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Shang, Z, Winter JM, Kauffman CA, Yang I, Fenical W.  2019.  Salinipeptins: Integrated genomic and chemical approaches reveal unusual D-amino acid-containing ribosomally synthesized and post-translationally modified peptides (RiPPs) from a Great Salt Lake Streptomyces sp. Acs Chemical Biology. 14:415-425.   10.1021/acschembio.8b01058   AbstractWebsite

Analysis of the full genome of an environmentally unique, halotolerant Streptomyces sp. strain GSL-6C, isolated from the Great Salt Lake, revealed a gene cluster encoding the biosynthesis of the salinipeptins, D-amino-acid containing members of the rare linaridin subfamily of ribosomally synthesized and post-translationally modified peptides (RiPPs). The sequence organization of the unmodified amino acid residues in salinipeptins A D (1-4) were suggested by genome annotation, and subsequently, their sequence and post-translational modifications were defined using a range of spectroscopic techniques and chemical derivatization approaches. The salinipeptins are unprecedented linaridins bearing nine D-amino acids, which are uncommon in RiPP natural products and are the first reported in the linaridin subfamily. Whole genome mining of GSL-6C did not reveal any homologues of the reported genes responsible for amino acid epimerization in RiPPs, inferring new epimerases may be involved in the conversion of L- to D-amino acids. In addition, the N-oxide and dimethylimidazolidin-4-one moieties in salinipeptins B and C, which are modified from N,N-dimethylalanine, are unknown in bacterial peptides. The three-dimensional structure of salinipeptin A, possessing four loops generated by significant hydrogen bonding, was established on the basis of observed nuclear Overhauser effect (NOE) correlations. This study demonstrates that integration of genomic information early in chemical analysis significantly facilitates the discovery and structure characterization of novel microbial secondary metabolites.

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.

Leutou, AS, Yang IH, Le TC, Hahn D, Lim KM, Nam SJ, Fenical W.  2018.  Fluvirucin B6, a new macrolactam isolated from a marine-derived actinomycete of the genus Nocardiopsis. Journal of Antibiotics. 71:609-612.   10.1038/s41429-018-0033-3   AbstractWebsite

A new 14-membered macrolactam natural product, fluvirucin B6 (1), was isolated from a marine-derived actinomycete, Nocardiopsis sp. CNQ-115, via HPLC-UV guided isolation. The chemical structure of 1 was elucidated by 1D and 2D NMR spectroscopic data analysis. Compound 1 showed a weak activity against Gram-positive bacteria, whereas it was inactive against Gram-negative bacteria.

Awakawa, T, Crusemann M, Munguia J, Ziemert N, Nizet V, Fenical W, Moore BS.  2015.  Salinipyrone and pacificanone are biosynthetic by-products of the rosamicin polyketide synthase. Chembiochem. 16:1443-1447.   10.1002/cbic.201500177   AbstractWebsite

Salinipyrones and pacificanones are structurally related polyketides from Salinispora pacifica CNS-237 that are proposed to arise from the same modular polyketide synthase (PKS) assembly line. Genome sequencing revealed a large macrolide PKS gene cluster that codes for the biosynthesis of rosamicin A and a series of new macrolide antibiotics. Mutagenesis experiments unexpectedly correlated salinipyrone and pacificanone biosynthesis to the rosamicin octamodule Spr PKS. Remarkably, this bifurcated polyketide pathway illuminates a series of enzymatic domain- and module-skipping reactions that give rise to natural polyketide product diversity. Our findings enlarge the growing knowledge of polyketide biochemistry and illuminate potential challenges in PKS bioengineering.

Jensen, PR, Chavarria KL, Fenical W, Moore BS, Ziemert N.  2014.  Challenges and triumphs to genomics-based natural product discovery. Journal of Industrial Microbiology & Biotechnology. 41:203-209.   10.1007/s10295-013-1353-8   AbstractWebsite

Genome sequencing is rapidly changing the field of natural products research by providing opportunities to assess the biosynthetic potential of strains prior to chemical analysis or biological testing. Ready access to sequence data is driving the development of new bioinformatic tools and methods to identify the products of silent or cryptic pathways. While genome mining has fast become a useful approach to natural product discovery, it has also become clear that identifying pathways of interest is much easier than finding the associated products. This has led to bottlenecks in the discovery process that must be overcome for the potential of genomics-based natural product discovery to be fully realized. In this perspective, we address some of these challenges in the context of our work with the marine actinomycete genus Salinispora, which is proving to be a useful model with which to apply genome mining as an approach to natural product discovery.

