Marine Drugs

59 pages, 4856 KiB

Open AccessEditor’s ChoiceReview

Extraction and Analytical Methods for the Characterization of Polyphenols in Marine Microalgae: A Review

by Gabriela Bermudez, Cristina Terenzi, Francesca Medri, Vincenza Andrisano and Serena Montanari

Mar. Drugs 2024, 22(12), 538; https://doi.org/10.3390/md22120538 - 30 Nov 2024

Cited by 3 | Viewed by 2221

Marine microalgae are emerging as promising sources of polyphenols, renowned for their health-promoting benefits. Recovering polyphenols from microalgae requires suitable treatment and extraction techniques to ensure their release from the biomass and analytical methodologies to assess their efficiency. This review provides a comprehensive [...] Read more.

Marine microalgae are emerging as promising sources of polyphenols, renowned for their health-promoting benefits. Recovering polyphenols from microalgae requires suitable treatment and extraction techniques to ensure their release from the biomass and analytical methodologies to assess their efficiency. This review provides a comprehensive comparison of traditional and cutting-edge extraction and analytical procedures applied for polyphenolic characterization in marine microalgae over the past 26 years, with a unique perspective on optimizing their recovery and identification. It addresses (I) cell disruption techniques, including bead milling, high-speed homogenization, pulsed electric field, ultrasonication, microwave, freeze-thawing, and enzymatic/chemical hydrolysis; (II) extraction techniques, such as solid–liquid extraction, ultrasound and microwave-assisted extraction, pressurized-liquid extraction, and supercritical CO₂; (III) analytical methods, including total phenolic and flavonoid content assays and advanced chromatographic techniques like GC-MS, HPLC-DAD, and HPLC-MS. Key findings showed bead milling and chemical hydrolysis as effective cell disruption techniques, pressurized-liquid extraction and microwave-assisted extraction as promising efficient extraction methods, and HPLC-MS as the finest alternative for precise phenolic characterization. Unlike previous reviews, this study uniquely integrates both extractive and analytical approaches in one work, focusing exclusively on marine microalgae, a relatively underexplored area compared to freshwater species, offering actionable insights to guide future research and industrial applications. Full article

(This article belongs to the Special Issue High-Value Algae Products)

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56 pages, 41424 KiB

Open AccessEditor’s ChoiceReview

Marine Fungi Bioactives with Anti-Inflammatory, Antithrombotic and Antioxidant Health-Promoting Properties Against Inflammation-Related Chronic Diseases

by Maria-Aliki Papikinou, Konstantinos Pavlidis, Paschalis Cholidis, Dimitrios Kranas, Theodora Adamantidi, Chryssa Anastasiadou and Alexandros Tsoupras

Mar. Drugs 2024, 22(11), 520; https://doi.org/10.3390/md22110520 - 18 Nov 2024

Cited by 3 | Viewed by 2431

Abstract

Fungi play a fundamental role in the marine environment, being promising producers of bioactive molecules in the pharmacological and industrial fields, which have demonstrated potential health benefits against cardiovascular and other chronic diseases. This review pertains to the analysis of the lipid compositions [...] Read more.

Fungi play a fundamental role in the marine environment, being promising producers of bioactive molecules in the pharmacological and industrial fields, which have demonstrated potential health benefits against cardiovascular and other chronic diseases. This review pertains to the analysis of the lipid compositions across various species of marine fungi and their constantly discovered substances, as well as their anti-inflammatory, antioxidant, and antithrombotic effects. The health-promoting aspects of these microorganisms will be explored, through the investigation of several mechanisms of action and interference of their bioactives in biochemical pathways. Despite exceptional results in this field, the potential of marine microorganisms remains largely unexplored due to the limited number of specialists in marine microbiology and mycology, a relatively recent science with significant contributions and potential in biodiversity and biotechnology. Full article

(This article belongs to the Special Issue Diversity of Marine Fungi as a Source of Bioactive Natural Products, 2nd Edition)

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18 pages, 5059 KiB

Open AccessEditor’s ChoiceArticle

Batzelladine D, a Marine Natural Product, Reverses the Fluconazole Resistance Phenotype Mediated by Transmembrane Transporters in Candida albicans and Interferes with Its Biofilm: An In Vitro and In Silico Study

by Levy T. S. Domingos, Daniel C. de Moraes, Mário F. C. Santos, José A. R. Curvelo, Brayan Bayona-Pacheco, Edgar A. Marquez, Anthony W. B. Martinez, Roberto G. S. Berlinck and Antonio Ferreira-Pereira

