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1.
Mar Drugs ; 22(2)2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38393038

RESUMO

The diatom lipidome actively regulates photosynthesis and displays a high degree of plasticity in response to a light environment, either directly as structural modifications of thylakoid membranes and protein-pigment complexes, or indirectly via photoprotection mechanisms that dissipate excess light energy. This acclimation is crucial to maintaining primary production in marine systems, particularly in polar environments, due to the large temporal variations in both the intensity and wavelength distributions of downwelling solar irradiance. This study investigated the hypothesis that Arctic marine diatoms uniquely modify their lipidome, including their concentration and type of pigments, in response to wavelength-specific light quality in their environment. We postulate that Arctic-adapted diatoms can adapt to regulate their lipidome to maintain growth in response to the extreme variability in photosynthetically active radiation. This was tested by comparing the untargeted lipidomic profiles, pigmentation, specific growth rates and carbon assimilation of the Arctic diatom Porosira glacialis vs. the temperate species Coscinodiscus radiatus during exponential growth under red, blue and white light. Here, we found that the chromatic wavelength influenced lipidome remodeling and growth in each strain, with P. glacialis showing effective utilization of red light coupled with increased inclusion of primary light-harvesting pigments and polar lipid classes. These results indicate a unique photoadaptation strategy that enables Arctic diatoms like P. glacialis to capitalize on a wide chromatic growth range and demonstrates the importance of active lipid regulation in the Arctic light environment.


Assuntos
Diatomáceas , Diatomáceas/química , Lipidômica , Fotossíntese/fisiologia , Luz , Lipídeos
3.
Front Microbiol ; 14: 1130018, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37152725

RESUMO

The suomilide and the banyasides are highly modified and functionalized non-ribosomal peptides produced by cyanobacteria of the order Nostocales. These compound classes share several substructures, including a complex azabicyclononane core, which was previously assumed to be derived from the amino acid tyrosine. In our study we were able to isolate and determine the structures of four suomilides, named suomilide B - E (1-4). The compounds differ from the previously isolated suomilide A by the functionalization of the glycosyl group. Compounds 1-4 were assayed for anti-proliferative, anti-biofilm and anti-bacterial activities, but no significant activity was detected. The sequenced genome of the producer organism Nostoc sp. KVJ20 enabled us to propose a biosynthetic gene cluster for suomilides. Our findings indicated that the azabicyclononane core of the suomilides is derived from prephenate and is most likely incorporated by a proline specific non-ribosomal peptide synthetase-unit.

4.
Front Microbiol ; 13: 1005625, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36478870

RESUMO

Actinobacteria are among the most prolific producers of bioactive secondary metabolites. In order to collect Arctic marine bacteria for the discovery of new bioactive metabolites, actinobacteria were selectively isolated during a research cruise in the Greenland Sea, Norwegian Sea and the Barents Sea. In the frame of the isolation campaign, it was investigated how different sample treatments, isolation media and sample-sources, such as animals and sediments, affected the yield of actinobacterial isolates to aid further isolation campaigns. Special attention was given to sediments, where we expected spores of spore forming bacteria to enrich. Beside actinobacteria a high share of bacilli was obtained which was not desired. An experimental protocol for down-scaled cultivation and extraction was tested and compared with an established low-throughput cultivation and extraction protocol. The heat-shock method proved suitable to enrich spore-, or endospore forming bacteria such as bacilli. Finally, a group bioactive compounds could be tentatively identified using UHPLC-MS/MS analysis of the active fractions.

5.
Mar Drugs ; 20(4)2022 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-35447892

RESUMO

Aquatic invertebrates are a major source of biomaterials and bioactive natural products that can find applications as pharmaceutics, nutraceutics, cosmetics, antibiotics, antifouling products and biomaterials. Symbiotic microorganisms are often the real producers of many secondary metabolites initially isolated from marine invertebrates; however, a certain number of them are actually synthesized by the macro-organisms. In this review, we analysed the literature of the years 2010-2019 on natural products (bioactive molecules and biomaterials) from the main phyla of marine invertebrates explored so far, including sponges, cnidarians, molluscs, echinoderms and ascidians, and present relevant examples of natural products of interest to public and private stakeholders. We also describe omics tools that have been more relevant in identifying and understanding mechanisms and processes underlying the biosynthesis of secondary metabolites in marine invertebrates. Since there is increasing attention on finding new solutions for a sustainable large-scale supply of bioactive compounds, we propose that a possible improvement in the biodiscovery pipeline might also come from the study and utilization of aquatic invertebrate stem cells.


