Tartrolon D induces immunogenic cell death in melanoma.

Tartrolon D (TRL) is produced by Teredinibacter turnerae, a symbiotic cellulose-degrading bacteria in shipworm gills. Immunogenic cell death (ICD) induction contributes to a better and longer-lasting response to anticancer treatment. Tumor cells undergoing ICD trigger activation of the immune system, as a vaccine. AIMS: This study aimed to evaluate ICD induction by TRL. MAIN METHODS: Cell viability was evaluated by SRB assay. Cell stress, cell death, ICD features and antigen-presenting molecules were evaluated by flow cytometry and immunoblot. KEY FINDINGS: TRL showed antiproliferative activity on 7 tumor cell lines (L929, HCT 116, B16-F10, WM293A, SK-MEL-28, PC-3M, and MCF-7) and a non-tumor cell (HEK293A), with an inhibition concentration mean (IC50) ranging from 0.03 µM to 13 µM. Metastatic melanomas, SK-MEL-28, B16-F10, and WM293A, were more sensitive cell lines, with IC50 ranging from 0.07 to 1.2 µM. TRL induced apoptosis along with autophagy and endoplasmic reticulum stress and release of typical damage-associated molecular patterns (DAMPs) of ICD such calreticulin, ERp57, and HSP70 exposure, and HMGB1 release. Additionally, melanoma B16-F10 exposed to TRL increased expression of antigen-presenting molecules MHC II and CD1d and induced activation of splenocytes of C57BL/6 mice. SIGNIFICANCE: In spite of recent advances provided by target therapy and immunotherapy, advanced metastatic melanoma is incurable for more than half of patients. ICD inducers yield better and long-lasting responses to anticancer treatment. Our findings shed light on an anticancer candidate of marine origin that induces ICD in melanoma.

The potential of marine natural products and their synthetic derivatives as drugs targeting ion channels.

Ion channels are a type of protein channel that play a vital role in numerous physiological functions by facilitating the passage of ions through cell membranes, thereby enabling ion and electrical signal transmission. As a crucial target for drug action, ion channels have been implicated in various diseases. Many natural products from marine organisms, such as fungi, algae, sponges, and sea cucumber, etc. have been found to have activities related to ion channels for decades. These interesting natural product molecules undoubtedly bring good news for the treatment of neurological and cardiovascular diseases. In this review, 92 marine natural products and their synthetic derivatives with ion channel-related activities that were identified during the period 2000-2024 were systematically reviewed. The synthesis and mechanisms of action of selected compounds were also discussed, aiming to offer insights for the development of drugs targeting ion channels.

Marine anticancer drugs in modulating miRNAs and antioxidant signaling.

Several marine drugs exert anticancer effects by inducing oxidative stress, which becomes overloaded and kills cancer cells when redox homeostasis is imbalanced. The downregulation of antioxidant signaling induces oxidative stress, while its upregulation attenuates oxidative stress. Marine drugs have miRNA-modulating effects against cancer cells. However, the potential antioxidant targets of such drugs have been rarely explored. This review aims to categorize the marine-drug-modulated miRNAs that downregulate their antioxidant targets, causing oxidative stress in anticancer treatments. We also categorize the downregulation of oxidative-stress-inducing miRNAs in antioxidant protection among non-cancer cells. We summarize the putative antioxidant targets of miRNA-modulating marine drugs by introducing a bioinformatics tool (miRDB). Finally, the marine drugs affecting antioxidant targets are surveyed. In this way, the connections between marine drugs and their modulating miRNA and antioxidant targets are innovatively categorized to provide a precise network for exploring their potential anticancer functions and protective effects on non-cancer cells.

Effects of Marine Natural Products on Liver Diseases.

The prevention and treatment of liver disease, a class of disease that seriously threatens human health, has always been a hot topic of medical research. In recent years, with the in-depth exploration of marine resources, marine natural products have shown great potential and value in the field of liver disease treatment. Compounds extracted and isolated from marine natural products have a variety of biological activities such as significant antiviral properties, showing potential in the management of alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), protection of the liver from fibrosis, protection from liver injury and inhibition of the growth of hepatocellular carcinoma (HCC). This paper summarizes the progress of research on marine natural products for the treatment of liver diseases in the past decade, including the structural types of active substances from different natural products and the mechanisms underlying the modulation of different liver diseases and reviews their future prospects.

