Marine Drugs

Puupehenone and puupehedione are natural products isolated from marine organisms. These compounds display a broad spectrum of biological activities, the in vitro antitubercular activity of puupehenone being a stand out, and are equipped with an interesting structural complexity. These products have served to stimulate the continual interest of the synthetic community. The first part of this article is a review of their total synthesis, using natural compounds which have the potential to be transformed into these marine compounds as starting materials; the synthetic routes employed to generate the basic skeleton; and the advances made to synthesize the pyran C ring with the required diastereoselectivity to obtain the natural products. Finally, this perspective shows a personal reflection of the authors on a possible unified and efficient retrosynthetic route that could allow easy access to these natural products, as well as their epimers at the C8 carbon and which could be used to address future biological issues in the production of pharmacologically active compounds. Full article

The biomass of microalgae and the compounds that can be obtained from their processing are of great interest for various economic sectors. Chlorophyll from green microalgae has biotechnological applications of great potential in different industrial areas such as food, animal feed, pharmaceuticals, cosmetics, and agriculture. In this paper, the experimental, technical and economic performance of biomass production from a microalgal consortium (Scenedesmus sp., Chlorella sp., Schroderia sp., Spirulina sp., Pediastrum sp., and Chlamydomonas sp.) was investigated in three cultivation systems (phototrophic, heterotrophic and mixotrophic) in combination with the extraction of chlorophyll (a and b) on a large scale using simulation; 1 ha was established as the area for cultivation. In the laboratory-scale experimental stage, biomass and chlorophyll concentrations were determined for 12 days. In the simulation stage, two retention times in the photobioreactor were considered, which generated six case studies for the culture stage. Subsequently, a simulation proposal for the chlorophyll extraction process was evaluated. The highest microalgae biomass concentration was 2.06 g/L in heterotrophic culture, followed by mixotrophic (1.98 g/L). Phototrophic and mixotrophic cultures showed the highest chlorophyll concentrations of 20.5 µg/mL and 13.5 µg/mL, respectively. The simulation shows that higher biomass and chlorophyll production is attained when using the mixotrophic culture with 72 h of retention that we considered to evaluate chlorophyll production (a and b). The operating cost of the entire process is very high; the cultivation stage has the highest operating cost (78%), mainly due to the high energy consumption of the photobioreactors. Full article

Tetrodotoxin (TTX) and its analogues are naturally occurring toxins historically responsible for human poisoning fatalities in Eastern Asia. It is typically linked to the consumption of pufferfish and, to a lesser extent, marine gastropods and crabs. In the scope of a comprehensive project to understand the prevalence of emergent toxins in edible marine organisms, we report, for the first time, the detection of TTX analogues in the soft tissues of edible crabs, the European fiddler crab (Afruca tangeri) and green crab (Carcinus maenas), harvested in southern Portugal. No TTX was detected in the analyzed samples. However, three TTX analogues were detected—an unknown TTX epimer, deoxyTTX, and trideoxyTTX. These three analogues were found in the European fiddler crab while only trideoxyTTX was found in the green crab, suggesting that the accumulation of TTX analogues might be influenced by the crabs’ different feeding ecology. These results highlight the need to widely monitor TTX and its analogues in edible marine species in order to provide adequate information to the European Food Safety Authority and to protect consumers. Full article

One possible scheme of Rugulopteryx okamurae biomass valorization based on a green, rapid and efficient fractionation technique was proposed. Microwave-assisted pressurized hot water extraction was the technology selected as the initial stage for the solubilization of different seaweed components. Operation at 180 °C for 10 min with a 30 liquid-to-solid ratio solubilized more than 40% of the initial material. Both the alginate recovery yield (3.2%) and the phenolic content of the water-soluble extracts (2.3%) were slightly higher when distilled water was used as solvent. However, the carbohydrate content in the extract (60%) was similar for both solvents, but the sulfate content was higher for samples processed with salt water collected from the same coast as the seaweeds. The antiradical capacity of the extracts was related to the phenolic content in the extracts, but the cytotoxicity towards HeLa229 cancer cells was highest (EC₅₀ = 48 µg/mL) for the extract obtained with distilled water at the lowest temperature evaluated. Operation time showed a relevant enhancement of the extraction performance and bioactive properties of the soluble extracts. The further fractionation and study of this extract would be recommended to extend its potential applications. However, due to the low extraction yield, emphasis was given to the solid residue, which showed a heating value in the range 16,102–18,413 kJ/kg and could be useful for the preparation of biomaterials according to its rheological properties. Full article