Assuntos
Produtos Biológicos , Animais , Organismos Aquáticos/metabolismo , Materiais Biocompatíveis/metabolismo , Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Equinodermos , Invertebrados/metabolismo , Biologia Marinha
6.
Mar Drugs ; 21(1)2022 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-36662175

RESUMO

Bacterial symbionts of marine invertebrates are rich sources of novel, pharmaceutically relevant natural products that could become leads in combatting multidrug-resistant pathogens and treating disease. In this study, the bioactive potential of the marine invertebrate symbiont Thalassomonas actiniarum was investigated. Bioactivity screening of the strain revealed Gram-positive specific antibacterial activity as well as cytotoxic activity against a human melanoma cell line (A2058). The dereplication of the active fraction using HPLC-MS led to the isolation and structural elucidation of cholic acid and 3-oxo cholic acid. T. actiniarum is one of three type species belonging to the genus Thalassomonas. The ability to generate cholic acid was assessed for all three species using thin-layer chromatography and was confirmed by LC-MS. The re-sequencing of all three Thalassomonas type species using long-read Oxford Nanopore Technology (ONT) and Illumina data produced complete genomes, enabling the bioinformatic assessment of the ability of the strains to produce cholic acid. Although a complete biosynthetic pathway for cholic acid synthesis in this genus could not be determined based on sequence-based homology searches, the identification of putative penicillin or homoserine lactone acylases in all three species suggests a mechanism for the hydrolysis of conjugated bile acids present in the growth medium, resulting in the generation of cholic acid and 3-oxo cholic acid. With little known currently about the bioactivities of this genus, this study serves as the foundation for future investigations into their bioactive potential as well as the potential ecological role of bile acid transformation, sterol modification and quorum quenching by Thalassomonas sp. in the marine environment.


Assuntos
Antibacterianos , Humanos , Ácido Cólico , Filogenia , DNA Bacteriano , Antibacterianos/farmacologia , Análise de Sequência de DNA
7.
Molecules ; 26(24)2021 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-34946641

RESUMO

As part of our search for bioactive metabolites from understudied marine microorganisms, the new chlorinated metabolite chlovalicin B (1) was isolated from liquid cultures of the marine basidiomycete Digitatispora marina, which was collected and isolated from driftwood found at Vannøya, Norway. The structure of the novel compound was elucidated by spectroscopic methods including 1D and 2D NMR and analysis of HRMS data, revealing that 1 shares its molecular scaffold with a previously isolated compound, chlovalicin. This represents the first compound isolated from the Digitatispora genus, and the first reported fumagillin/ovalicin-like compound isolated from Basidiomycota. Compound 1 was evaluated for antibacterial activities against a panel of five bacteria, its ability to inhibit bacterial biofilm formation, for antifungal activity against Candida albicans, and for cytotoxic activities against malignant and non-malignant human cell lines. Compound 1 displayed weak cytotoxic activity against the human melanoma cell line A2058 (~50% survival at 50 µM). No activity was detected against biofilm formation or C. albicans at 50 µM, or against bacterial growth at 100 µM nor against the production of cytokines by the human acute monocytic leukemia cell line THP-1 at 50 µM.