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.

Park, EJ, Pezzuto JM, Jang KH, Nam SJ, Bucarey SA, Fenical W.  2012.  Suppression of nitric oxide synthase by thienodolin in lipopolysaccharide-stimulated RAW 264.7 murine macrophage cells. Natural Product Communications. 7:789-794. AbstractWebsite

The measurement of nitric oxide in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells is used as a model for evaluating the anti-inflammatory or chemopreventive potential of substances. Thienodolin, isolated from a Streptomyces sp. derived from Chilean marine sediment, inhibited nitric oxide production in LPS-stimulated RAW 264.7 cells (IC50 = 17.2 +/- 1.2 mu M). At both the mRNA and protein levels, inducible nitric oxide synthase (iNOS) was suppressed in a dose-dependent manner. Mitogen-activated protein kinases (MAPKs), one major upstream signaling pathway involved in the transcription of iNOS, were not affected by treatment of thienodolin. However, the compound blocked the degradation of I kappa B alpha resulting in inhibition of NF-kappa B p65 nuclear translocation, and inhibited the phosphorylation of signal transducers and activators of transcription 1 (STAT1) at Tyr701. This study supports further exploration of thienodolin as a potential therapeutic agent with a unique mechanistic activity.

Edlund, A, Loesgen S, Fenical W, Jensen PR.  2011.  Geographic distribution of secondary metabolite genes in the marine actinomycete Salinispora arenicola. Applied and Environmental Microbiology. 77:5916-5925.   10.1128/aem.00611-11   AbstractWebsite

The molecular fingerprinting technique terminal-restriction fragment length polymorphism (T-RFLP) was used in combination with sequence-based approaches to evaluate the geographic distribution of secondary metabolite biosynthetic genes in strains of the marine actinomycete Salinispora arenicola. This study targeted ketosynthase (KS) domains from type I polyketide synthase (PKS) genes and revealed four distinct clusters, the largest of which was comprised of strains from all six global locations sampled. The remaining strains fell into three smaller clusters comprised of strains derived entirely from the Red Sea, the Sea of Cortez, or around the Island of Guam. These results reveal variation in the secondary metabolite gene collectives maintained by strains that are largely clonal at the 16S rRNA level. The location specificities of the three smaller clusters provide evidence that collections of secondary metabolite genes in subpopulations of S. arenicola are endemic to these locations. Cloned KS sequences support the maintenance of distinct sets of biosynthetic genes in the strains associated with each cluster and include four that had not previously been detected in S. arenicola. Two of these new sequences were observed only in strains derived from Guam or the Sea of Cortez. Transcriptional analysis of one of the new KS sequences in conjunction with the production of the polyketide arenicolide A supports a link between this sequence and the associated biosynthetic pathway. From the perspective of natural product discovery, these results suggest that screening populations from distant locations can enhance the discovery of new natural products and provides further support for the use of molecular fingerprinting techniques, such as T-RFLP, to rapidly identify strains that possess distinct sets of biosynthetic genes.

Freel, KC, Nam SJ, Fenical W, Jensen PR.  2011.  Evolution of secondary metabolite genes in three closely related marine actinomycete species. Applied and Environmental Microbiology. 77:7261-7270.   10.1128/aem.05943-11   AbstractWebsite