Studies estimate that nearly 2 million new cases of gastric cancer will occur worldwide during the next two decades, which will increase mortality associated with cancer and the demand for new treatments. Marine algae of the Laurencia genus have secondary metabolites known for their cytotoxic action, such as terpenes and acetogenins. The species Laurencia obtusa has demonstrated cytotoxicity against many types of tumors in previous analyses. In this study, we determined the structure of terpenes, acetogenins, and one fatty acid of Laurencia using mass spectrometry (ESI-FT-ICR/MS). In vitro cytotoxicity assays were performed with adenocarcinoma gastric cells (AGS) to select the most cytotoxic fraction of the crude extract of L. obtusa. The Hex:AcOEt fraction was the most cytotoxic, with IC₅₀ 9.23 µg/mL. The selectivity index of 15.56 shows that the Hex:AcOEt fraction is selective to cancer cells. Compounds obtained from L. obtusa were tested by the analysis of crystallographic complexes. Molecular docking calculations on the active site of the HIF-2α protein showed the highest affinity for sesquiterpene chermesiterpenoid B, identified from HEX:AcOEt fraction, reaching a score of 65.9. The results indicate that L. obtusa presents potential compounds to be used in the treatment of neoplasms, such as gastric adenocarcinoma. Full article

The incorporation of bromine, iodine or fluorine into the tricyclic core structure of thiaplakortone A (1), a potent antimalarial marine natural product, is reported. Although yields were low, it was possible to synthesise a small nine-membered library using the previously synthesised Boc-protected thiaplakortone A (2) as a scaffold for late-stage functionalisation. The new thiaplakortone A analogues (3–11) were generated using N-bromosuccinimide, N-iodosuccinimide or a Diversinate™ reagent. The chemical structures of all new analogues were fully characterised by 1D/2D NMR, UV, IR and MS data analyses. All compounds were evaluated for their antimalarial activity against Plasmodium falciparum 3D7 (drug-sensitive) and Dd2 (drug-resistant) strains. Incorporation of halogens at positions 2 and 7 of the thiaplakortone A scaffold was shown to reduce antimalarial activity compared to the natural product. Of the new compounds, the mono-brominated analogue (compound 5) displayed the best antimalarial activity with IC₅₀ values of 0.559 and 0.058 μM against P. falciparum 3D7 and Dd2, respectively, with minimal toxicity against a human cell line (HEK293) observed at 80 μM. Of note, the majority of the halogenated compounds showed greater efficacy against the P. falciparum drug-resistant strain. Full article

The pharmacological treatment of cancer-related pain is unsatisfactory. Tetrodotoxin (TTX) has shown analgesia in preclinical models and clinical trials, but its clinical efficacy and safety have not been quantified. For this reason, our aim was to perform a systematic review and meta-analysis of the clinical evidence that was available. A systematic literature search was conducted in four electronic databases (Medline, Web of Science, Scopus, and ClinicalTrials.gov) up to 1 March 2023 in order to identify published clinical studies evaluating the efficacy and security of TTX in patients with cancer-related pain, including chemotherapy-induced neuropathic pain. Five articles were selected, three of which were randomized controlled trials (RCTs). The number of responders to the primary outcome (≥30% improvement in the mean pain intensity) and those suffering adverse events in the intervention and placebo groups were used to calculate effect sizes using the log odds ratio. The meta-analysis showed that TTX significantly increased the number of responders (mean = 0.68; 95% CI: 0.19–1.16, p = 0.0065) and the number of patients suffering non-severe adverse events (mean = 1.13; 95% CI: 0.31–1.95, p = 0.0068). However, TTX did not increase the risk of suffering serious adverse events (mean = 0.75; 95% CI: −0.43–1.93, p = 0.2154). In conclusion, TTX showed robust analgesic efficacy but also increased the risk of suffering non-severe adverse events. These results should be confirmed in further clinical trials with higher numbers of patients. Full article