Total Synthesis and Biological Profiling of Putative (±)-Marinoaziridine B and (±)-N-Methyl Marinoaziridine A.

The total synthesis of two new marine natural products, (±)-marinoaziridine B 7 and (±)-N-methyl marinoaziridine A 8, was accomplished. The (±)-marinoaziridine 7 was prepared in a six-step linear sequence with a 2% overall yield. The key steps in our strategy were the preparation of the chiral epoxide (±)-5 using the Johnson Corey Chaykovsky reaction, followed by the ring-opening reaction and the Staudinger reaction. The N,N-dimethylation of compound (±)-7 gives (±)-N-methyl marinoaziridine A 8. The NMR spectra of synthetized (±)-marinoaziridine B 7 and isolated natural product did not match. The compounds are biologically characterized using relevant in silico, in vitro and in vivo methods. In silico ADMET and bioactivity profiling predicted toxic and neuromodulatory effects. In vitro screening by MTT assay on three cell lines (MCF-7, H-460, HEK293T) showed that both compounds exhibited moderate to strong antiproliferative and cytotoxic effects. Antimicrobial tests on bacterial cultures of Escherichia coli and Staphylococcus aureus demonstrated the dose-dependent inhibition of the growth of both bacteria. In vivo toxicological tests were performed on zebrafish Danio rerio and showed a significant reduction of zebrafish mortality due to N-methylation in (±)-8.

Anti-Biofilm Extracts and Molecules from the Marine Environment.

Pathogenic bacteria and their biofilms are involved in many diseases and represent a major public health problem, including the development of antibiotic resistance. These biofilms are known to cause chronic infections for which conventional antibiotic treatments are often ineffective. The search for new molecules and innovative solutions to combat these pathogens and their biofilms has therefore become an urgent need. The use of molecules with anti-biofilm activity would be a potential solution to these problems. The marine world is rich in micro- and macro-organisms capable of producing secondary metabolites with original skeletons. An interest in the chemical strategies used by some of these organisms to regulate and/or protect themselves against pathogenic bacteria and their biofilms could lead to the development of bioinspired, eco-responsible solutions. Through this original review, we listed and sorted the various molecules and extracts from marine organisms that have been described in the literature as having strictly anti-biofilm activity, without bactericidal activity.

Polymer degrading marine Microbulbifer bacteria: an un(der)utilized source of chemical and biocatalytic novelty.

Microbulbifer is a genus of halophilic bacteria that are commonly detected in the commensal marine microbiomes. These bacteria have been recognized for their ability to degrade polysaccharides and other polymeric materials. Increasingly, Microbulbifer genomes indicate these bacteria to be an untapped reservoir for novel natural product discovery and biosynthetic novelty. In this review, we summarize the distribution of Microbulbifer bacteria, activities of the various polymer degrading enzymes that these bacteria produce, and an up-to-date summary of the natural products that have been isolated from Microbulbifer strains. We argue that these bacteria have been hiding in plain sight, and contemporary efforts into their genome and metabolome mining are going to lead to a proliferation of Microbulbifer-derived natural products in the future. We also describe, where possible, the ecological interactions of these bacteria in marine microbiomes.

Unlocking the therapeutic potential of bioactive exopolysaccharide produced by marine actinobacterium Streptomyces vinaceusdrappus AMG31: A novel approach to drug development.