The marine actinomycete genus Salinispora is composed of three closely related species. These bacteria are a rich source of secondary metabolites, which are produced in species-specific patterns. This study examines the distribution and phylogenetic relationships of genes involved in the biosynthesis of secondary metabolites in the salinosporamide and staurosporine classes, which have been reported for S. tropica and S. arenicola, respectively. The focus is on "Salinispora pacifica," the most recently discovered and phylogenetically diverse member of the genus. Of 61 S. pacifica strains examined, 15 tested positive for a ketosynthase (KS) domain linked to the biosynthesis of salinosporamide K, a new compound in the salinosporamide series. Compound production was confirmed in two strains, and the domain phylogeny supports vertical inheritance from a common ancestor shared with S. tropica, which produces related compounds in the salinosporamide series. There was no evidence for interspecies recombination among salA KS sequences, providing further support for the geographic isolation of these two salinosporamide-producing lineages. In addition, staurosporine production is reported for the first time for S. pacifica, with 24 of 61 strains testing positive for staD, a key gene involved in the biosynthesis of this compound. High levels of recombination were observed between staD alleles in S. pacifica and the cooccurring yet more distantly related S. arenicola, which produces a similar series of staurosporines. The distributions and phylogenies of the biosynthetic genes examined provide insight into the complex processes driving the evolution of secondary metabolism among closely related bacterial species.

Kersten, RD, Yang YL, Xu YQ, Cimermancic P, Nam SJ, Fenical W, Fischbach MA, Moore BS, Dorrestein PC.  2011.  A mass spectrometry-guided genome mining approach for natural product peptidogenomics. Nature Chemical Biology. 7:794-802.   10.1038/nchembio.684   AbstractWebsite

Peptide natural products show broad biological properties and are commonly produced by orthogonal ribosomal and nonribosomal pathways in prokaryotes and eukaryotes. To harvest this large and diverse resource of bioactive molecules, we introduce here natural product peptidogenomics (NPP), a new MS-guided genome-mining method that connects the chemotypes of peptide natural products to their biosynthetic gene clusters by iteratively matching de novo tandem MS (MS(n)) structures to genomics-based structures following biosynthetic logic. In this study, we show that NPP enabled the rapid characterization of over ten chemically diverse ribosomal and nonribosomal peptide natural products of previously unidentified composition from Streptomycete bacteria as a proof of concept to begin automating the genome-mining process. We show the identification of lantipeptides, lasso peptides, linardins, formylated peptides and lipopeptides, many of which are from well-characterized model Streptomycetes, highlighting the power of NPP in the discovery of new peptide natural products from even intensely studied organisms.

Eustaquio, AS, Nam SJ, Penn K, Lechner A, Wilson MC, Fenical W, Jensen PR, Moore BS.  2011.  The discovery of salinosporamide K from the marine bacterium "Salinispora pacifica" by genome mining gives insight into pathway evolution. Chembiochem. 12:61-64.   10.1002/cbic.201000564   AbstractWebsite

Evolving biosynthesis: Genome mining of the marine bacterium “Salinispora pacifica” has led to the discovery of the new proteasome inhibitor, salinosporamide K. Analysis of its biosynthetic gene cluster revealed a loss of gene function in relation to the salinosporamide A biosynthetic locus of Salinispora tropica that accounts for the structural differences in the two natural products.

Gallagher, KA, Fenical W, Jensen PR.  2010.  Hybrid isoprenoid secondary metabolite production in terrestrial and marine actinomycetes. Current Opinion in Biotechnology. 21:794-800.   10.1016/j.copbio.2010.09.010   AbstractWebsite

Terpenoids are among the most ubiquitous and diverse secondary metabolites observed in nature. Although actinomycete bacteria are one of the primary sources of microbially derived secondary metabolites, they rarely produce compounds in this biosynthetic class. The terpenoid secondary metabolites that have been discovered from actinomycetes are often in the form of biosynthetic hybrids called hybrid isoprenoids (His). His include significant structural diversity and biological activity and thus are important targets for natural product discovery. Recent screening of marine actinomycetes has led to the discovery of a new lineage that is enriched in the production of biologically active HI secondary metabolites. These strains represent a promising resource for natural product discovery and provide unique opportunities to study the evolutionary history and ecological functions of an unusual group of secondary metabolites.

