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The green macroalga Ulva rigida represents a promising feedstock for biorefinary due to its fast growth and cosmopolitan distribution. The main component of the cell walls of U. rigida is a sulfated glucuronorhamnan polysaccharide known as ulvan. Herein it was found that due to the high (hydrogen)sulfate group content of ulvan, hydrothermal autohydrolysis at 130 °C renders a high percentage of rhamnose (78–79 % recovery from the initial content in the raw material), a rare sugar of high added value. In addition, acid catalysis by a triflate-based graphene oxide under oxygen-free conditions at 180 °C affords moderate amounts of tartaric acid (24–26 %). The same triflate-based graphene oxide catalyst under oxygen pressure yields remarkably high percentages of succinic acid (65 %). The catalyst preserves its activity for at least five consecutive reuses., Financial support by the Spanish Ministry of Economy and Competitiveness (Severo Ochoa SEV2016-0683, RTI2018-890237-CO2-R1) and Generalitat Valenciana (Prometeo 2017−083) is gratefully acknowledged. Vasile I. Parvulescu kindly acknowledges UEFISCDI for financial support (project PN-III-P4-ID-PCE-2016-0146, Nr. 121/2017).

Proteasome activation has been shown to promote cellular and organismal healthspan and to protect against aggregation-related conditions, such as Alzheimer's disease (AD). Various natural compounds have been described for their proteasome activating properties but scarce data exist on marine metabolites that often possess unique chemical structures, exhibiting pronounced bioactivities with novel mechanisms of action. In this study, we have identified for the first time a marine structural proteasome activator, namely (1R,3E,6R,7Z,11S,12S)-dolabella-3,7,18-trien-6,17-olide (DBTO). DBTO activates the 20S proteasome complex in cell-free assays but also in cellulo. Continuous supplementation of human primary fibroblasts with DBTO throughout their cellular lifespan confers an improved healthspan while ameliorated health status is also observed in wild type (wt) Caenorhabditis elegans (C. elegans) nematodes supplemented with DBTO. Furthermore, treatment of various AD nematode models, as well as of human cells of neuronal origin challenged with exogenously added Aβ peptide, with DBTO results in enhanced protection against Aβ-induced proteotoxicity. In total, our results reveal the first structural proteasome activator derived from the marine ecosystem and highlight its potential as a compound that might be used for healthspan maintenance and preventive strategies against proteinopathies, such as AD.

Ulvan, a sulphated polysaccharide located in the cell walls of green algae that possesses unique structural properties albeit its repeating unit shares chemical affinity with glycosoaminoglycans, such as hyaluronan and chondroitin sulphate, has been increasingly studied over the years for applications in the pharmaceutical field. The increasing knowledge on ulvan's chemical properties and biological activities has triggered its utilization in hybrid materials, given its potential efficacy in biomedical applications. In the present review, the use of ulvan in the design of different biomaterials, including membranes, particles, hydrogels, 3D porous structures and nanofibers, is presented. The applications of these structures may vary from drug delivery to wound dressing or bone tissue engineering. In this context, general information regarding the structure and chemical variability, extraction processes, physicochemical properties, and biological activities of ulvan is reported.

Hybrid composites of synthetic and natural polymers represent materials of choice for bone tissue engineering. Ulvan, a biologically active marine sulfated polysaccharide, is attracting great interest in the development of novel biomedical scaffolds due to recent reports on its osteoinductive properties. Herein, a series of hybrid polycaprolactone scaffolds containing ulvan either alone or in blends with κ-carrageenan and chondroitin sulfate was prepared and characterized. The impact of the preparation methodology and the polysaccharide composition on their morphology, as well as on their mechanical, thermal, water uptake and porosity properties was determined, while their osteoinductive potential was investigated through the evaluation of cell adhesion, viability, and osteogenic differentiation of seeded human adipose-derived mesenchymal stem cells. The results verified the osteoinductive ability of ulvan, showing that its incorporation into the polycaprolactone matrix efficiently promoted cell attachment and viability, thus confirming its potential in the development of biomedical scaffolds for bone tissue regeneration applications.