Assuntos
Antibacterianos , Antifúngicos , Bactérias/crescimento & desenvolvimento , Basidiomycota/química , Candida albicans/crescimento & desenvolvimento , Sesquiterpenos , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Cicloexanonas/química , Cicloexanonas/isolamento & purificação , Cicloexanonas/farmacologia , Compostos de Epóxi/química , Compostos de Epóxi/isolamento & purificação , Compostos de Epóxi/farmacologia , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Sesquiterpenos/farmacologia
8.
Front Microbiol ; 12: 730740, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659158

RESUMO

The emergence of drug-resistant bacteria is increasing rapidly in all parts of the world, and the need for new antibiotics is urgent. In our continuous search for new antimicrobial molecules from under-investigated Arctic marine microorganisms, a marine fungus belonging to the family Lulworthiaceae (Lulworthiales, Sordariomycetes, and Ascomycota) was studied. The fungus was isolated from driftwood, cultivated in liquid medium, and studied for its potential for producing antibacterial compounds. Through bioactivity-guided isolation, a novel sulfated biarylic naphtho-α-pyrone dimer was isolated, and its structure was elucidated by spectroscopic methods, including 1D and 2D NMR and HRMS. The compound, named lulworthinone (1), showed antibacterial activity against reference strains of Staphylococcus aureus and Streptococcus agalactiae, as well as several clinical MRSA isolates with MICs in the 1.56-6.25 µg/ml range. The compound also had antiproliferative activity against human melanoma, hepatocellular carcinoma, and non-malignant lung fibroblast cell lines, with IC50 values of 15.5, 27, and 32 µg/ml, respectively. Inhibition of bacterial biofilm formation was observed, but no eradication of established biofilm could be detected. No antifungal activity was observed against Candida albicans. During the isolation of 1, the compound was observed to convert into a structural isomer, 2, under acidic conditions. As 1 and 2 have high structural similarity, NMR data acquired for 2 were used to aid in the structure elucidation of 1. To the best of our knowledge, lulworthinone (1) represents the first new bioactive secondary metabolite isolated from the marine fungal order Lulworthiales.

9.
Molecules ; 26(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34500726

RESUMO

The Lacinutrix genus was discovered in 2005 and includes 12 Gram-negative bacterial species. To the best of our knowledge, the secondary metabolite production potential of this genus has not been explored before, and examination of Lacinutrix species may reveal novel chemistry. As part of a screening project of Arctic marine bacteria, the Lacinutrix sp. strain M09B143 was cultivated, extracted, fractionated and tested for antibacterial and cytotoxic activities. One fraction had antibacterial activity and was subjected to mass spectrometry analysis, which revealed two compounds with elemental composition that did not match any known compounds in databases. This resulted in the identification and isolation of two novel isobranched lyso-ornithine lipids, whose structures were elucidated by mass spectrometry and NMR spectroscopy. Lyso-ornithine lipids consist of a 3-hydroxy fatty acid linked to the alpha amino group of an ornithine amino acid through an amide bond. The fatty acid chains were determined to be iso-C15:0 (1) and iso-C16:0 (2). Compound 1 was active against the Gram-positive S. agalactiae, while 2 showed cytotoxic activity against A2058 human melanoma cells.


Assuntos
Flavobacteriaceae/metabolismo , Lipídeos/química , Ornitina/química , Regiões Árticas , Espectroscopia de Ressonância Magnética
10.
IMA Fungus ; 12(1): 21, 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34372938

RESUMO

Marine fungi remain poorly covered in global genome sequencing campaigns; the 1000 fungal genomes (1KFG) project attempts to shed light on the diversity, ecology and potential industrial use of overlooked and poorly resolved fungal taxa. This study characterizes the genomes of three marine fungi: Emericellopsis sp. TS7, wood-associated Amylocarpus encephaloides and algae-associated Calycina marina. These species were genome sequenced to study their genomic features, biosynthetic potential and phylogenetic placement using multilocus data. Amylocarpus encephaloides and C. marina were placed in the Helotiaceae and Pezizellaceae (Helotiales), respectively, based on a 15-gene phylogenetic analysis. These two genomes had fewer biosynthetic gene clusters (BGCs) and carbohydrate active enzymes (CAZymes) than Emericellopsis sp. TS7 isolate. Emericellopsis sp. TS7 (Hypocreales, Ascomycota) was isolated from the sponge Stelletta normani. A six-gene phylogenetic analysis placed the isolate in the marine Emericellopsis clade and morphological examination confirmed that the isolate represents a new species, which is described here as E. atlantica. Analysis of its CAZyme repertoire and a culturing experiment on three marine and one terrestrial substrates indicated that E. atlantica is a psychrotrophic generalist fungus that is able to degrade several types of marine biomass. FungiSMASH analysis revealed the presence of 35 BGCs including, eight non-ribosomal peptide synthases (NRPSs), six NRPS-like, six polyketide synthases, nine terpenes and six hybrid, mixed or other clusters. Of these BGCs, only five were homologous with characterized BGCs. The presence of unknown BGCs sets and large CAZyme repertoire set stage for further investigations of E. atlantica. The Pezizellaceae genome and the genome of the monotypic Amylocarpus genus represent the first published genomes of filamentous fungi that are restricted in their occurrence to the marine habitat and form thus a valuable resource for the community that can be used in studying ecological adaptions of fungi using comparative genomics.