Newton, GL, Jensen PR, MacMillan JB, Fenical W, Fahey RC.  2008.  An N-acyl homolog of mycothiol is produced in marine actinomycetes. Archives of Microbiology. 190:547-557.   10.1007/s00203-008-0405-3   AbstractWebsite

Marine actinomycetes have generated much recent interest as a potentially valuable source of novel antibiotics. Like terrestrial actinomycetes the marine actinomycetes are shown here to produce mycothiol as their protective thiol. However, a novel thiol, U25, was produced by MAR2 strain CNQ703 upon progression into stationary phase when secondary metabolite production occurred and became the dominant thiol. MSH and U25 were maintained in a reduced state during early stationary phase, but become significantly oxidized after 10 days in culture. Isolation and structural analysis of the monobromobimane derivative identified U25 as a homolog of mycothiol in which the acetyl group attached to the nitrogen of cysteine is replaced by a propionyl residue. This N-propionyl-desacetyl-mycothiol was present in 13 of the 17 strains of marine actinomycetes examined, including five strains of Salinispora and representatives of the MAR2, MAR3, MAR4 and MAR6 groups. Mycothiol and its precursor, the pseudodisaccharide 1-O-(2-amino-2-deoxy-alpha-Dglucopyranosyl)-Dmyo-inositol, were found in all strains. High levels of mycothiol S-conjugate amidase activity, a key enzyme in mycothiol-dependent detoxification, were found in most strains. The results demonstrate that major thiol/disulfide changes accompany secondary metabolite production and suggest that mycothiol-dependent detoxification is important at this developmental stage.

Oh, DC, Gontang EA, Kauffman CA, Jensen PR, Fenical W.  2008.  Salinipyrones and pacificanones, mixed-precursor polyketides from the marine actinomycete Salinispora pacifica. Journal of Natural Products. 71:570-575.   10.1021/np0705155   AbstractWebsite

Chemical examination of a phylogenetically unique strain of the obligate marine actinomycete Salinispora pacifica led to the discovery of four new polyketides, salinipyrones A and B (1, 2) and pacificanones A and B (3, 4). These compounds appear to be derived from a mixed-precursor polyketide biosynthesis involving acetate, propionate, and butyrate building blocks. Spectral analysis, employing NMR, IR, UV, and CD methods and chemical derivatization, was used to assign the structures and absolute configurations of these new metabolites. Salinipyrones A and B displayed exactly opposite CD spectra, indicating their pseudoenantiomeric relationship. This relationship was shown to be a consequence of the geometric isomerization of one double bond. The phenomenon of polyketide module skipping is proposed to explain the unusual biosynthesis of the salinipyrones and the pacificanones.

Udwary, DW, Zeigler L, Asolkar RN, Singan V, Lapidus A, Fenical W, Jensen PR, Moore BS.  2007.  Genome sequencing reveals complex secondary metabolome in the marine actinomycete Salinispora tropica. Proceedings of the National Academy of Sciences of the United States of America. 104:10376-10381.   10.1073/pnas.0700962104   AbstractWebsite

Recent fermentation studies have identified actinomycetes of the marine-dwelling genus Salinispora as prolific natural product producers. To further evaluate their biosynthetic potential, we sequenced the 5,183,331-bp S. tropica CNB-440 circular genome and analyzed all identifiable secondary natural product gene clusters. Our analysis shows that S. tropica dedicates a large percentage of its genome (approximate to 9.9%) to natural product assembly, which is greater than previous Streptomyces genome sequences as well as other natural product-producing actinomycetes. The S. tropica genome features polyketide synthase systems of every known formally classified family, nonribosomal peptide synthetases, and several hybrid clusters. Although a few clusters appear to encode molecules previously identified in Streptomyces species, the majority of the 17 biosynthetic loci are novel. Specific chemical information about putative and observed natural product molecules is presented and discussed. In addition, our bioinformatic analysis not only was critical for the structure elucidation of the polyene macrolactam salinilactam A, but its structural analysis aided the genome assembly of the highly repetitive slm loci. This study firmly establishes the genus Salinispora as a rich source of drug-like molecules and importantly reveals the powerful interplay between genomic analysis and traditional natural product isolation studies.