Acidic exopolysaccharide (EPS) was produced by a marine actinobacterium Streptomyces vinaceusdrappus strain AMG31 with the highest yield of 10.6 g/l. The synthesized EPS has an average molecular weight of 5.1 × 104 g/mol and contains arabinose, glucose, galacturonic acid (0.5:2:2 M ratio), with 39.77 % uronic acid residues and 18.8 % sulfate detected. EPS exhibited antioxidant activities with 93.8 % DPPH radical scavenging and 344.7 µg/mg total antioxidant capacity. It displayed anti-inflammatory effects by inhibiting 5-LOX and COX-2. Regarding the cytotoxic activity, the IC50 values are 301.6 ± 11.8, 260.8 ± 12.2, 29.4 ± 13.5, 351.3 ± 11.2, 254.1 ± 9.8, and 266.5 ± 10.4 µg/ml for PC-3, HEP-2, MCF-7, HCT-116, A-549, HepG-2 respectively, which indicate that the produced EPS does not have strong cytotoxic activities. Moreover, the EPS showed anti-Alzheimer activity via inhibition of the Butyrylcholinesterase enzyme, with the highest percentage of 84.5 % at 100 µg/ml. Interestingly, the EPS showed superior anti-obesity activity by inhibiting lipase enzyme with a rate of 95.3 % compared to orlistat as a positive control (96.8 %) at a concentration of 1000 µg/ml. Additionally, the produced EPS displayed the highest anti-diabetic properties by inhibiting α-amylase (IC50 31.49 µg/ml) and α-glucosidase (IC50 6.48 µg/ml), suggesting antidiabetic potential analogous to acarbose. EPS exhibited promising antibacterial and antibiofilm activity against a wide range of Gram-positive and Gram-negative pathogenic bacteria.

Isolation, Structure Elucidation, and Biological Activity of the Selective TACR2 Antagonist Tumonolide and its Aldehyde from a Marine Cyanobacterium.

The macrocyclic tumonolide (1) with enamide functionality and the linear tumonolide aldehyde (2) are new interconverting natural products from a marine cyanobacterium with a peptide-polyketide skeleton, representing a hybrid of apratoxins and palmyrolides or laingolides. The planar structures were established by NMR and mass spectrometry. The relative configuration of the stereogenically-rich apratoxin-like polyketide portion was determined using J-based configuration analysis. The absolute configuration of tumonolide (1) was determined by chiral analysis of the amino acid units and computational methods, followed by NMR chemical shift and ECD spectrum prediction, indicating all-R configuration for the polyketide portion, as in palmyrolide A and contrary to the all-S configuration in apratoxins. Functional screening against a panel of 168 GPCR targets revealed tumonolide (1) as a selective antagonist of TACR2 with an IC50 of 7.0 µM, closely correlating with binding affinity. Molecular docking studies established the binding mode and rationalized the selectivity for TACR2 over TACR1 and TACR3. RNA sequencing upon treatment of HCT116 colorectal cancer cells demonstrated activation of the pulmonary fibrosis idiopathic signaling pathway and the insulin secretion signaling pathway at 20 µM, indicating its potential to modulate these pathways.

Cephalostatins and ritterazines: Distinctive dimeric marine-derived steroidal pyrazine alkaloids with intriguing anticancer activities.

Cephalostatins and ritterazines represent fascinating classes of dimeric marine derived steroidal alkaloids with unique chemical structures and promising biological activities. Originally isolated from marine tube worms and the tunicate Ritterella tokioka collected off the coast of Japan, cephalostatins and ritterazines display potent anticancer effects by inducing apoptosis, disrupting cell cycle progression, and targeting multiple molecular pathways. This review covers the chemistry and bioactivities of 45 cephalostatins and ritterazines from 1988 to 2024, highlighting their complex structures and medicinal contributions. With insights into their structure activity relationships (SAR). Key structural elements, such as the pyrazine ring and 5/6 spiroketal moieties, are found crucial for their biological effects, suggesting interactions with lipid membranes or hydrophobic protein domains. Additionally, the formation of oxocarbenium ions from spiroketal cleavage may enhance their potency by covalently modifying DNA. The pharmacokinetics, ADMET and Drug likeness properties of these steroidal alkaloids are thoroughly addressed. Drug likeness analysis shows that these compounds fit well with the Rule of 4 (Ro4) for Protein-Protein Interaction Drugs (PPIDs), underscoring their potential in this area. Ten compounds (20, 27, 33, 34, 39, 40, 41, 42, 43, and 45) have demonstrated favourable pharmacokinetic and ADMET profiles, making them promising candidates for further research. Future efforts should focus on alternative administration routes, structural modifications, and innovative delivery systems, such as prodrugs and nanoparticles, to improve bioavailability and therapeutic effects. Advances in synthetic chemistry, mechanistic insights, and interdisciplinary collaborations will be essential for translating cephalostatins and ritterazines into effective anticancer therapies.

