Marine Drugs最新文献

Macrocyclic drugs are promising for targeting undruggable proteins, including those in cancer. Our prior work identified BE-43547A₂ (BE) as a selective inhibitor of pancreatic cancer stem cells in PANC-1 cultures, but its high lipophilicity limits clinical application. To address this, we designed derivatives retaining BE's backbone while modifying tail groups to improve its properties. A concise total synthesis enabled a versatile late-stage intermediate (compound 17), serving as a platform for efficient diversification of BE analogs via modular click chemistry. This approach introduced a central triazole ring connected by flexible alkyl spacers. Key properties, including lipophilicity, solubility, and Caco-2 permeability, were experimentally determined. These derivatives exhibited reduced lipophilicity and improved solubility but unexpectedly lost cellular activity. Direct target engagement studies using MicroScale Thermophoresis (MST) revealed compound-dependent deactivation mechanisms: certain derivatives retained binding to eEF1A1 with only modestly reduced affinity (e.g., compound 29), while others showed no detectable binding (e.g., compound 31). Microsecond-scale molecular dynamics simulations and free-energy calculations showed that, for derivatives retaining target affinity, tail modifications disrupted the delicate balance of drug-membrane and drug-solvent interactions, resulting in substantially higher transmembrane free-energy penalties (>5 kcal/mol) compared to active compounds (<2 kcal/mol). These insights emphasize the need to simultaneously preserve both target engagement and optimal permeability when modifying side chains in cell-permeable macrocyclic peptides, positioning compound 17 as a robust scaffold for future lead optimization. This work furnishes a blueprint for balancing drug-like properties with therapeutic potency in macrocyclic therapeutics.

Although extensive research has been conducted on algal polysaccharides worldwide, Mediterranean species remain comparatively understudied, despite the region's rich biodiversity and the presence of several endemic taxa with promising biotechnological potential. This review provides an overview of the major polysaccharides isolated from Mediterranean macroalgae, highlighting their structural features and bioactivities, as well as potential structure-activity relationships. Furthermore, the extraction and purification strategies used to isolate these biomolecules, ranging from conventional chemical approaches to emerging green technologies, were overlooked. Overall, the growing evidence of potent biological activities, combined with advances in sustainable extraction, underscores the significant potential of Mediterranean macroalgal polysaccharides as valuable resources unlocking new opportunities for their application in pharmaceutical, cosmetic, biomedical, and biotechnology fields.

Background: Marine-derived secondary metabolites such as phlorotannins from the edible brown alga Ecklonia cava exhibit diverse bioactivities. However, their mechanisms in inflammation-associated cancer remain insufficiently understood.

Methods: This study explored the anticancer potential of three major phlorotannins (dieckol, 7-phloroeckol, and 8,8'-bieckol) through network pharmacology, molecular docking, molecular dynamics simulations, and in vitro validation in SKOV3 ovarian cancer cells and tumor-associated macrophages (TAMs).

Results: Computational analyses revealed stable binding of phlorotannins to IL-17RA, with 7-phloroeckol and 8,8'-bieckol preferentially engaging loop-proximal regions of the receptor, while dieckol interacted with spatially distinct residues. In SKOV3 ovarian cancer cells, phlorotannins suppressed migration and invasion by approximately 40 to 60%, accompanied by reduced MMP expression linked to IL-17RA-Act1 signaling attenuation and by increased TIMP1 expression in association with transient ERK1/2 activation. In TAMs, phlorotannins attenuated pro-tumorigenic cytokine production and polarization marker expression, indicating suppression of tumor-supportive immune activity.

Conclusions: Collectively, these findings demonstrate that E. cava-derived phlorotannins exert anti-metastatic effects through dual regulation of IL-17RA/Act1 and ERK1/2 signaling pathways, offering mechanistic insight into their therapeutic potential against inflammation-driven malignancies.