Miller, ED, Kauffman CA, Jensen PR, Fenical W.  2007.  Piperazimycins: Cytotoxic hexadepsipeptides from a marine-derived bacterium of the genus Streptomyces. Journal of Organic Chemistry. 72:323-330.   10.1021/jo061064g   AbstractWebsite

[graphics] Three potent cancer cell cytotoxins, piperazimycins A-C (1-3), have been isolated from the fermentation broth of a Streptomyces sp., cultivated from marine sediments near the island of Guam. The structures of these cyclic hexadepsipeptides were assigned by a combination of spectral, chemical, and crystallographic methods. The piperazimycins are composed of rare amino acids, including hydroxyacetic acid, alpha-methylserine, gamma-hydroxypiperazic acid, and gamma-chloropiperazic acid. The novel amino acid residues 2-amino-8-methyl-4,6-nonadienoic acid and 2-amino-8-methyl-4,6-decadienoic acid were found as components of piperazimycins A and C, respectively. When screened in the National Cancer Institute's 60 cancer cell line panel, piperazimycin A exhibited potent in vitro cytotoxicity toward multiple tumor cell lines with a mean GI(50) of 100 nM.

Williams, PG, Asolkar RN, Kondratyuk T, Pezzuto JM, Jensen PR, Fenical W.  2007.  Saliniketals A and B, bicyclic polyketides from the marine actinomycete Salinispora arenicola. Journal of Natural Products. 70:83-88.   10.1021/np0604580   AbstractWebsite

An extensive study of the secondary metabolites produced by several strains of the marine actinomycete Salinispora arenicola has led to the isolation of two unusual bicyclic polyketides, saliniketals A and B (1, 2). The structures, which contain a new 1,4-dimethyl-2,8-dioxabicyclo[3.2.1]octan-3-yl ring, were assigned mainly by 2D NMR spectroscopic methods. Unexpectedly, chemical derivatization of saliniketal A with Mosher's acid chloride resulted in a functional group interconversion of an unsaturated primary amide to the corresponding nitrile in a quantitative yield under unusually mild conditions. Saliniketals A and B were found to inhibit ornithine decarboxylase induction, an important target for the chemoprevention of cancer, with IC50 values of 1.95 +/- 0.37 and 7.83 +/- 1.2 mu g/mL, respectively.

Jensen, PR, Williams PG, Oh DC, Zeigler L, Fenical W.  2007.  Species-specific secondary metabolite production in marine actinomycetes of the genus Salinispora. Applied and Environmental Microbiology. 73:1146-1152.   10.1128/aem.01891-06   AbstractWebsite

Here we report associations between secondary metabolite production and phylogenetically distinct but closely related marine actinomycete species belonging to the genus Salinispora. The pattern emerged in a study that included global collection sites, and it indicates that secondary metabolite production can be a species-specific, phenotypic trait associated with broadly distributed bacterial populations. Associations between actinomycete phylotype and chemotype revealed an effective, diversity-based approach to natural product discovery that contradicts the conventional wisdom that secondary metabolite production is strain specific. The structural diversity of the metabolites observed, coupled with gene probing and phylogenetic analyses, implicates lateral gene transfer as a source of the biosynthetic genes responsible for compound production. These results conform to a model of selection-driven pathway fixation occurring subsequent to gene acquisition and provide a rare example in which demonstrable physiological traits have been correlated to the fine-scale phylogenetic architecture of an environmental bacterial community.

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.

Oh, DC, Williams PG, Kauffman CA, Jensen PR, Fenical W.  2006.  Cyanosporasides A and B, chloro- and cyano-cyclopenta a indene glycosides from the marine actinomycete "Salinispora pacifica". Organic Letters. 8:1021-1024.   10.1021/ol052686b   AbstractWebsite

Two structurally novel cyclopenta[a]indene glycosides, cyanosporasides A and B (1 and 2) have been isolated from the culture broth of a new species of the obligate marine actinomycete genus Salinispora. The structures and absolute stereochemistries of these compounds were determined by spectral and chemical methods. The cyanosporasides possess a new 3-keto-pyranohexose sugar as well as a cyano- and chloro-substituted cyclopenta[a]indene ring system. The cyanosporasides are proposed to be cyclization products of an enediyne precursor.