Mar. Drugs 2024, 22(11), 502; https://doi.org/10.3390/md22110502 - 5 Nov 2024

Cited by 1 | Viewed by 1490

Abstract

Numerous Candida species are responsible for fungal infections; however, Candida albicans stands out among the others. Treatment with fluconazole is often ineffective due to the resistance phenotype mediated by transmembrane transporters and/or biofilm formation, mechanisms of resistance commonly found in C. albicans strains. [...] Read more.

Numerous Candida species are responsible for fungal infections; however, Candida albicans stands out among the others. Treatment with fluconazole is often ineffective due to the resistance phenotype mediated by transmembrane transporters and/or biofilm formation, mechanisms of resistance commonly found in C. albicans strains. A previous study by our group demonstrated that batzelladine D can inhibit the Pdr5p transporter in Saccharomyces cerevisiae. In the present study, our aim was to investigate the efficacy of batzelladine D in inhibiting the main efflux pumps of Candida albicans, CaCdr1p and CaCdr2p, as well as to evaluate the effect of the compound on C. albicans biofilm. Assays were conducted using a clinical isolate of Candida albicans expressing both transporters. Additionally, to allow the study of each transporter, S. cerevisiae mutant strains overexpressing CaCdr1p or CaCdr2p were used. Batzelladine D was able to reverse the fluconazole resistance phenotype by acting on both transporters. The compound synergistically improved the effect of fluconazole against the clinical isolate when tested in the Caenorhabditis elegans animal model. Moreover, the compound disrupted the preformed biofilm. Based on the obtained data, the continuation of batzelladine D studies as a potential new antifungal agent and/or chemosensitizer in Candida albicans infections can be suggested. Full article

(This article belongs to the Special Issue Marine Anti-Biofilm Compounds from Natural to Synthetic Compounds)

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9 pages, 2337 KiB

Open AccessEditor’s ChoiceCommunication

Discovery of Anti-Inflammatory Alkaloids from Sponge Stylissa massa Suggests New Biosynthetic Pathways for Pyrrole–Imidazole Alkaloids

by Xiaojing Liu, Qi Wang, Yun Zhang and Hanting Zhang

Mar. Drugs 2024, 22(10), 477; https://doi.org/10.3390/md22100477 - 18 Oct 2024

Cited by 3 | Viewed by 1564

Abstract

Pyrrole–imidazole alkaloids (PIAs) are a class of marine sponge derived natural products which have complex carbon frameworks and broad bioactivities. In this study, four new alkaloids, stylimassalins A–B (1–2), 3, and 5, together with two known compounds [...] Read more.

Pyrrole–imidazole alkaloids (PIAs) are a class of marine sponge derived natural products which have complex carbon frameworks and broad bioactivities. In this study, four new alkaloids, stylimassalins A–B (1–2), 3, and 5, together with two known compounds (4 and 6), were isolated from Stylissa massa. Compounds 2, 4, and 6 are the C-2 brominated analogues of 1, 3, and 5, respectively. Their structures display three different scaffolds, of which scaffold 1 (compounds 1,2) is new. A new biosynthetic pathway from oroidin, through spongiacidin, to latonduine and scaffold 1 was proposed by our group, in which the C12-N13-cleavaged compounds of spongiacidin (scaffold 2), dubbed seco-spongiacidins (3 and 4), are recognized as a key bridged scaffold, to afford PIA analogues (1,2 and 5,6). An anti-inflammatory evaluation in a zebrafish inflammation model induced by copper sulphate (CuSO₄) demonstrated that stylimassalins A and B (1 and 2) could serve as a promising lead scaffold for treating inflammation. Full article

(This article belongs to the Special Issue Bio-Active Components from Marine Sponges)

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14 pages, 3526 KiB

Open AccessEditor’s ChoiceArticle

Talaroterpenoids A–F: Six New Seco-Terpenoids from the Marine-Derived Fungus Talaromyces aurantiacus

by Zi-Hong Peng, Hui Jia, Yan-Liang Luo, Li-Jun Zhang, Jia-Tong Zhou, Yuan-Han Xie, Li-Jun Wang, Jiang-Ke Qin, Jun Li, Guo-Hai Zhang, Rui-Yun Yang and Wei-Feng Xu

Mar. Drugs 2024, 22(10), 475; https://doi.org/10.3390/md22100475 - 18 Oct 2024

Cited by 1 | Viewed by 1489

Abstract

Six new highly oxidized seco-terpenoids, including three 3-nor-labdane type diterpenes, talaroterpenoids A–C (1–3), and three meroterpenoids containing an orthoester group, talaroterpenoids D–F (6–8), together with five known compounds (4–5 [...] Read more.