The ubiquitin-proteasome system (UPS) is a key player in the maintenance of cellular protein homeostasis (proteostasis). Since proteasome function declines upon aging leading to the acceleration of its progression and the manifestation of age-related pathologies, many attempts have been performed towards proteasome activation as a strategy to promote healthspan and longevity. The marine environment hosts a plethora of organisms that produce a vast array of primary and secondary metabolites, the majority of which are unique, exhibiting a wide spectrum of biological activities. The fact that these biologically important compounds are also present in edible marine organisms has sparked the interest for elucidating their potential health-related applications. In this review, we focus on the antioxidant, anti-aging, anti-aggregation and anti-photoaging properties of various marine constituents. We further discuss representatives of marine compounds classes with regard to their potential (direct or indirect) action on UPS components that could serve as UPS modulators and exert beneficial effects on conditions such as oxidative stress, aging and age-related diseases., Graphical abstract Image 1, Highlights • Proteasome has been implicated in oxidative stress, aging and age-related diseases. • Various marine natural products exert strong antioxidant activities. • Various marine natural products possess anti-aging and anti-aggregation properties. • Various marine natural products can serve as potential proteasome modulators. • Various marine natural products represent promising anti-photoaging agents.

CXCR4 chemokine receptor represents an attractive pharmacological target due to its key role in cancer metastasis and inflammatory diseases. Starting from our previously-developed pharmacophoric model, we applied a combined computational and experimental approach that led to the identification of the hydantoin alkaloids parazoanthines, isolated from the Mediterranean Sea anemone Parazoanthus axinellae, as novel CXCR4 antagonists. Parazoanthine analogues were then synthesized to evaluate the contribution of functional groups to the overall activity. Within the panel of synthesized natural and non-natural parazoanthines, parazoanthine-B was identified as the most potent CXCR4 antagonist with an IC50 value of 9.3 nM, even though all the investigated compounds were able to antagonize in vitro the down-stream effects of CXC12, albeit with variable potency and efficacy. The results of our study strongly support this class of small molecules as potent CXCR4 antagonists in tumoral pathologies characterized by an overexpression of this receptor. Furthermore, their structure–activity relationships allowed the optimization of our pharmacophoric model, useful for large-scale in silico screening.

In this work sixteen hydroxyl ammonium Protic Ionic Liquids derived from a proton transfer reaction between four different substituted amines and four different low molecular weight aliphatic and alicyclic carboxylic acids have been synthesized. The synthesized PILs were structurally characterized by NMR and FT-IR spectroscopy whereas two of their more important physicochemical properties namely viscosity and glass transition temperature (T g ) were evaluated. The effect of alkyl chain length and substitution on the anionic and cationic component of the PILs scaffold has been discussed for the studied properties. It seems that T g values are mainly affected by the carboxylate anion structure whereas viscosity is controlled mainly by the structural features of the cationic part of the PILs. In order to estimate their environmental impact and reinforce their “green” character, biodegradation studies, as well as toxicity evaluation experiments have also been conducted. The synthesized PILs can be confidently labelled as green considering that they are not toxic or present low toxicity to the nauplii of the brine shrimp A. salina whereas they show biodegradability levels between 41–64%, according to the manometric respirometric method which measures the biological oxygen demand (BOD 5 ) by microorganisms in order to degrade PILs via bio-oxidation in five days.

Twenty one sesquiterpenes were isolated from the organic extract of the Caribbean gorgonian Pseudopterogogia rigida. Among them, seven bisabolanes (1, 2, 9–11, 13 and 14), six cadinanes (15–20) and one sesquiterpene featuring a new tricyclic carbon skeleton (21) are new natural products, while two (6 and 7) are reported for the first time from a natural source. The structures of the new compounds were established by detailed analyses of their NMR and MS data. The isolated metabolites were evaluated for their inhibitory activity against CDC25 phosphatases, which represent possible targets related to cancer therapy. Compounds 4 and 18 were the most active with IC50 values of 1.88 and 3.44 μM, respectively, against the CDC25A isoform.