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.

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.

Spyere, A, Rowley DC, Jensen PR, Fenical W.  2003.  New neoverrucosane diterpenoids produced by the marine gliding bacterium Saprospira grandis. Journal of Natural Products. 66:818-822.   10.1021/np0205351   AbstractWebsite

Chemical examination of the culture broth extracts of the marine gliding bacterium Saprospira grandis (ATCC 23116) has resulted in the isolation of four new diterpenoids of the neoverrucosane class. The structures of the new diterpenoids, compounds 1-4, were assigned by combined spectroscopic methods emphasizing 2D NMR experiments. The relative stereochemistry of 1 was determined by 2D ROESY NMR methods, while the absolute stereochemistry was assigned by application of the modified Mosher method. This study adds to the rare observation of terpene production by prokaryotic microorganisms and suggests that marine gliding bacteria may be a significant source for new terpenoid secondary metabolites.

Mayer, AMS, Jacobson PB, Fenical W, Jacobs RS, Glaser KB.  1998.  Pharmacological characterization of the pseudopterosins: Novel anti-inflammatory natural products isolated from the Caribbean soft coral, Pseudopterogorgia elisabethae. Life Sciences. 62:PL401-PL407.   10.1016/s0024-3205(98)00229-x   AbstractWebsite

Pseudopterosin E (PSE), a C-10 linked fucose glycoside and pseudopterosin A (PSA), a C-9 xylose glycoside isolated from the marine gorgonian Pseudopterogorgia elisabethae were both effective in reducing PMA-induced mouse ear edema when administered topically (ED50 (mu g/ear) PSE(38), PSA(8)) or systemically (ED50 (mg/kg, i.p.) PSE (14), PSA (32)). Both compounds exhibited in vivo analgesic activity in phenyl-p-benzoquinone-induced writhing (ED50 (mg/kg, i.p.) PSE(14), PSA(4). PSE inhibited zymosan-induced writhing (ED50 = 6 mg/kg, i.p.), with a concomitant dose-dependent inhibition of peritoneal exudate 6-keto-prostaglandin F-1 alpha (ED50 = 24 mg/kg) and leukotriene C-4 (ED50 = 24 mg/kg). In vitro, the pseudopterosins were inactive as inhibitors of phospholipase A(2), cyclooxygenase, cytokine release, or as regulators of adhesion molecule expression. PSA inhibited prostaglandin E-2 and leukotriene C-4 production in zymosan-stimulated murine peritoneal macrophages (IC50 = 4 mu M and 1 mu M, respectively); however, PSE was much less effective. These data suggest that the pseudopterosins may mediate their antiinflammatory effects by inhibiting eicosanoid release from inflammatory cells in a concentration and dose-dependent manner. (C) 1998 Elsevier Science Inc.

Mayer, AMS, Paul VJ, Fenical W, Norris JN, Decarvalho MS, Jacobs RS.  1993.  Phospholipase A2 inhibitors from marine algae. Hydrobiologia. 261:521-529. AbstractWebsite

Twelve out of twenty-nine compounds isolated from benthic marine algae from the phyla Chlorophyta, Phaeophyta and Rhodophyta have been found to be potent inhibitors of bee venom derived phospholipase A2 (PLA2) (> 50 %) in the muM range. The compounds investigated were from: Bryopsis pennata, Rhipocephalus phoenix, Caulerpa prolifera, C. racemosa, C. bikinensis, Cymopolia barbata, Laurencia ef. palisada, Laurencia sp., Ochtodes crockeri, Liagora farinosa, Sphaerococcus coronipifolius, Phacelocarpus labillardieri, Dictyota sp., Bifurcaria galapagensis, Stypopodium zonale, Dictyopteris undulata, Stoechospermum marginatum, Dictyopteris divaricata, Dilophusfasciola and Dilophus sp. This is the first report of bee venom PLA2 inhibition in vitro by pure compounds isolated from marine algae.