrinone.

Cheng, YB, Jensen PR, Fenical W.  2013.  Cytotoxic and antimicrobial napyradiomycins from two marine-derived streptomyces strains. European Journal of Organic Chemistry. :3751-3757.   10.1002/ejoc.201300349   AbstractWebsite

The cancer-cell-cytotoxicity-guided fractionation of the acetone extracts of two cultured marine-derived Streptomyces strains belonging to the MAR4 group yielded six new napyradiomycins, compounds A-F (1-6), together with three known compounds, napyradiomycins B2-B4 (7-9). Napyradiomycins 1-4 are new members of the napyradiomycin C-type meroterpenoids, which possess a linear monoterpene bridge between C-7 and C-10a. Compound 4 has an additional tetrahydropyran ring fused to the phenol moiety. Compounds 5-9 are related to the napyradiomycin B-type meroterpenoids. The structures of all new compounds were assigned by interpretation of 1D and 2D NMR, MS, and other spectroscopic data. The relative configurations were assigned based upon interpretation of ROESY 2D NMR experiments. The cytotoxicity of 1-9 against the human colon carcinoma cell line HCT-116 and their antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA) are presented.

Cheng, XC, Jensen PR, Fenical W.  1999.  Arenaric acid, a new pentacyclic polyether produced by a marine bacterium (Actinomycetales). Journal of Natural Products. 62:605-607.   10.1021/np9801357   AbstractWebsite

Arenaric acid (Pa), a new pentacyclic polyether related to the antibiotics K-41A and oxolonomycin, was isolated as its sodium salt (Ib) from the culture broth of an estuarine bacterial isolate of the genus Streptomyces. The structure of arenaric acid was established by spectroscopic methods involving comprehensive 2D NMR measurements.

Cho, JY, Kwon HC, Williams PG, Jensen PR, Fenical W.  2006.  Azamerone, a terpenoid phthalazinone from a marine-derived bacterium related to the genus Streptomyces (actinomycetales). Organic Letters. 8:2471-2474.   10.1021/ol060630r   AbstractWebsite

A novel meroterpenoid, azamerone, was isolated from the saline culture of a new marine-derived bacterium related to the genus Streptomyces. Azamerone is composed of an unprecedented chloropyranophthalazinone core with a 3-chloro-6-hydroxy-2,2,6-trimethylcyclohexylmethyl side chain. The structure was rigorously determined by NMR spectroscopy and X-ray crystallography. A possible biosynthetic origin of this unusual ring system is proposed.

Cho, JY, Kwon HC, Williams PG, Kauffman CA, Jensen PR, Fenical W.  2006.  Actinofuranones A and B, polyketides from a marine-derived bacterium related to the genus Streptomyces (Actinomycetales). Journal of Natural Products. 69:425-428.   10.1021/np050402q   AbstractWebsite

Two new polyketides, actinofuranones A (1) and B (2), were isolated from the culture extract of a marine-derived Streptomyces strain designated CNQ766. The structures of 1 and 2 were elucidated by interpretation of NMR and other spectroscopic data and by chemical derivatization. The relative stereochemistries of these new molecules were assigned on the basis of analysis of NOE data and vicinal H-1-H-1 coupling constants, while the absolute configurations of the asymmetric centers were determined using the modified Mosher's method.

Cho, JY, Williams PG, Kwon HC, Jensen PR, Fenical W.  2007.  Lucentamycins A-D, cytotoxic peptides from the marine-derived actinomycete Nocardiopsis lucentensis. Journal of Natural Products. 70:1321-1328.   10.1021/np070101b   AbstractWebsite

Four new 3-methyl-4-ethylideneproline-containing peptides, lucentamycins A-D (1-4), have been isolated from the fermentation broth of a marine-derived actinomycete identified by phylogenetic methods as Nocardiopsis lucentensis (strain CNR-712). The planar structures of the new compounds were assigned on the basis of 1D and 2D NMR spectroscopic techniques, while the absolute configurations of the amino acid residues were determined by application of the advanced Marfey method. Lucentamycins A (1) and B (2) showed significant in vitro cytotoxicity against HCT-116 human colon carcinoma.