11.
PLoS One ; 16(7): e0255370, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34324572

RESUMO

The aim of this study was to evaluate the potential of diatom (microalgae) biomass as a lice-reducing ingredient in salmon feed. The original hypothesis was based on the fact that polyunsaturated aldehydes (PUAs), e.g. 2-trans, 4-trans decadenial (A3) produced by diatoms can function as grazing deterrents and harm copepod development. Salmon lice (Lepeophtheirus salmonis) is a copepod, and we intended to test if inclusion of diatom biomass in the feed could reduce the infestation of lice on salmon. We performed experiments where salmon kept in tanks were offered four different diets, i.e. basic feed with diatoms, fish oil, Calanus sp. oil or rapeseed oil added. After a feeding period of 67 days a statistically representative group of fishes, tagged with diet group origin, were pooled in a 4000L tank and exposed to salmon lice copepodites whereafter lice infestation was enumerated. Salmon from all four diet groups had good growth with SGR values from 1.29 to 1.44% day-1 (increase from ca. 130 g to 350 g). At the termination of the experiment the number of lice on salmon offered diatom feed were statistically significantly lower than on salmon fed the other diets. Mean lice infestation values increased from diatom feed through Calanus and fish oil to standard feed with terrestrial plant ingredients. Analysis of the chemical composition of the different diets (fatty acids, amino acids) failed to explain the differences in lice infestation. The only notable result was that diatom and Calanus feed contained more FFA (free fatty acids) than feed with fish oil and the control feed. None of the potential deleterious targeted polyunsaturated aldehydes could be detected in skin samples of the salmon. What was exclusive for salmon that experienced reduced lice was diatom inclusion in the feed. This therefore still indicates the presence of some lice deterring ingredient, either in the feed, or an ingredient can have triggered production of an deterrent in the fish. An obvious follow up of this will be to perform experiments with different degrees of diatom inclusion in the feeds, i.e. dose response experiments combined with targeted PUA analyses, as well as to perform large scale experiments under natural conditions in aquaculture pens.


Assuntos
Biomassa , Diatomáceas , Dieta , Doenças dos Peixes , Salmão , Animais , Aquicultura , Copépodes
12.
Mar Drugs ; 19(2)2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546196

RESUMO

"One strain many compounds" (OSMAC) based approaches have been widely used in the search for bioactive compounds. Introducing stress factors like nutrient limitation, UV-light or cocultivation with competing organisms has successfully been used in prokaryote cultivation. It is known that diatom physiology is affected by changed cultivation conditions such as temperature, nutrient concentration and light conditions. Cocultivation, though, is less explored. Hence, we wanted to investigate whether grazing pressure can affect the metabolome of the marine diatom Porosira glacialis, and if the stress reaction could be detected as changes in bioactivity. P. glacialis cultures were mass cultivated in large volume bioreactor (6000 L), first as a monoculture and then as a coculture with live zooplankton. Extracts of the diatom biomass were screened in a selection of bioactivity assays: inhibition of biofilm formation, antibacterial and cell viability assay on human cells. Bioactivity was found in all bioassays performed. The viability assay towards normal lung fibroblasts revealed that P. glacialis had higher bioactivity when cocultivated with zooplankton than in monoculture. Cocultivation with diatoms had no noticeable effect on the activity against biofilm formation or bacterial growth. The metabolic profiles were analyzed showing the differences in diatom metabolomes between the two culture conditions. The experiment demonstrates that grazing stress affects the biochemistry of P. glacialis and thus represents a potential tool in the OSMAC toolkit.