Six new (1, 2, and 4-7) and two previously reported (3 and 8) disulfides, along with 4-butyl-2,6-cycloheptadienone, γ-tocopherol, and δ-tocopherol, were isolated from an organic extract of the brown alga Dictyopteris membranacea, collected at Gerolimenas Bay, Greece. The structure elucidation of the isolated natural products was based on analysis of their spectroscopic data. Compounds 1, 3-6, and 8 were evaluated for their antibacterial and anti-inflammatory activities. None of the compounds displayed antibacterial activity against two resistant strains of Staphylococcus aureus and one strain of Escherichia coli. In contrast, metabolite 5 was able to cause strong inhibition of NO production with an IC50 value of 3.8 μM using an LPS stimulation assay.

Vagiallene (1), a rearranged C15 acetogenin with a molecular formula and a carbon skeleton unprecedented in natural products, was isolated as a trace constituent from the organic extract of the red alga Laurencia obtusa from Lefkada island. The planar structure and the relative configuration of 1 were established on the basis of extensive analysis of its spectroscopic data, while its absolute configuration was determined by comparison of its experimental and quantum-mechanically predicted electronic circular dichroism spectra.

Covering: 1957 to 2017 Algae constitute a heterogeneous group of eukaryotic photosynthetic organisms, mainly found in the marine environment. Algae produce numerous metabolites that help them cope with the harsh conditions of the marine environment. Because of their structural diversity and uniqueness, these molecules have recently gained a lot of interest for the identification of medicinally useful agents, including those with potential anticancer activities. In the current review, which is not a catalogue-based one, we first highlight the major biological events that lead to various types of cancer, including metastatic ones, to chemoresistance, thus to any types of current anticancer treatment relating to the use of chemotherapeutics. We then review algal metabolites for which scientific literature reports anticancer activity. Lastly, we focus on algal metabolites with promising anticancer activity based on their ability to target biological characteristics of cancer cells responsible for poor treatment outcomes. Thus, we highlight compounds that have, among others, one or more of the following characteristics: selectivity in reducing the proliferation of cancer cells over normal ones, potential for killing cancer cells through non-apoptotic signaling pathways, ability to circumvent MDR-related efflux pumps, and activity in vivo in relevant pre-clinical models.

Terpenes are a large class of natural products, many of which are used in cosmetics, pharmaceuticals, or biofuels. However, terpene's industrial application is frequently hindered by limited availability of natural sources or low yields of chemical synthesis. In this report, we developed a modular platform based on standardized and exchangeable parts to reproduce and potentially expand the diversity of terpene structures in Saccharomyces cerevisiae. By combining different module-specific parts, we exploited the substrate promiscuity of class I diterpene synthases to produce an array of labdane-type scaffolds. These were subsequently modified by a scaffold decoration module consisting of a mutant library of a promiscuous cytochrome P450 to afford a range of hydroxylated diterpenes. Further P450 protein engineering yielded dedicated and efficient catalysts for specific products. Terpenes produced include precursors of pharmacologically important compounds, molecules that are difficult to obtain from natural sources, or new natural products. The approach described here provides a platform on which additional gene mining, combinatorial biosynthesis, and protein engineering efforts can be integrated to sustainably explore the terpene chemical space.

