Cytotoxic furanoditerpenes from the sponge Spongia tubulifera collected in the Mexican Caribbean

[Abstract] Two new spongian furanoditerpenes, 3β-hydroxyspongia-13(16),14-dien-2-one (1) and 19-dehydroxy-spongian diterpene 17 (2), along with five known terpenes, the spongian furanoditerpenes 9-nor-3-hydroxyspongia-3,13(16),14-trien-2-one (3), 3β,19 dihydroxyspongia-13(16),14-dien-2-one (epispongiadiol) (4) and spongian diterpene 17 (5), the furanoditerpene ambliol C (6), and the sesterterpene scalarin (7), were isolated from the methanolic extract of the sponge Spongia tubulifera, collected in the Mexican Caribbean. The planar structures of the new compounds were elucidated by 1D/2D NMR and IR spectroscopic analysis, high resolution electrospray mass spectrometry (HRESIMS), and comparison of their spectral data with those reported in the literature. Absolute configurations were determined by comparison of the experimental electronic circular dichroism (ECD) spectrum with those calculated by time-dependent density functional theory (TDDFT). Compounds 1, 4, and 6 displayed weak cytotoxic activity against different human tumour cell lines.Ministerio de Economía y Competitividad; AGL2015-63740-C2-2-RMinisterio de Economía y Competitividad; RTC-2016-4611-

Uptake of sympagic organic carbon by the Barents Sea benthos linked to sea ice seasonality

On Arctic shelves, where primary production occurs in both the pelagic and sympagic (ice-associated) habitats, sympagic organic material (OM) can constitute a disproportionate fraction of benthic diets due to higher sinking rates and lower grazing pressure than pelagic OM. Less documented is how sympagic OM assimilation across feeding guilds varies seasonally and in relation to sea ice duation. We therefore investigated the relative abundance of sympagic vs pelagic OM in Barents Sea shelf megabenthos in the summer and winter of 2018 and 2019, from 10 stations where sea ice duration ranged from 0 to 245 days per year. We use highly branched isoprenoids, which are lipid biomarkers produced with distinct molecular structures by diatoms in sea ice and the water column, to determine the ratio of sympagic-to-pelagic OM assimilated by benthic organisms. From 114 samples of 25 taxa analysed, we found that the proportion of sympagic OM assimilated ranged from 0.4% to 95.8% and correlated strongly (r2 = 0.754) with the duration of sea ice cover. The effect of sea ice duration was more evident in fauna collected during summer than winter, indicating that sympagic signals are more evident in the summer than in the winter at higher latitudes. Our data show that sympagic production can supply a high fraction of carbon for Barents Sea benthos, although this is highly variable and likely dependent on availability and patchiness of sympagic OM deposition. These results are comparable to similar studies conducted on benthos in the Pacific Arctic and highlight the variable importance of sympagic OM in the seasonal ice zone of Arctic inflow shelves, which are the Arctic regions with highest rates of sea ice loss.publishedVersio

Small molecule inhibitors of CRM1

The transport through the nuclear pore complex is used by cancer cells to evade tumor-suppressive mechanisms. Several tumor-suppressors have been shown to be excluded from the cell nucleus in cancer cells by the nuclear export receptor CRM1 and abnormal expression of CRM1 is oncogenic. Inhibition of CRM1 has long been postulated as potential approach for the treatment of cancer and to overcome therapy resistance. Furthermore, the nuclear export of viral components mediated by the CRM1 is crucial in various stages of the viral lifecycle and assembly of many viruses from diverse families, including coronavirus. However, the first nuclear export inhibitors failed or never entered into clinical trials. More recently CRM1 reemerged as a cancer target and a successful proof of concept was achieved with the clinical approval of Selinexor. The chemical complexity of natural products is a promising perspective for the discovery of new nuclear export inhibitors with a favorable toxicity profile. Several screening campaigns have been performed and several natural product-based nuclear export inhibitors have been identified. With this review we give an overview over the role of CRM1-mediated nuclear export in cancer and the effort made to identify and develop nuclear export inhibitors in particular from natural sources.This work was supported by Fundação para a Ciência e a Tecnologia (FCT) Research Center Grant UID/BIM/04773/2013 Centre for Biomedical Research 1334 and by the Spanish Ministry of Science, Innovation and Universities through Grant RTI2018-094629-B-I00 to WL. BF was supported by FCT-SFRH/BPD/100434/2014 and Marie Curie Individual Fellowship project TRIBBLES (#748585). This work was also supported by two LPCC-NRS/Terry Fox grants (2016/2017; 2017/2018).info:eu-repo/semantics/publishedVersio

Bioactivities and extract dereplication of actinomycetales isolated from marine sponges