Marine-Derived Phosphoeleganin and Its Semisynthetic Derivative Decrease IL6 Levels and Improve Insulin Signaling in Human Hepatocellular Carcinoma Cells.

Marine natural products constitute a great source of potential new antidiabetic drugs. The aim of this study was to evaluate the role of phosphoeleganin (PE), a polyketide purified from the Mediterranean ascidian Sidnyum elegans, and its derivatives PE/2 and PE/3 on insulin sensitivity in human hepatocellular carcinoma (HepG2) cells. In our experiments, insulin stimulates the phosphorylation of its receptor (INSR) and AKT by 1.5- and 3.5-fold, respectively, whereas in the presence of PE, PE/2, and PE/3, the insulin induced INSR phosphorylation is increased by 2.1-, 2-, and 1.5-fold and AKT phosphorylation by 7.1-, 6.0-, and 5.1-fold, respectively. Interestingly, PE and PE/2 have an additive effect on insulin-mediated reduction of phosphoenolpyruvate carboxykinase (PEPCK) expression. Finally, PE and PE/2, but not PE/3, decrease interleukin 6 (IL6) secretion and expression before and after palmitic acid incubation, while in the presence of high glucose (HG), only PE reduces IL6. Levels of other cytokines are not significantly affected by PE and its derivates. All these data suggest that PE and its synthetic-derived compound, PE/2, significantly decrease IL6 and improve hepatic insulin signaling. As IL6 impairs insulin action, it could be hypothesized that PE and PE/2, by inhibiting IL6, may improve the hepatic insulin pathway.

Evaluation of the efficacy of marine natural products against PARP-1/2 proteins in high-grade serous ovarian cancer: insights into MD and SMD simulations.

High-grade serous ovarian cancer (HGSOC) is the most malignant and ubiquitous phenotype of epithelial ovarian cancer. Originating in the fallopian tubes and rapidly spreading to the ovaries, this highly heterogeneous disease is a result of serous tubal intraepithelial carcinoma. The proteins known as poly(ADP-ribose) polymerase (PARP) aid in the development of HGSOC by repairing the cancer cells that proliferate and spread metastatically. By using molecular docking to screen 1100 marine natural products (MNPs) from different marine environments against PARP-1/2 proteins, prominent PARP inhibitors (PARPi) were identified. Four compounds, alisiaquinone A, alisiaquinone C, ascomindone D and (+)-zampanolide referred to as MNP-1, MNP-2, MNP-3 and MNP-4, respectively, were chosen based on their binding affinity towards PARP-1/2 proteins, and their bioavailability and drug-like qualities were accessed using ADMET analysis. To investigate the structural stability and dynamics of these complexes, molecular dynamics simulations were performed for 200 ns. These results were compared with the complexes of olaparib (OLA), a PARPi that has been approved by the FDA for the treatment of advanced ovarian cancer. We determined that MNP-4 exhibited stronger binding energies with PARP-1/2 proteins than OLA by using MM/PBSA calculations. Hotspot residues from PARP-1 (E883, M890, Y896, D899 and Y907) and PARP-2 (Y449, F450, A451, S457 and Y460) showed strong interactions with the compounds. To comprehend the unbinding mechanism of MNP-4 complexed with PARP-1/2, steered molecular dynamics (SMD) simulations were performed. We concluded from the free energy landscape (FEL) map that PARP-1/2 are well-stabilised when the compound MNP-4 is bound rather than being pulled away from its binding pockets. This finding provides significant evidence regarding PARPi, which could potentially be employed in the therapeutic treatment of HGSOC.Communicated by Ramaswamy H. Sarma.

Antibacterial properties of natural products from marine fungi reported between 2012 and 2023: a review.

The oceans are rich in diverse microorganisms, animals, and plants. This vast biological complexity is a major source of unique secondary metabolites. In particular, marine fungi are a promising source of compounds with unique structures and potent antibacterial properties. Over the last decade, substantial progress has been made to identify these valuable antibacterial agents. This review summarizes the chemical structures and antibacterial activities of 223 compounds identified between 2012 and 2023. These compounds, effective against various bacteria including drug-resistant strains such as methicillin-resistant Staphylococcus aureus, exhibit strong potential as antibacterial therapeutics. The review also highlights the relevant challenges in transitioning from drug discovery to product commercialization. Emerging technologies such as metagenomics and synthetic biology are proposed as viable solutions. This paper sets the stage for further research on antibacterial compounds derived from marine fungi and advocates a multidisciplinary approach to combat drug-resistant bacteria.