Assuntos
Biomassa , Diatomáceas/metabolismo , Zooplâncton/metabolismo , Animais , Biofilmes/crescimento & desenvolvimento , Sobrevivência Celular/fisiologia , Diatomáceas/isolamento & purificação , Células HT29 , Humanos , Metaboloma/fisiologia , Zooplâncton/isolamento & purificação
13.
J Sci Food Agric ; 101(6): 2422-2427, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33011991

RESUMO

BACKGROUND: Low growth temperatures and the special light qualities of midnight sun in northern Scandinavia, have both been shown to improve eating quality of swede root bulbs. To study the combined effect of these factors on root development and sensory-related compounds, plants were grown in phytotron under different 24 h supplemental light-emitting diode (LED) light colours, at constant 15 °C, or reduced end-of-season temperature at 9 °C. RESULTS: Far-red LED (740 nm) light induced longer leaves and produced more roundly shaped bulbs, than the other light quality treatments. At constant 15 °C, supplemental light of far-red LED also produced a stronger purple crown skin colour than the other LED treatments. This difference between light quality treatments disappeared at 9 °C, as all bulb crowns developed a purple colour. There were no significant effects of LED-supplements on sugar concentrations, while the reduced temperature on average did increase concentrations of d-fructose and d-glucose. Total glucosinolate concentrations were not different among treatments, although the most abundant glucosinolate, progoitrin, on average was present in highest concentration under LEDs containing far-red light, and in lower concentration at 9 °C compared to 15 °C. CONCLUSION: The light quality of 24 h photoperiods in combination with temperature appears primarily important for growth and morphological traits in swede root bulbs. Influence of light quality and low temperature on appearance and sensory-related compounds may be utilized in marketing of root vegetables with special quality related to growth conditions of high latitude origin. © 2020 Society of Chemical Industry.


Assuntos
Brassica napus/efeitos da radiação , Glucosinolatos/análise , Raízes de Plantas/química , Raízes de Plantas/crescimento & desenvolvimento , Açúcares/química , Brassica napus/química , Brassica napus/crescimento & desenvolvimento , Brassica napus/metabolismo , Temperatura Baixa , Glucosinolatos/metabolismo , Humanos , Luz , Fotoperíodo , Folhas de Planta/química , Folhas de Planta/crescimento & desenvolvimento , Folhas de Planta/metabolismo , Folhas de Planta/efeitos da radiação , Raízes de Plantas/metabolismo , Raízes de Plantas/efeitos da radiação , Açúcares/metabolismo , Paladar , Verduras/química , Verduras/crescimento & desenvolvimento , Verduras/metabolismo , Verduras/efeitos da radiação
14.
Microorganisms ; 8(7)2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32674317

RESUMO

Siderophores are compounds with high affinity for ferric iron. Bacteria produce these compounds to acquire iron in iron-limiting conditions. Iron is one of the most abundant metals on earth, and its presence is necessary for many vital life processes. Bacteria from the genus Serratia contribute to the iron respiration in their environments, and previously several siderophores have been isolated from this genus. As part of our ongoing search for medicinally relevant compounds produced by marine microbes, a co-culture of a Shewanella sp. isolate and a Serratia sp. isolate, grown in iron-limited conditions, was investigated, and the rare siderophore serratiochelin A (1) was isolated with high yields. Compound 1 has previously been isolated exclusively from Serratia sp., and to our knowledge, there is no bioactivity data available for this siderophore to date. During the isolation process, we observed the degradation product serratiochelin C (2) after exposure to formic acid. Both 1 and 2 were verified by 1-D and 2-D NMR and high-resolution MS/MS. Here, we present the isolation of 1 from an iron-depleted co-culture of Shewanella sp. and Serratia sp., its proposed mechanism of degradation into 2, and the chemical and biological characterization of both compounds. The effects of 1 and 2 on eukaryotic and prokaryotic cells were evaluated, as well as their effect on biofilm formation by Staphylococcus epidermidis. While 2 did not show bioactivity in the given assays, 1 inhibited the growth of the eukaryotic cells and Staphylococcus aureus.