In the beginning of the twenty-first century, humanity faces great challenges regarding diseases and health-related quality of life. A drastic rise in bacterial antibiotic resistance, in the number of cancer patients, in the obesity epidemics and in chronic diseases due to life expectation extension are some of these challenges. The discovery of novel therapeutics is fundamental and it may come from underexplored environments, like marine habitats, and microbial origin. Actinobacteria are well-known as treasure chests for the discovery of novel natural compounds. In this study, eighteen Actinomycetales isolated from marine sponges of three Erylus genera collected in Portuguese waters were tested for bioactivities with the main goal of isolating and characterizing the responsible bioactive metabolites. The screening comprehended antimicrobial, anti-fungal, anti-parasitic, anti-cancer and anti-obesity properties. Fermentations of the selected strains were prepared using ten different culturing media. Several bioactivities against the fungus Aspergillus fumigatus, the bacteria Staphylococcus aureus methicillin-resistant (MRSA) and the human liver cancer cell line HepG2 were obtained in small volume cultures. Screening in higher volumes showed consistent anti-fungal activity by strain Dermacoccus sp. #91-17 and Micrococcus luteus Berg02-26. Gordonia sp. Berg02-22.2 showed anti-parasitic (Trypanosoma cruzi) and anti-cancer activity against several cell lines (melanoma A2058, liver HepG2, colon HT29, breast MCF7 and pancreatic MiaPaca). For the anti-obesity assay, Microbacterium foliorum #91-29 and #91-40 induced lipid reduction on the larvae of zebrafish (Danio rerio). Dereplication of the extracts from several bacteria showed the existence of a variety of secondary metabolites, with some undiscovered molecules. This work showed that Actinomycetales are indeed good candidates for drug discovery.This research was partially supported by the Strategic Funding UID/Multi/04423/2013 through national funds provided by FCT – Foundation for Science and Technology and European Regional Development Fund (ERDF), in the framework of the programme PT2020, the EU H2020-TWINN-2015, BLUEandGREEN – Boosting scientific excellence and innovation capacity in biorefineries based on marine resources (Project No. 692419) and the European ERA-NET Marine Biotechnology project CYANOBESITY (ERA-MBT/0001/2015), financed by national funds through FCT (Foundation for Science and Technology, Portugal). Ralph Urbatzka was supported by a FCT postdoc grant (SFRH/BPD/112287/2015). The MEDINA authors disclosed the receipt of financial support from Fundación MEDINA, a public-private partnership of Merck Sharp & Dohme de España S.A./Universidad de Granada/Junta de Andalucía. Moreover, some of the equipment used in this work was supported by the Ministerio de Ciencia e Innovación and the European Union (Grant INP-2011-0016-PCT-010000-ACT6)

Synthesis of Trichodermin Derivatives and Their Antimicrobial and Cytotoxic Activities

Trichothecene mycotoxins are recognized as highly bioactive compounds that can be used in the design of new useful bioactive molecules. In Trichoderma brevicompactum, the first specific step in trichothecene biosynthesis is carried out by a terpene cyclase, trichodiene synthase, that catalyzes the conversion of farnesyl diphosphate to trichodiene and is encoded by the tri5 gene. Overexpression of tri5 resulted in increased levels of trichodermin, a trichothecene-type toxin, which is a valuable tool in preparing new molecules with a trichothecene skeleton. In this work, we developed the hemisynthesis of trichodermin and trichodermol derivatives in order to evaluate their antimicrobial and cytotoxic activities and to study the chemo-modulation of their bioactivity. Some derivatives with a short chain at the C-4 position displayed selective antimicrobial activity against Candida albicans and they showed MIC values similar to those displayed by trichodermin. It is important to highlight the cytotoxic selectivity observed for compounds 9, 13, and 15, which presented average IC50 values of 2 g/mL and were cytotoxic against tumorigenic cell line MCF-7 (breast carcinoma) and not against Fa2N4 (non-tumoral immortalized human hepatocytes)

Antiviral and Antiproliferative Potential of Marine Organisms from the Yucatan Peninsula, Mexico