Synthesis and Cheminformatics-Directed Antibacterial Evaluation of Echinosulfonic Acid-Inspired Bis-Indole Alkaloids.

Synthetic efforts toward complex natural product (NP) scaffolds are useful ones, particularly those aimed at expanding their bioactive chemical space. Here, we utilised an orthogonal cheminformatics-based approach to predict the potential biological activities for a series of synthetic bis-indole alkaloids inspired by elusive sponge-derived NPs, echinosulfone A (1) and echinosulfonic acids A-D (2-5). Our work includes the first synthesis of desulfato-echinosulfonic acid C, an α-hydroxy bis(3'-indolyl) alkaloid (17), and its full NMR characterisation. This synthesis provides corroborating evidence for the structure revision of echinosulfonic acids A-C. Additionally, we demonstrate a robust synthetic strategy toward a diverse range of α-methine bis(3'-indolyl) acids and acetates (11-16) without the need for silica-based purification in either one or two steps. By integrating our synthetic library of bis-indoles with bioactivity data for 2048 marine indole alkaloids (reported up to the end of 2021), we analyzed their overlap with marine natural product chemical diversity. Notably, the C-6 dibrominated α-hydroxy bis(3'-indolyl) and α-methine bis(3'-indolyl) analogues (11, 14, and 17) were found to contain significant overlap with antibacterial C-6 dibrominated marine bis-indoles, guiding our biological evaluation. Validating the results of our cheminformatics analyses, the dibrominated α-methine bis(3'-indolyl) alkaloids (11, 12, 14, and 15) were found to exhibit antibacterial activities against methicillin-sensitive and -resistant Staphylococcus aureus. Further, while investigating other synthetic approaches toward bis-indole alkaloids, 16 incorrectly assigned synthetic α-hydroxy bis(3'-indolyl) alkaloids were identified. After careful analysis of their reported NMR data, and comparison with those obtained for the synthetic bis-indoles reported herein, all of the structures have been revised to α-methine bis(3'-indolyl) alkaloids.

Role of marine natural products in the development of antiviral agents against SARS-CoV-2: potential and prospects.

A novel coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has surfaced and caused global concern owing to its ferocity. SARS-CoV-2 is the causative agent of coronavirus disease 2019; however, it was only discovered at the end of the year and was considered a pandemic by the World Health Organization. Therefore, the development of novel potent inhibitors against SARS-CoV-2 and future outbreaks is urgently required. Numerous naturally occurring bioactive substances have been studied in the clinical setting for diverse disorders. The intricate infection and replication mechanism of SARS-CoV-2 offers diverse therapeutic drug targets for developing antiviral medicines by employing natural products that are safer than synthetic compounds. Marine natural products (MNPs) have received increased attention in the development of novel drugs owing to their high diversity and availability. Therefore, this review article investigates the infection and replication mechanisms, including the function of the SARS-CoV-2 genome and structure. Furthermore, we highlighted anti-SARS-CoV-2 therapeutic intervention efforts utilizing MNPs and predicted SARS-CoV-2 inhibitor design. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-023-00215-9.

Novel Bioactive Natural Products from Marine-Derived Penicillium Fungi: A Review (2021-2023).

Marine-derived Penicillium fungi are productive sources of structurally unique and diverse bioactive secondary metabolites, representing a hot topic in natural product research. This review describes structural diversity, bioactivities and statistical research of 452 new natural products from marine-derived Penicillium fungi covering 2021 to 2023. Sediments are the main sources of marine-derived Penicillium fungi for producing nearly 56% new natural products. Polyketides, alkaloids, and terpenoids displayed diverse biological activities and are the major contributors to antibacterial activity, cytotoxicity, anti-inflammatory and enzyme inhibitory capacities. Polyketides had higher proportions of new bioactive compounds in new compounds than other chemical classes. The characteristics of studies in recent years are presented.

Marine Microalgal Products with Activities against Age-Related Cardiovascular Diseases.