Choi, EJ, Beatty DS, Paul LA, Fenical W, Jensen PR.  2013.  Mooreia alkaloidigena gen. nov., sp nov and Catalinimonas alkaloidigena gen. nov., sp nov., alkaloid-producing marine bacteria in the proposed families Mooreiaceae fam. nov and Catalimonadaceae fam. nov in the phylum Bacteroidetes. International Journal of Systematic and Evolutionary Microbiology. 63:1219-1228.   10.1099/ijs.0.043752-0   AbstractWebsite

Bacterial strains CNX-216(T) and CNU-914(T) were isolated from marine sediment samples collected from Palmyra Atoll and off Catalina Island, respectively. Both strains were Gram-negative and aerobic and produce deep-orange to pink colonies and alkaloid secondary metabolites. Cells of strain CNX-216(T) were short, non-motile rods, whereas cells of strain CNU-914(T) were short, curved rods with gliding motility. The DNA G + C contents of CNX-216(T) and CNU-914(T) were respectively 57.7 and 44.4 mol%. Strains CNX-216(T) and CNU-914(T) contained MK-7 as the predominant menaquinone and iso-C-15:0 and C-(16:1)omega 5c as the major fatty acids. Phylogenetic analyses revealed that both strains belong to the order Cytophagales in the phylum Bacteroicletes. Strain CNX-216(T) exhibited low 16S rRNA gene sequence identity (87.1 %) to the nearest type strain, Cesiribacter roseus 311(T), and formed a well-supported lineage that is outside all currently described families in the order Cytophagales. Strain CNU-914(T) shared 97.6% 16S rRNA gene sequence identity with 'Porifericola rhodea' N5EA6-3A2B and, together with 'Tunicatimonas pelagia' N5DB8-4 and four uncharacterized marine bacteria isolated as part of this study, formed a lineage that is clearly distinguished from other families in the order Cytophagales. Based on our polyphasic taxonomic characterization, we propose that strains CNX-216(T) and CNU-914(T) represent novel genera and species, for which we propose the names Mooreia alkaloidigena gen. nov., sp. nov. (type strain CNX-216(T) =DSM 25187(T) =KCCM 90102(T)) and Catalinimonas alkaloidigena gen. nov., sp. nov. (type strain CNU-914(T) =DSM 25186(T) =KCCM 90101(T)) within the new families Mooreiaceae fam. nov. and Catalimonadaceae fam. nov.

Choi, EJ, Nam SJ, Paul L, Beatty D, Kauffman CA, Jensen PR, Fenical W.  2015.  Previously uncultured marine bacteria linked to novel alkaloid production. Chemistry & Biology. 22:1270-1279.   10.1016/j.chembiol.2015.07.014   AbstractWebsite

Low-nutrient media and long incubation times facilitated the cultivation of 20 taxonomically diverse Gram-negative marine bacteria within the phyla Bacteroidetes and Proteobacteria. These strains comprise as many as three new families and include members of clades that had only been observed using culture-independent techniques. Chemical studies of the type strains representing two new families within the order Cytophagales led to the isolation of nine new alkaloid secondary metabolites that can be grouped into four distinct structure classes, including azepinones, aziridines, quinolones, and pyrazinones. Several of these compounds possess antibacterial properties and appear, on structural grounds, to be produced by amino acid-based biosynthetic pathways. Our results demonstrate that relatively simple cultivation techniques can lead to the isolation of new bacterial taxa that are capable of the production of alkaloid secondary metabolites with antibacterial activities. These findings support continued investment in cultivation techniques as a method for natural product discovery.

Crusemann, M, O'Neill EC, Larson CB, Melnik AV, Floros DJ, da Silva RR, Jensen PR, Dorrestein PC, Moore BS.  2017.  Prioritizing natural product diversity in a collection of 146 bacterial strains based on growth and extraction protocols. Journal of Natural Products. 80:588-597.   10.1021/acsjnatprod.6b00722   AbstractWebsite

In order to expedite the rapid and efficient discovery and isolation of novel specialized metabolites, while minimizing the waste of resources on rediscovery of known compounds, it is crucial to develop efficient approaches for strain prioritization, rapid dereplication, and the assessment of favored cultivation and extraction conditions. Herein we interrogated bacterial strains by systematically evaluating cultivation and extraction parameters with LC-MS/MS analysis and subsequent dereplication through the Global Natural Product Social Molecular Networking (GNPS) platform. The developed method is fast, requiring minimal time and sample material, and is compatible with high throughput extract analysis, thereby streamlining strain prioritization and evaluation of culturing parameters. With this approach, we analyzed 146 marine Salinispora and Streptomyces strains that were grown and extracted using multiple different protocols. In total, 603 samples were analyzed, generating approximately 1.8 million mass spectra. We constructed a comprehensive molecular network and identified 15 molecular families of diverse natural products and their analogues. The size and breadth of this network shows statistically supported trends in molecular diversity when comparing growth and extraction conditions. The network provides an extensive survey of the biosynthetic capacity of the strain collection and a method to compare strains based on the variety and novelty of their metabolites. This approach allows us to quickly identify patterns in metabolite production that can be linked to taxonomy, culture conditions, and extraction methods, as well as informing the most valuable growth and extraction conditions.