The present study investigates the molecular characteristics of fucoidan obtained from the brown Irish seaweed Ascophyllum nodosum, employing hydrothermal-assisted extraction (HAE) followed by a three-step purification protocol. The dried seaweed biomass contained 100.9 mg/g of fucoidan, whereas optimised HAE conditions (solvent, 0.1N HCl; time, 62 min; temperature, 120 °C; and solid to liquid ratio, 1:30 (w/v)) yielded 417.6 mg/g of fucoidan in the crude extract. A three-step purification of the crude extract, involving solvents (ethanol, water, and calcium chloride), molecular weight cut-off filter (MWCO; 10 kDa), and solid-phase extraction (SPE), resulted in 517.1 mg/g, 562.3 mg/g, and 633.2 mg/g of fucoidan (p < 0.05), respectively. In vitro antioxidant activity, as determined by 1,1-diphenyl-2-picryl-hydrazyl radical scavenging and ferric reducing antioxidant power assays, revealed that the crude extract exhibited the highest antioxidant activity compared to the purified fractions, commercial fucoidan, and ascorbic acid standard (p < 0.05). The molecular attributes of biologically active fucoidan-rich MWCO fraction was characterised by quadruple time of flight mass spectrometry and Fourier-transform infrared (FTIR) spectroscopy. The electrospray ionisation mass spectra of purified fucoidan revealed quadruply ([M+4H]⁴⁺) and triply ([M+3H]³⁺) charged fucoidan moieties at m/z 1376 and m/z 1824, respectively, and confirmed the molecular mass 5444 Da (~5.4 kDa) from multiply charged species. The FTIR analysis of both purified fucoidan and commercial fucoidan standard exhibited O-H, C-H, and S=O stretching which are represented by bands at 3400 cm⁻¹, 2920 cm⁻¹, and 1220–1230 cm⁻¹, respectively. In conclusion, the fucoidan recovered from HAE followed by a three-step purification process was highly purified; however, purification reduced the antioxidant activity compared to the crude extract. Full article

Multidrug resistance (MDR) caused by ATP-Binding Cassette Subfamily B Member 1 (ABCB1, P-glycoprotein, P-gp) is a major barrier for the success of chemotherapy in clinics. In this study, we designed and synthesized a total of 19 Lissodendrins B analogues and tested their ABCB1-mediated MDR reversal activity in doxorubicin (DOX)-resistant K562/ADR and MCF-7/ADR cells. Among all derivatives, compounds D₁, D₂, and D₄ with a dimethoxy-substituted tetrahydroisoquinoline fragment possessed potent synergistic effects with DOX and reversed ABCB1-mediated drug resistance. Notably, the most potent compound D₁ merits multiple activities, including low cytotoxicity, the strongest synergistic effect, and effectively reversing ABCB1-mediated drug resistance of K562/ADR (RF = 1845.76) and MCF-7/ADR cells (RF = 207.86) to DOX. As a reference substance, compound D₁ allows for additional mechanistic studies on ABCB1 inhibition. The synergistic mechanisms were mainly related to the increased intracellular accumulation of DOX via inhibiting the efflux function of ABCB1 rather than from affecting the expression level of ABCB1. These studies suggest that compound D₁ and its derivatives might be potential MDR reversal agents acting as ABCB1 inhibitors in clinical therapeutics and provide insight into a design strategy for the development of ABCB1 inhibitors. Full article

The eradication of bacterial biofilm represents a crucial strategy to prevent a clinical problem associated with microbial persistent infection. In this study we evaluated the ability of the exopolysaccharide (EPS) B3-15, produced by the marine Bacillus licheniformis B3-15, to prevent the adhesion and biofilm formation of Pseudomonas aeruginosa ATCC 27853 and Staphylococcus aureus ATCC 29213 on polystyrene and polyvinyl chloride surfaces. The EPS was added at different times (0, 2, 4 and 8 h), corresponding to the initial, reversible and irreversible attachment, and after the biofilm development (24 or 48 h). The EPS (300 µg/mL) impaired the initial phase, preventing bacterial adhesion even when added after 2 h of incubation, but had no effects on mature biofilms. Without exerting any antibiotic activity, the antibiofilm mechanisms of the EPS were related to the modification of the (i) abiotic surface properties, (ii) cell-surface charges and hydrophobicity, and iii) cell-to-cell aggregation. The addition of EPS downregulated the expression of genes (lecA and pslA of P. aeruginosa and clfA of S. aureus) involved in the bacterial adhesion. Moreover, the EPS reduced the adhesion of P. aeruginosa (five logs-scale) and S. aureus (one log) on human nasal epithelial cells. The EPS could represent a promising tool for the prevention of biofilm-related infections. Full article