15.
Mar Drugs ; 18(3)2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32192075

RESUMO

Microalgae have been shown to be excellent producers of lipids, pigments, carbohydrates, and a plethora of secondary metabolites with possible applications in the pharmacological, nutraceutical, and cosmeceutical sectors. Recently, various microalgal raw extracts have been found to have anti-inflammatory properties. In this study, we performed the fractionation of raw extracts of the diatom Cylindrotheca closterium, previously shown to have anti-inflammatory properties, obtaining five fractions. Fractions C and D were found to significantly inhibit tumor necrosis factor alpha (TNF-⍺) release in LPS-stimulated human monocyte THP-1 cells. A dereplication analysis of these two fractions allowed the identification of their main components. Our data suggest that lysophosphatidylcholines and a breakdown product of chlorophyll, pheophorbide a, were probably responsible for the observed anti-inflammatory activity. Pheophorbide a is known to have anti-inflammatory properties. We tested and confirmed the anti-inflammatory activity of 1-palmitoyl-sn-glycero-3-phosphocholine, the most abundant lysophosphatidylcholine found in fraction C. This study demonstrated the importance of proper dereplication of bioactive extracts and fractions before isolation of compounds is commenced.


Assuntos
Anti-Inflamatórios/farmacologia , Clorofila/farmacologia , Diatomáceas , Lisofosfatidilcolinas/farmacologia , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Anti-Inflamatórios/química , Clorofila/química , Humanos , Lisofosfatidilcolinas/química , Oceanos e Mares , Células THP-1/efeitos dos fármacos , Células THP-1/metabolismo
16.
Nat Prod Res ; 34(14): 2059-2064, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30784299

RESUMO

The new guanidine alkaloid Dendrobeaniamine A (1) was isolated from the organic extract of the Arctic marine bryozoan Dendrobeania murrayana. The chemical structure of 1 was elucidated by spectroscopic experiments, including 1D and 2D NMR and HRESIMS analysis. Compound 1 is a lipoamino acid, consisting of a C12 fatty acid anchored to the amino acid arginine. The bioactivity of 1 was evaluated using cellular and biochemical assays, but the compound did not show cytotoxic, antimicrobial, anti-inflammatory or antioxidant activities.


Assuntos
Alcaloides/isolamento & purificação , Briozoários/química , Alcaloides/química , Alcaloides/farmacologia , Animais , Antibacterianos/química , Antineoplásicos/química , Ácidos Graxos/química , Ácidos Graxos/isolamento & purificação , Guanidina/química , Estrutura Molecular , Análise Espectral
17.
Molecules ; 24(21)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694159

RESUMO

Two bacterial isolates from the Barents Sea, both belonging to the genus Algibacter, were found to yield extracts with anti-bacterial bioactivity. Mass spectrometry guided dereplication and purification of the active extracts lead to the isolation of the same active principle in both extracts. The structure of the bioactive compound was identified via mass spectrometry and nuclear resonance spectroscopy and it turned out to be the known lipopeptide Lipid 430. We discovered and determined its previously unknown anti-bacterial activity against Streptococcus agalactiae and revealed a cytotoxic effect against the A2058 human melanoma cell line at significantly lower concentrations compared to its anti-bacterial concentration. Flow cytometry and microscopy investigations of the cytotoxicity against the melanoma cell line indicated that Lipid 430 did not cause immediate cell lysis. The experiments with melanoma cells suggest that the compound functions trough more complex pathways than acting as a simple detergent.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Citotoxinas/química , Citotoxinas/farmacologia , Flavobacteriaceae/química , Lipídeos/química , Lipídeos/farmacologia , Linhagem Celular Tumoral , Células HT29 , Humanos , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Melanoma/tratamento farmacológico , Streptococcus agalactiae/efeitos dos fármacos
18.
J Med Chem ; 62(22): 10167-10181, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31647655