This work was performed under the frame of COST Action collaboration (COST Action CM1106). The generous contribution of AIRC (The Italian Association for Cancer Research) IG14536 to G.D. is gratefully acknowledged. A.H. acknowledges support from the János Bolyai fellowship of the Hungarian Academy of Sciences. Background: Epithelial ovarian cancer has a poor prognosis, mostly due to its late diagnosis and to the development of drug resistance after a first platinum-based regimen. The presence of a specific population of “cancer stem cells” could be responsible of the relapse of the tumor, and of the development of resistance to therapy. For this reason, it would be important to specifically target this subpopulation of tumor cells in order to increase the response to therapy. Method: We screened a chemical compound library assembled during the COST CM1106 action to search for compound classes active in targeting ovarian stem cells. We here report the results of the high-throughput screening assay in two ovarian cancer stem cells and the differentiated cells derived from them. Results and conclusion: Interestingly there were compounds active only on stem cells, only on differentiated cells and compounds active on both cell populations. Even if these data need to be validated in ad hoc dose response cytotoxic experiments, the ongoing analysis of the compound structures will open up to mechanistic drug studies to select compounds able to improve the prognosis of ovarian cancer patients. Postprint

A chemical investigation of the organic extract of the sea hare Aplysia depilans, collected off Skyros Island, Greece, yielded eight new brominated diterpenes (1-8), featuring the rare dactylomelane skeleton, together with the previously reported luzodiol (9). The structure elucidation and the assignment of the relative configurations of the new natural products were based on extensive NMR spectroscopic and MS spectrometric analyses. Compounds 1-9 were evaluated for their cytotoxic activities against five human tumor cell lines, but were proven inactive.

Protic Ionic Liquids (PILs) are promising solvents with desirable physicochemical properties for a variety of applications. They are considered as greener alternatives to common organic solvents but in order to efficiently be characterized as green their environmental impact has to be assessed. In the present study, the design, synthesis and an initial potential hazard assessment of 11 naphthenic and benzoic acid based PILs is presented. PILs’ “greenness” is enhanced considering that they are non-toxic according to the aquatic toxicity evaluation and most of them show satisfactorily to extremely high biodegradability level. Moreover, two of their most important physicochemical properties, viscosity and glass transition temperature (Tg), were determined for selected ILs. The effect of the aromatic and alicyclic ring on the anions, the size and the presence of a hydroxyl substituent at anions and cations has been also discussed for the studied environmental and physicochemical properties.

Seven new ( 1 – 3 , 5 and 8 – 10 ) and three previously reported ( 4 , 6 and 7 ) 4α-methylated steroids were isolated from the organic extract of the gorgonian Litophyton mollis . The structures and the relative configurations of the isolated natural products were determined on the basis of extensive analyses of their NMR and MS data. Metabolites 1 and 5 – 8 exhibited cytotoxic activity against K562 human chronic myelogenous leukemia cells with IC 50 values below 10 μM, while at the same time displaying low toxicity against healthy PBMCs.

Thirteen new minor diterpenes featuring the dolabellane skeleton (1-13) were isolated from the organic extracts of the brown alga Dilophus spiralis, collected in Elafonissos Island. The structures and relative configurations of the isolated natural products were elucidated on the basis of extensive analyses of their spectroscopic data (NMR, MS, IR). The absolute configuration of 1 was determined by using the modified Mosher's method, whereas the structure of 2 was confirmed by single-crystal X-ray diffraction analysis. The antibacterial activities of metabolites 1-9 and 13 were evaluated against six strains of Staphylococcus aureus, including multidrug- and methicillin-resistant variants. Compounds 1 and 4 exhibited noteworthy levels of activity with MIC values in the range of 2-8 μg/mL.

Bioactivity-guided separation of the aqueous methanolic extract of Yucca desmettiana leaves, which in a preliminary screening exhibited significant molluscicidal activity, led to the isolation and structure elucidation of two new steroidal saponins (1 and 2). The structures of desmettianosides A and B, identified as bisdesmosidic furostanol glycosides with six and five sugar units, respectively, were established by detailed spectroscopic analyses of their NMR and MS data. Compounds 1 and 2 exhibited high molluscicidal activity against Biomphalaria alexandrina snails with LC100 values of 6 and 11 mg/L, respectively.

The ability of a crude onion peroxidase preparation to act as a biocatalyst for the oxidative dimerization–cyclization of methyl p-coumarate, methyl caffeate and methyl ferulate is presented. The products of the reaction have been fully characterized and were found to possess potent antioxidant activity in a ferric reducing antioxidant power (FRAP) assay.