Industrial wastes with hazardous dyes serve as a major source of water pollution, which is considered to have an enormous impact on public health. In this study, an eco-friendly adsorbent, the porous siliceous frustules extracted from the diatom species Halamphora cf. salinicola, grown under laboratory conditions, has been identified. The porous architecture and negative surface charge under a pH of 7, provided by the various functional groups via Si–O, N–H, and O–H on these surfaces, revealed by SEM, the N₂ adsorption/desorption isotherm, Zeta-potential measurement, and ATR-FTIR, respectively, made the frustules an efficient mean of removal of the diazo and basic dyes from the aqueous solutions, 74.9%, 94.02%, and 99.81% against Congo Red (CR), Crystal Violet (CV), and Malachite Green (MG), respectively. The maximum adsorption capacities were calculated from isotherms, as follows: 13.04 mg g⁻¹, 41.97 mg g⁻¹, and 33.19 mg g⁻¹ against CR, CV, and MG, respectively. Kinetic and isotherm models showed a higher correlation to Pore diffusion and Sips models for CR, and Pseudo-Second Order and Freundlich models for CV and MG. Therefore, the cleaned frustules of the thermal spring-originated diatom strain Halamphora cf. salinicola could be used as a novel adsorbent of a biological origin against anionic and basic dyes. Full article

A shorter synthesis of the demethyl(oxy)aaptamine skeleton was developed via oxidative intramolecular cyclization of 1-(2-azidoethyl)-6-methoxyisoquinolin-7-ol followed by dehydrogenation with a hypervalent iodine reagent. This is the first example of oxidative cyclization at the ortho-position of phenol that does not involve spiro-cyclization, resulting in the improved total synthesis of 3-(phenethylamino)demethyl(oxy)aaptamine, a potent anti-dormant mycobacterial agent. Full article

Chemical interactions have been shown to regulate several marine life processes, including selection of food sources, defense, behavior, predation, and mate recognition. These chemical communication signals have effects not only at the individual scale, but also at population and community levels. This review focuses on chemical interactions between marine fungi and microalgae, summarizing studies on compounds synthetized when they are cultured together. In the current study, we also highlight possible biotechnological outcomes of the synthetized metabolites, mainly for human health applications. In addition, we discuss applications for bio-flocculation and bioremediation. Finally, we point out the necessity of further investigating microalgae-fungi chemical interactions because it is a field still less explored compared to microalga–bacteria communication and, considering the promising results obtained until now, it is worthy of further research for scientific advancement in both ecology and biotechnology fields. Full article

Sulfitobacter is one of the major sulfite-oxidizing alphaproteobacterial groups and is often associated with marine algae and corals. Their association with the eukaryotic host cell may have important ecological contexts due to their complex lifestyle and metabolism. However, the role of Sulfitobacter in cold-water corals remains largely unexplored. In this study, we explored the metabolism and mobile genetic elements (MGEs) in two closely related Sulfitobacter faviae strains isolated from cold-water black corals at a depth of ~1000 m by comparative genomic analysis. The two strains shared high sequence similarity in chromosomes, including two megaplasmids and two prophages, while both contained several distinct MGEs, including prophages and megaplasmids. Additionally, several toxin-antitoxin systems and other types of antiphage elements were also identified in both strains, potentially helping Sulfitobacter faviae overcome the threat of diverse lytic phages. Furthermore, the two strains shared similar secondary metabolite biosynthetic gene clusters and genes involved in dimethylsulfoniopropionate (DMSP) degradation pathways. Our results provide insight into the adaptive strategy of Sulfitobacter strains to thrive in ecological niches such as cold-water corals at the genomic level. Full article

Natural Products (NP) are essential for the discovery of novel drugs and products for numerous biotechnological applications. The NP discovery process is expensive and time-consuming, having as major hurdles dereplication (early identification of known compounds) and structure elucidation, particularly the determination of the absolute configuration of metabolites with stereogenic centers. This review comprehensively focuses on recent technological and instrumental advances, highlighting the development of methods that alleviate these obstacles, paving the way for accelerating NP discovery towards biotechnological applications. Herein, we emphasize the most innovative high-throughput tools and methods for advancing bioactivity screening, NP chemical analysis, dereplication, metabolite profiling, metabolomics, genome sequencing and/or genomics approaches, databases, bioinformatics, chemoinformatics, and three-dimensional NP structure elucidation. Full article