Cueto, M, MacMillan JB, Jensen PR, Fenical W.  2006.  Tropolactones A-D, four meroterpenoids from a marine-derived fungus of the genus Aspergillus. Phytochemistry. 67:1826-1831.   10.1016/j.phytochem.2006.01.008   AbstractWebsite

Four cytotoxic meroterpenoids, tropolactones A-D, were isolated from the whole broth extract of a marine-derived fungus of the genus Aspergillus. The structures of the meroterpenoids were established through a variety of two-dimensional NMR techniques. The absolute configuration of tropolactone A was determined using the modified Mosher method. Tropolactones A-C contain an interesting substituted 2,4,6-cycloheptatriene (tropone) ring, which presumably arises through an oxidative ring expansion from tropolactone D. Tropolactones A, B and C showed in vitro cytotoxicity against human colon carcinoma (HCT-116) with IC50 values of 13.2, 10.9 and 13.9 mu g/mL. (c) 2006 Published by Elsevier Ltd.

Cueto, M, Jensen PR, Fenical W.  2002.  Aspergilloxide, a novel sesterterpene epoxide from a marine-derived fungus of the genus Aspergillus. Organic Letters. 4:1583-1585.   10.1021/ol0258076   AbstractWebsite

A new sesterterpene epoxide-diol, aspergilloxide (1), was isolated from the extract of a cultured marine-derived fungus (strain CNM-713) identified as an undescribed member of the genus Aspergillus. The structure of 1 was determined by interpretation of NMR data and by chemical methods. The absolute stereochemistry of aspergilloxide was assigned by application of the modified Mosher method. The carbon skeleton of 1 represents a new addition to the architectural diversity of the sesterterpenoid (C-25) class of secondary metabolites.

Cueto, M, Jensen PR, Fenical W.  2000.  N-methylsansalvamide, a cytotoxic cyclic depsipeptide from a marine fungus of the genus Fusarium. Phytochemistry. 55:223-226.   10.1016/s0031-9422(00)00280-6   AbstractWebsite

N-Methylsansalvamide (1), a new cyclic depsipeptide. was isolated from extracts of a cultured marine fungus, strain CNL-619, identified as a member of the genus Fusarium. N-Methylsansalvamide exhibits weak in vitro cytotoxicity in the NCI human tumor cell line screen (GI(50) 8.3 muM). The structure of 1 was determined by combined spectral and chemical methods. (C) 2000 Elsevier Science Ltd. All rights reserved.

Cueto, M, Jensen PR, Kauffman C, Fenical W, Lobkovsky E, Clardy J.  2001.  Pestalone, a new antibiotic produced by a marine fungus in response to bacterial challenge. Journal of Natural Products. 64:1444-1446.   10.1021/np0102713   AbstractWebsite

The isolation and structure determination of a new chlorinated benzophenone antibiotic, pestalone (1), is described. The new compound was produced by a cultured marine fungus only when a unicellular marine bacterium, strain CNJ-328, was co-cultured in the fungal fermentation. The fungus, isolated from the surface of the brown alga Rosenvingea sp. collected in the Bahamas Islands, was identified as an undescribed member of the genus Pestalotia. The structure of 1, initially assigned with only modest confidence by combined spectral and chemical data, was confirmed by single-crystal X-ray analysis. Pestalone (1) exhibits moderate in vitro cytotoxicity in the National Cancer Institute's 60 human tumor cell line screen (mean GI(50) = 6.0 muM). More importantly, pestalone shows potent antibiotic activity against methicillin-resistant Staphylococcus aureus (MIC = 37 ng/mL) and vancomycin-resistant Enterococcus faecium (MIC = 78 ng/mL), indicating that pestalone should be evaluated in advanced models of infectious disease.