Glandulaurencianols A and B were isolated from the organic extract of the red alga, Laurencia glandulifera, collected from the island of Crete in South Greece. Investigation of the mollusk, Aplysia punctata, collected from the coast of Nea Makri, Central Greece, resulted in the isolation of glandulaurencianols A and C. The structures of the new metabolites, as well as their relative configurations, were established on the basis of thorough analyses of their spectroscopic data.

Seventeen diterpenes featuring the dolabellane skeleton (1-17) were isolated from the organic extracts of the brown alga Dilophus spiralis. Seven compounds are new natural products (1, 3, 5, 6, 11, 14, 15) and eight are structurally revised (2, 4, 7-10, 12, 13), among which three are reported for the first time from a natural source (4, 9, 10). The structure elucidation and the assignment of the relative configurations of the isolated natural products were based on detailed analyses of their spectroscopic data. The structure of metabolite 10 was confirmed by single-crystal X-ray diffraction analysis, whereas the absolute configurations of compounds 2, 4-10, 12, and 13 were determined using the modified Mosher's method on the semisynthetic product 18 and chemical interconversions. The antibacterial activities of compounds 1-18 were evaluated against six strains of Staphylococcus aureus, including multidrug- and methicillin-resistant variants.

Seven new (1-7) and seven previously reported (8-14) halogenated metabolites were isolated from the organic extract of the Brazilian red alga Laurencia catarinensis. The structure elucidation and the assignment of the relative configurations of the new natural products were based on detailed NMR and MS spectroscopic analyses, whereas the structure of metabolite 6 was confirmed by single-crystal X-ray diffraction analysis. The absolute configuration of metabolite 1 was determined using the modified Mosher's method. The in vitro cytotoxicity of compounds 1-14 was evaluated against HT29, MCF7, and A431 cell lines.

Seven new diterpenes, featuring the rare 2,6-cyclo-xenicane skeleton, along with eleven previously reported metabolites were isolated from the organic extracts of the brown algae Dilophus fasciola and Dilophus spiralis. The structure elucidation of the isolated natural products was based on detailed analyses of their spectroscopic data (NMR, MS, IR, UV), whereas the assignment of their relative configurations was assisted by molecular modelling studies.

Examination of the digestive and hermaphroditic glands' organic extract of the sea hare Aplysia fasciata yielded 16 metabolites, including eight sesquiterpenes, three diterpenes, and five C(15)-acetogenins. Among them, three sesquiterpenes, 6-hydroxy-1-brasilene (1), epibrasilenol acetate (2), and 6-epi-beta-snyderol (3), one acetogenin, (3Z,9Z)-7-chloro-6-hydroxy-12-oxo-pentadeca-3,9-dien-1-yne (4), and one diterpene, 16-acetoxy-15-bromo-7-hydroxy-9(11)-parguerene (5), are new natural products. The structure elucidation and the assignment of the relative configurations of the isolated natural products were established on the basis of extensive analyses of their spectroscopic data (NMR, MS, IR).

Three new (1, 4, 9) and nine previously reported (2, 3, 5-8, 10-12) 5alpha,8alpha-epidioxysterols were isolated from the organic extracts of the gorgonian Eunicella cavolini and the ascidian Trididemnum inarmatum. The structures and relative configurations of 1-12 were established on the basis of detailed NMR spectroscopic analyses and comparison with the literature. The growth inhibitory effects of 1-12 were evaluated against MCF-7 human breast cancer cells. Compound 1, bearing a cyclopropyl moiety in the side chain, exhibited the highest antiproliferative activity.

Four new natural products (1–4), along with three previously reported metabolites (5–7), all belonging to the pregnane class of steroids were isolated from the organic extract of the gorgonian Eunicella cavolini. The structures and relative configurations of the isolated compounds were determined through NMR spectroscopic techniques and chemical interconversions, while their absolute stereochemistry was determined using the modified Mosher's method. Activity evaluation of 1–7 towards MCF-7 human breast cancer cells showed partial growth inhibitory effects for all metabolites bearing an 11α-acetoxy moiety.