Angiogenesis and metastasis represent two challenging targets to combat cancer development in the later stages of its progression. Numerous studies have indicated the important role of natural products in blocking tumor angiogenesis signaling pathways in several advanced tumors. In recent years, the marine polysaccharides fucoidans emerged as promising anticancer compounds showing potent antitumor activity in both in vitro and in vivo models of different types of cancers. The objective of this review is to focus on the antiangiogenic and antimetastatic activities of fucoidans with special emphasis on preclinical studies. Independently from their source, fucoidans inhibit several angiogenic regulators, primarily vascular endothelial growth factor (VEGF). A glance towards fucoidans’ ongoing clinical trials and pharmacokinetic profile is provided to present the main challenges that still need to be addressed for their bench-to-bedside translation. Full article

There is a growing interest in using brown algal extracts thanks to the bioactive substances they produce for adaptation to the marine benthic environment. We evaluated the anti-aging and photoprotective properties of two types of extracts (50%-ethanol and DMSO) obtained from different portions, i.e., apices and thalli, of the brown seaweed, Ericaria amentacea. The apices of this alga, which grow and develop reproductive structures during summer when solar radiation is at its peak, were postulated to be rich in antioxidant compounds. We determined the chemical composition and pharmacological effects of their extracts and compared them to the thallus-derived extracts. All the extracts contained polyphenols, flavonoids and antioxidants and showed significant biological activities. The hydroalcoholic apices extracts demonstrated the highest pharmacological potential, likely due to the higher content of meroditerpene molecular species. They blocked toxicity in UV-exposed HaCaT keratinocytes and L929 fibroblasts and abated the oxidative stress and the production of pro-inflammatory cytokines, typically released after sunburns. Furthermore, the extracts showed anti-tyrosinase and anti-hydrolytic skin enzyme activity, counteracting the collagenase and hyaluronidase degrading activities and possibly slowing down the formation of uneven pigmentation and wrinkles in aging skin. In conclusion, the E. amentacea apices derivatives constitute ideal components for counteracting sunburn symptoms and for cosmetic anti-aging lotions. Full article

Alaria esculenta is a brown seaweed farmed in many European countries for its biomass rich in useful bio compounds. This study aimed to identify the optimal growing season to maximise biomass production and quality. The seeded longlines of the brown seaweed were deployed in the southwest of Ireland in October and November 2019 and samples of the biomass were harvested in different dates, between March and June 2020. Biomass gain and composition, phenolic and flavonoid content (TPC and TFC) and biological activities (antioxidant and anti-hypertensive activities) of seaweed extracts prepared with Alcalase were evaluated. The biomass production was significantly higher for the line deployed in October (>20 kg·m⁻¹). In May and June, an increasing amount of epiphytes was observed on the surface of A. esculenta. The protein content of A. esculenta varied between 11.2 and 11.76% and fat content was relatively low (1.8–2.3%). Regarding the fatty acids profile, A. esculenta was rich in polyunsaturated fatty acids (PUFA), especially in eicosapentaenoic acid (EPA). The samples analysed were very rich in Na, K, Mg, Fe, Mn, Cr and Ni. The content of Cd, Pb Hg was relatively low and below the maximum levels allowed. The highest TPC and TFC were obtained in extracts prepared with A. esculenta collected in March and levels of these compounds decreased with time. In general, the highest radical scavenging activities (ABTS and DPPH), as well as chelating activities (Fe²⁺ and Cu²⁺) were observed in early spring. Extracts from A. esculenta collected in March and April presented higher ACE inhibitory activity. The extracts from seaweeds harvested in March exhibited higher biological activity. It was concluded that an earlier deployment allows for maximising growth and harvest of biomass earlier when its quality is at the highest levels. The study also confirms the high content of useful bio compounds that can be extracted from A. esculenta and used in the nutraceutical and pharmaceutical industry. Full article

Tissue engineering and regenerative medicine (TERM) holds great promise for addressing the growing need for innovative therapies to treat disease conditions. To achieve this, TERM relies on various strategies and techniques. The most prominent strategy is the development of a scaffold. Polyvinyl alcohol-chitosan (PVA-CS) scaffold emerged as a promising material in this field due to its biocompatibility, versatility, and ability to support cell growth and tissue regeneration. Preclinical studies showed that the PVA-CS scaffold can be fabricated and tailored to fit the specific needs of different tissues and organs. Additionally, PVA-CS can be combined with other materials and technologies to enhance its regenerative capabilities. Furthermore, PVA-CS represents a promising therapeutic solution for developing new and innovative TERM therapies. Therefore, in this review, we summarized the potential role and functions of PVA-CS in TERM applications. Full article