[Abstract] Viral infections are one of the main human health problems in recent decades and the cancer remains one of the most lethal diseases worldwide. The development of new antiviral drugs for the treatment of human adenovirus (HAdV) infections continues to be a challenging goal for medicinal chemistry. There is no specific antiviral drug approved to treat infections caused by HAdV so far and the off-label treatments currently available show great variability in their effectiveness. In relation to cancer, most of the available drugs are designed to act on specific targets by altering the activity of involved transporters and genes. Taking into account the high antiviral and antiproliferative activity against tumor cell lines displayed by some marine natural products reported in the literature, sixty five marine organisms were selected: 51 sponges (Porifera), 13 ascidians (Chordata), and 1 gorgonian (Cnidaria), collected from Yucatan Peninsula, Mexico, to evaluate their antiviral activity against human adenovirus type 5 (HAdV5) and their anticancer properties against five human tumor cell lines, namely human lung carcinoma (A549), human skin melanoma (A2058), hepatocyte carcinoma (HepG2), breast adenocarcinoma (MCF7), and pancreas carcinoma (MiaPaca-2). Eleven extracts displayed anti-HAdV activity being the organic extracts of Dysidea sp., Agelas citrina, Chondrilla sp., Spongia tubulifera, and Monanchora arbuscula the five most active ones. On the other hand, 24 extracts showed antiproliferative activity against at least one tumor cell line, being the extracts of the ascidian Eudistoma amanitum and the sponge Haliclona (Rhizoniera) curacaoensis the most active ones. This work constitutes the first wide antiviral and antiproliferative screening report of extracts from the marine sponges, ascidians, and a gorgonian collected from the Yucatan Peninsula, Mexico.This work was supported by Grants RTI2018-093634-B-C22 and RTC-2016-4611-1 (AEI/FEDER, EU) from the State Agency for Research (AEI) of Spain, both co-funded by the FEDER Programme from the European Union, BLUEBIOLAB (0474_BLUEBIOLAB_1_E), Programme INTERREG V A of Spain-Portugal (POCTEP). The study was also funded by projects GRC2018/039 and Agrupación Estratégica CICA-INIBIC ED431E 2018/03 (Consejería de Educación, Universidad y Formación Profesional de la Junta de Galicia) from the Xunta de Galicia (autonomous government of the region). DP-P received a fellowship from the program National Council of Science and Technology (CONACYT) of Mexico and the Secretariat of Research, Innovation and Higher Education (SIIES) of Yucatan (Mexico). Also supported by Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009) – co-financed by “A way to achieve Europe” ERDF, the Instituto de Salud Carlos III, Proyectos de Desarrollo Tecnológico en Salud (DTS17/00130 and PI18/01191), and the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT). JS-C is a researcher belonging to the program “Nicolás Monardes” (C-0059-2018), Servicio Andaluz de Salud, Junta de Andalucía, Spain. The antiproliferative studies were financed with internal funds from Fundación MEDINAXunta de Galicia; 0474_BLUEBIOLAB_1_EXunta de Galicia; GRC2018/039Xunta de Galicia; ED431E 2018/03Junta de Andalucía; C-0059-201

Dermacozine N, the First Natural Linear Pentacyclic Oxazinophenazine with UV–Vis Absorption Maxima in the Near Infrared Region, Along with Dermacozines O and P Isolated from the Mariana Trench Sediment Strain Dermacoccus abyssi MT 1.1T

Three dermacozines, dermacozines N–P (1–3), were isolated from the piezotolerant Actinomycete strain Dermacoccus abyssi MT 1.1T, which was isolated from a Mariana Trench sediment in 2006. Herein, we report the elucidation of their structures using a combination of 1D/2D NMR, LC-HRESI-MSn, UV–Visible, and IR spectroscopy. Further confirmation of the structures was achieved through the analysis of data from density functional theory (DFT)–UV–Visible spectral calculations and statistical analysis such as two tailed t-test, linear regression-, and multiple linear regression analysis applied to either solely experimental or to experimental and calculated 13C-NMR chemical shift data. Dermacozine N (1) bears a novel linear pentacyclic phenoxazine framework that has never been reported as a natural product. Dermacozine O (2) is a constitutional isomer of the known dermacozine F while dermacozine P (3) is 8-benzoyl-6-carbamoylphenazine-1-carboxylic acid. Dermacozine N (1) is unique among phenoxazines due to its near infrared (NIR) absorption maxima, which would make this compound an excellent candidate for research in biosensing chemistry, photodynamic therapy (PDT), opto-electronic applications, and metabolic mapping at the cellular level. Furthermore, dermacozine N (1) possesses weak cytotoxic activity against melanoma (A2058) and hepatocellular carcinoma cells (HepG2) with IC50 values of 51 and 38 μM, respectively

Synthesis, characterization and complex evaluation of antibacterial activity and cytotoxicity of new arylmethylidene ketones and pyrimidines with camphane skeletons

The synthesis of 20 arylidenecamphors and 15 pyrimidines with camphane skeleton is described in the current report. A modified method for preparation of sterically hindered 2- aminopyrimidines in two steps was demonstrated. The evaluation of their in vitro activity against Mycobacterium tuberculosis H37Rv showed different MIC values (up to 0.91 μM for ketone 39). Compound 35 demonstrated moderate (8.23 μM), but sustainable activity toward a collection of drug-resistant M. tuberculosis strains. Many of the compounds (especially among 2-aminopyridines 42–56) exhibited good to excellent activity against different strains of pathogenic bacteria and fungi (MIC up to 0.60 μM for compound 50), compared with reference antibiotics. Many of the newly designed compounds possess also in vitro cytotoxicity.This study was supported by: Bulgarian National Science Fund- project KP-06-H39/7 and Spanish Ministry of Science, Innovation and Universities- Grant RTI2018-094629-BI00. MEDINA’s authors disclosed the receipt of financial support from Fundación MEDINA, a public-private partnership of Merck Sharp and Dohme de EspañaS.A./Universidad de Granada/Junta de Andalucía