Five new dolastanes (1–5) were isolated from the brown alga Dilophus spiralis. The structural elucidation of the isolated compounds and the assignment of relative stereochemistry were based on analyses of their spectroscopic data. The structure proposed for 1 was confirmed by single crystal X-ray diffraction analysis, whereas its absolute stereochemistry was determined using the modified Mosher's method. The cytotoxicity of 1–4 was evaluated against seven cell lines.

The essential oils of the flower heads and leaves of Santolina rosmarinifolia L. (Compositae) cultivated in Romania were obtained through hydrodistillation and analysed by GC-MS. Forty-two components were identified, representing 92.3-94.0% of the whole composition of the samples. Their in vitro antimicrobial activity against gram-positive and gram-negative bacteria strains and the fungus Candida albicans was determined using the agar-diffusion method and the broth dilution method.

Perezoperezone (1), curcuperezone (2), and diperezone (3), belonging to the rare class of bisabolane dimers, were isolated as minor constituents of the organic extract of the Caribbean soft coral, Pseudopterogorgia rigida. The structures of the new compounds 1 and 2 were established by detailed analyses of their NMR and MS data. 2013 Published by Elsevier Ltd.

Dilospiranes A and B (1 and 2), two diterpenes featuring unprecedented carbocycles, were isolated from the organic extract of the brown alga Dilophus spiralis, collected from the coast of Elafonissos Island, Greece. The structures and the relative configurations of the isolated natural products were determined on the basis of extensive analyses of their spectroscopic data.

Extracts from three Origanum species, including Origanum microphyllum, Origanum dictamnus and Origanum vulgare subsp. hirtum, native to the island of Crete (southern Greece), were partly fractionated through successive partition with ethyl acetate and n-butanol. All the fractions obtained were profiled with regard to their major polyphenolic constituents, using liquid chromatography-diode array-mass spectrometry. Furthermore, the antioxidant potency of each fraction was assessed by estimating the antiradical activity (A(AR)) and the hydroxyl free radical scavenging activity (SA(HFR)). The chromatographic analyses revealed a rich profile mainly for the ethyl acetate fractions, composed principally by flavones, which were accompanied by a limited number of phenylpropanoids, flavanones and dihydroflavonols. The highest values of antioxidant activity were displayed by the ethyl acetate extract of O. dictamnus, which also possessed the richest polyphenolic composition.

Parnapimarol (1), a new pimarane diterpene, along with nepetaparnone (2) and nepetanudone (3), one new and one previously reported nepetalactone dimer, respectively, were isolated from the dichloromethane extract of the aerial parts of Nepeta parnassica, collected on Mt. Parnassos, Greece. The structures and relative configurations of 1-3 were determined on the basis of their spectroscopic characteristics (1D and 2D NMR, IR, MS). The structure of 2 was confirmed by single-crystal X-ray diffraction analysis. The insecticidal activity of 1-3 against ants and mosquito larvae was also evaluated.

Three new dolastane diterpenes (1-3) and five previously reported perhydroazulenes were isolated from the organic extracts of the brown alga Dilophus spiralis. The structure elucidation and the assignment of the relative configurations of the isolated natural products were based on extensive analyses of their spectroscopic data, whereas the absolute configuration of metabolite 2 was determined through its chemical conversion to a previously isolated compound of known configuration.

Four new 9,11-secosterols (2, 4-6), along with two previously reported ones (1, 3) were isolated from the organic extract of the gorgonian Eunicella cavolini. The structures and relative configurations of the isolated natural products were established on the basis of detailed NMR spectroscopic analysis. Metabolites 1 and 2 were found to strongly inhibit the growth of LNCaP human prostate adenocarcinoma cells and the estrogen-dependent growth of MCF-7 human breast adenocarcinoma cells.