Diarrheic shellfish toxins (DSTs), especially okadaic acid (OA) and its related compounds, are lipophilic marine biotoxins mainly synthesized by dinoflagellates of the genera Dinophysis and Prorocentrum. These compounds bioaccumulate in filter-feeding shellfish like mussels and clams, posing a considerable public health risk due to their strong gastrointestinal effects when contaminated seafood is consumed. This review offers a thorough overview of the current understanding of OA-group toxins with a focus on the molecular mechanisms of toxicity, including cytoskeletal disruption, apoptosis, inflammation, oxidative stress, and mitochondrial dysfunction. Additionally, their ecological impacts on aquatic organisms and patterns of bioaccumulation are explored. Recent advances in detection methods and regulatory frameworks are discussed, highlighting the necessity for robust monitoring systems to safeguard seafood safety. Enhanced knowledge of the toxicity, distribution, and fate of DSP (diarrheic shellfish poisoning) is essential for improving risk assessment and managing marine biotoxins. Despite methodological advances, gaps remain regarding chronic exposure and species-specific detoxification pathways.

GC-MS oxylipin profiling of brown and red algal thalli was performed. Brown algae (Fucus distichus and Alaria esculenta) were collected from the Barents Sea coastline nearby Teriberka, Murmansk region, Kola Peninsula, Russia, while other brown and red algae were sourced from the Pacific coast of the Russian Far East. Triols and δ-ketols (epoxyalcohol synthase products) were found in most brown and red algae. Several Heterokontophyta and Rhodophyta species possessed α-ketols (products of allene oxide synthase) and related vic-diols. Plasmodiophorols and ectocarpins (hydroperoxide bicyclase (HPB) products) were found only in brown algae from the Ectocarpales, Fucales, and Laminariales orders, not in brown algae from the Desmarestiales or Dictyotales orders, or in any red algae. Therefore, plasmodiophorol A and other HPB products could be used as chemotaxonomic markers for the classification of the separate orders of algae within Heterokontophyta. The in vitro incubations of F. distichus thalli with linoleic and α-linolenic acid resulted in the formation of α-ketols and the hydroperoxide bicyclase product, plasmodiophorol A.

Sea cucumber peptides have been shown to possess a number of functions, including antioxidant, anti-inflammatory, anti-tumor, and anti-fatigue effects, as well as immune regulation and promotion of collagen synthesis. Among these, high F-value oligopeptides are a promising natural active ingredient demonstrating excellent anti-fatigue effects. This study utilized fresh sea cucumbers as the primary raw material, employing membrane separation technology to investigate the simultaneous separation of sea cucumber polysaccharides and peptides. The process for removing aromatic amino acids during the preparation of high F-value oligopeptides from sea cucumbers was optimized, and the mechanism underlying their anti-fatigue effects was explored. A two-step enzymatic hydrolysis method using neutral protease and composite flavor protease was employed, followed by membrane separation using a 10,000 Da molecular weight ultrafiltration membrane, yielding a sea cucumber peptide yield of 45.00 ± 0.12% and a sea cucumber polysaccharide yield of 51.28 ± 0.63%. Following the removal of aromatic amino acids by means of activated carbon adsorption, the F-value of the high-F-value oligopeptides attained 23.82, with a yield of 24.56%. The experimental findings demonstrated that high-F-value oligopeptides exhibited a substantial increase in the swimming duration of mice and a notable enhancement in their grip strength. These observations signified their substantial anti-fatigue potential. Furthermore, studies have indicated that sea cucumber high-F-value oligopeptides reduce metabolites produced by exercise, enhance muscle protection, increase the activity of antioxidant enzymes in the body, and alleviate fatigue, thereby achieving an anti-fatigue effect.

Alginate lyases are commonly employed for producing alginate oligosaccharides (AOS), but their industrial application is often constrained by low thermal stability and catalytic efficiency. This study engineered mutants of alginate lyase Alyw203 from marine Vibrio based on B-factor values and negative ΔΔG values. The L172V mutant exhibited a 2.43-fold increase in half-life at 40 °C, reduced K_m (from 107 to 65 mg/mL), and enhanced k_cat/K_m (from 0.07 to 0.35 mL/mg/s), indicating improved thermal stability, substrate affinity, and catalytic efficiency. Molecular dynamics simulations revealed that these improvements originated from reconstructed hydrogen bond networks, which stabilized enzyme-substrate interactions and reduced conformational flexibility. These results demonstrate that rational design focused on strengthening hydrogen bonding can simultaneously improve both stability and activity, offering a promising strategy for industrial AOS production.