RESUMO

In this work, we demonstrate that the indole-oxazole-pyrrole framework of the breitfussin family of natural products is a promising scaffold for kinase inhibition. Six new halogenated natural products, breitfussin C-H (3 - 8) were isolated and characterized from the Arctic, marine hydrozoan Thuiaria breitfussi. The structures of two of the new natural products were also confirmed by total synthesis. Two of the breitfussins (3 and 4) were found to selectively inhibit the survival of several cancer cell lines, with the lowest IC50 value of 340 nM measured against the drug-resistant triple negative breast cancer cell line MDA-MB-468, while leaving the majority of the tested cell lines not or significantly less affected. When tested against panels of protein kinases, 3 gave IC50 and Kd values as low as 200 and 390 nM against the PIM1 and DRAK1 kinases, respectively. The activity was confirmed to be mediated through ATP competitive binding in the ATP binding pocket of the kinases. Furthermore, evaluation of potential off-target and toxicological effects, as well as relevant in vitro ADME parameters for 3 revealed that the breitfussin scaffold holds promise for the development of selective kinase inhibitors.


Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/química , Regiões Árticas , Sítios de Ligação , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Embrião não Mamífero/efeitos dos fármacos , Feminino , Humanos , Hidrocarbonetos Bromados/química , Hidrozoários/química , Indóis/química , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/toxicidade , Proteínas Proto-Oncogênicas c-pim-1/química , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Testes de Toxicidade , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Peixe-Zebra/embriologia
19.
SLAS Discov ; 24(3): 398-413, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30616481

RESUMO

Compound screening in biological assays and subsequent optimization of hits is indispensable for the development of new molecular research tools and drug candidates. To facilitate such discoveries, the European Research Infrastructure EU-OPENSCREEN was founded recently with the support of its member countries and the European Commission. Its distributed character harnesses complementary knowledge, expertise, and instrumentation in the discipline of chemical biology from 20 European partners, and its open working model ensures that academia and industry can readily access EU-OPENSCREEN's compound collection, equipment, and generated data. To demonstrate the power of this collaborative approach, this perspective article highlights recent projects from EU-OPENSCREEN partner institutions. These studies yielded (1) 2-aminoquinazolin-4(3 H)-ones as potential lead structures for new antimalarial drugs, (2) a novel lipodepsipeptide specifically inducing apoptosis in cells deficient for the pVHL tumor suppressor, (3) small-molecule-based ROCK inhibitors that induce definitive endoderm formation and can potentially be used for regenerative medicine, (4) potential pharmacological chaperones for inborn errors of metabolism and a familiar form of acute myeloid leukemia (AML), and (5) novel tankyrase inhibitors that entered a lead-to-candidate program. Collectively, these findings highlight the benefits of small-molecule screening, the plethora of assay designs, and the close connection between screening and medicinal chemistry within EU-OPENSCREEN.


Assuntos
Comportamento Cooperativo , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos , Europa (Continente) , Ensaios de Triagem em Larga Escala , Humanos , Relação Estrutura-Atividade
20.
Mycology ; 11(3): 230-242, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-33062384

RESUMO

During a research cruise in 2016, we isolated fungi from sediments, seawater, driftwood, fruiting bodies, and macroalgae using three different media to assess species richness and potential bioactivity of cultivable marine fungi in the High Arctic region. Ten stations from the Svalbard archipelago (73-80 °N, 18-31 °E) were investigated and 33 fungal isolates were obtained. These grouped into 22 operational taxonomic units (OTUs) using nuc rDNA internal transcribed spacer regions (ITS1-5.8S-ITS2 = ITS) with acut-off set at 98% similarity. The taxonomic analysis showed that 17 OTUs belonged to Ascomycota, one to Basidiomycota, two to Mucoromycota and two were fungal-like organisms. The nuc rDNA V1-V5 regions of 18S (18S) and D1-D3 regions of 28S (28S) were sequenced from representative isolates of each OTU for comparison to GenBank sequences. Isolates of Lulworthiales and Eurotiales were the most abundant, with seven isolates each. Among the 22 OTUs, nine represent potentially undescribed species based on low similarity to GenBank sequences and 10 isolates showed inhibitory activity against Gram-positive bacteria in an agar diffusion plug assay. These results show promise for the Arctic region as asource of novel marine fungi with the ability to produce bioactive secondary metabolites with antibacterial properties.

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