Heart disease is one of the leading causes of death worldwide, and it is estimated that 17.9 million people die of it each year. The risk factors for cardiovascular diseases are attributable to an unhealthy and sedentary lifestyle, poor nutrition, stress, genetic predisposition, diabetes, obesity, and aging. Marine microalgae have been the subject of numerous studies for their potential activity against several human diseases. They produce a plethora of primary and secondary metabolites such as essential nutrients, vitamins, pigments, and omega-3 fatty acid. Many of these molecules have antioxidant properties and have been shown to play a role in the prevention of heart diseases. The aim of this review is to summarize recent studies on the discovery of marine microalgal compounds and bioactivities for cardiovascular diseases, including in vitro and in vivo studies, showing and discussing recent discoveries and trends. The most promising results were found for microalgal polysaccharides, peptides and carotenoids. In conclusion, the overall data summarized here show that microalgae-based supplementation has the potential to improve age-related cardiovascular diseases and we expect more clinical studies in the future.

Design and Synthesis of Marine Polybrominated Diphenyl Ether Derivatives as Potential Anti-Inflammatory Agents.

Natural polybrominated diphenyl ethers are generally isolated from sponges and possess a broad range of biological activities. Through screening of our marine natural product library, we discovered that polybrominated diphenyl ethers 5 and 6 exhibit considerable anti-inflammatory activity. In order to expand our repertoire of derivatives for further biological activity studies, we designed and synthesized a series of 5-related polybrominated diphenyl ethers. Importantly, compound 5a showed comparable anti-inflammatory activity while much lower cytotoxicity on lipopolysaccharide (LPS)-induced RAW264.7 cells. Additionally, western blotting analysis showed that 5a reduced the expression of phosphorylated extracellular signal-regulated kinase (p-ERK). Besides, molecular docking experiments were conducted to predict and elucidate the potential mechanisms underlying the varying anti-inflammatory activities exhibited by compounds 5a, 5, and 6.

Marine natural products: potential agents for depression treatment.

Depression is a common psychiatric disorder. Due to the disadvantages of current clinical drugs, including poor efficacy and unnecessary side effects, research has shifted to novel natural products with minimal or no adverse effects as therapeutic alternatives. The ocean is a vast ecological home, with a wide variety of organisms that can produce a large number of natural products with unique structures, some of which have neuroprotective effects and are a valuable source for the development of new drugs for depression. In this review, we analyzed preclinical and clinical studies of natural products derived from marine organisms with antidepressant potential, including the effects on the pathophysiology of depression, and the underlying mechanisms of these effects. It is expected to provide a reference for the development of new antidepressant drugs.

An Efficient and Scalable "Second Generation" Total Synthesis of the Marine Polyketide Limaol Endowed with Antiparasitic Activity.

The cluster of four skipped exo-methylene substituents on the "northern" wing of limaol renders this dinoflagellate-derived marine natural product unique in structural terms. This arguably non-thermodynamic array gains kinetic stability by virtue of populating local conformations which impede isomerization to a partly or fully conjugated polyene. This analysis suggested that the difficulties encountered during the late stages of our first total synthesis of this polyketide had not been caused by an overly fragile character of this unusual substructure; rather, an unfavorable steric microenvironment about the spirotricyclic core was identified as the likely cause. To remedy the issue, the protecting groups on this central fragment were changed; in effect, this amendment allowed all strategic and practical problems to be addressed. As a result, the overall yield over the longest linear sequence was multiplied by a factor of almost five and the material throughput increased more than eighty-fold per run. Key-to-success was a gold-catalyzed spirocyclization reaction; the reasons why a Brønsted acid cocatalyst is needed and the origin of the excellent levels of selectivity were delineated. The change of the protecting groups also allowed for much improved fragment coupling processes; most notably, the sequence of a substrate-controlled carbonyl addition reaction followed by Mitsunobu inversion that had originally been necessary to affix the southern tail to the core could be replaced by a reagent controlled asymmetric allylation. Finally, a much-improved route to the "northern" sector was established by leveraging the power of asymmetric hydrogenation of a 2-pyrone derivative. Limaol was found to combine appreciable antiparasitic activity with very modest cytotoxicity.