Plant growth regulators (PGRs) significantly contribute to enhancing crop quality and yield. There is an urgent market demand for innovative natural PGRs. Marine natural products have the potential to serve as valuable sources of PGRs. To discover natural siderophore-type PGRs from marine natural products, according to a systematic pipeline for efficient lead-structure discovery from microbial natural products (SPLSD), a unique desferrioxamine-like siderophore biosynthetic gene cluster was discovered and activated by genome mining and culture regulation from a novel species, Streptomonospora nanhaiensis 12A09^T. Some potentially new desferrioxamine derivatives were further discovered by the LC-MS/MS molecular network. Three new desferrioxamine derivatives, desferrioxamines C1, C2, and G3 (1-3) and three known ones, terragine E (4) and desferrioxamines E and D2 (5-6), were selectively isolated and identified using chromatography and spectroscopy techniques from S. nanhaiensis 12A09^T. In the ferric iron-chelating assay, 4 and 5 showed moderate Fe (III)-complexing capability, compared with desferrioxamine mesylate. In the plant growth-regulatory assay, 1, 5, and 6 potently boosted the root length of Oryza sativa and Brassica campestris seedlings, equivalent to gibberellin. This study reports the first discovery of desferrioxamine derivatives exhibiting plant growth-promoting activity. These findings offer valuable lead compounds for PGRs.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are essential omega-3 polyunsaturated fatty acids (n-3 PUFAs) with well-established health benefits. They occur primarily in marine resources, while their quantitative distribution within the glycerolipidome is rarely analyzed. Therefore, we investigated major commercial sources, including 12 microalgal species, the protist Schizochytrium sp., four fish species, and nine commercial n-3 supplements (fish, krill and Schizochytrium-derived "algal" oils) by high-performance thin-layer chromatography-gas chromatography-mass spectrometry (HPTLC-GC-MS). The class-resolved mapping of EPA and DHA revealed signature lipid profiles across all sources. In microalgae, 60-80% of EPA was localized in glycolipids, whereas in Schizochytrium and fish, >90% of DHA occurred in triacylglycerols. Krill oils exhibited phospholipid-rich profiles with ~70% of phosphatidylcholine-bound DHA. Nutritional indices also highlighted major differences: fish and fish oils showed favorable PUFA-to-saturated FA ratios (>0.45) and hypocholesterolemic-to-hypercholesterolemic ratios (>1), while Schizochytrium-based "algal" oils even surpassed these values. The microalgae Nannochloropsis granulata contained the highest EPA content in biomass form, combined with favorable nutritional indices. Beyond total n-3 content in relation to recommended daily intake values, the lipid-class distribution and nutritional indices should be considered decisive metrics for evaluating the health relevance of n-3 resources in the human diet.

Natural products are and continue to be a remarkable resource, rich in structural diversity, and endowed with valuable chemical and biological properties that have advanced both science and society. Some natural products, especially those from marine organisms, are chemically reactive, and during extraction and handling can partially or totally transform into artifacts. All too often overlooked or mischaracterised as natural products, artifacts can be invaluable indicators of a uniquely evolved and primed chemical space, with enhanced chemical and biological properties highly prized for drug discovery. To demonstrate this potential, we review a wide selection of marine and microbial case studies, revealing the factors that initiate artifact formation (e.g., solvents, heat, pH, light and air oxidation) and commenting on the mechanisms behind artifact formation. We conclude with reflections on how to recognise and control artifact formation, and how to exploit knowledge of artifacts as a window into unique regions of natural product chemical space-to better inform the development of future marine bioproducts.