Six new highly oxidized seco-terpenoids, including three 3-nor-labdane type diterpenes, talaroterpenoids A–C (1–3), and three meroterpenoids containing an orthoester group, talaroterpenoids D–F (6–8), together with five known compounds (4–5 and 9–11), were isolated from the marine-derived fungus Talaromyces aurantiacus. Their chemical structures were elucidated through 1D, 2D NMR, HRESIMS, J-based configuration analysis (JBCA), computational ECD calculations, and single-crystal X-ray diffraction analysis. Compounds 1 and 2 contain an unusual 6,20-γ-lactone-bridged scaffold. Compounds 10 and 11 presented inhibitory effects on NO release in lipopolysaccharide (LPS)-induced BV-2 cells with IC₅₀ values of 11.47 and 11.32 μM, respectively. Talaroterpenoid C (3) showed moderate antifungal activity against A. alternata and P. theae Steyaert. Full article

(This article belongs to the Special Issue Pharmacological Potential of Marine Natural Products, 2nd Edition)

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18 pages, 2458 KiB

Open AccessEditor’s ChoiceArticle

Semisynthesis, Structure Elucidation and Anti-Mycobacterium marinum Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactones with Interesting Ketal Groups

by Jun-Na Yin, Cui-Fang Wang, Xiu-Li Zhang, Ya-Jie Cheng, Yan-Wei Wu, Qun Zhang, Chang-Lun Shao, Mei-Yan Wei and Yu-Cheng Gu

Mar. Drugs 2024, 22(10), 431; https://doi.org/10.3390/md22100431 - 25 Sep 2024

Cited by 1 | Viewed by 1340

Abstract

The incidence of Mycobacterium marinum infection is on the rise; however, the existing drug treatment cycle is lengthy and often requires multi-drug combination. Therefore, there is a need to develop new and effective anti-M. marinum drugs. Cochliomycin A, a 14-membered resorcylic acid [...] Read more.

The incidence of Mycobacterium marinum infection is on the rise; however, the existing drug treatment cycle is lengthy and often requires multi-drug combination. Therefore, there is a need to develop new and effective anti-M. marinum drugs. Cochliomycin A, a 14-membered resorcylic acid lactone with an acetonide group at C-5′ and C-6′, exhibits a wide range of antimicrobial, antimalarial, and antifouling activities. To further explore the effect of this structural change at C-5′ and C-6′ on this compound’s activity, we synthesized a series of compounds with a structure similar to that of cochliomycin A, bearing ketal groups at C-5′ and C-6′. The R/S configuration of the diastereoisomer at C-13′ was further determined through an NOE correlation analysis of CH₃ or CH₂ at the derivative C-13′ position and the H-5′ and H-6′ by means of a 1D NOE experiment. Further comparative ¹H NMR analysis of diastereoisomers showed the difference in the chemical shift (δ) value of the diastereoisomers. The synthetic compounds were screened for their anti-microbial activities in vitro. Compounds 15–24 and 28–35 demonstrated promising activity against M. marinum, with MIC₉₀ values ranging from 70 to 90 μM, closely approaching the MIC₉₀ of isoniazid. The preliminary structure–activity relationships showed that the ketal groups with aromatic rings at C-5′ and C-6′ could enhance the inhibition of M. marinum. Further study demonstrated that compounds 23, 24, 29, and 30 had significant inhibitory effects on M. marinum and addictive effects with isoniazid and rifampicin. Its effective properties make it an important clue for future drug development toward combatting M. marinum resistance. Full article

(This article belongs to the Special Issue Pharmacological Potential of Marine Natural Products, 2nd Edition)

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12 pages, 1638 KiB

Open AccessEditor’s ChoiceArticle

Staurosporine as a Potential Treatment for Acanthamoeba Keratitis Using Mouse Cornea as an Ex Vivo Model

by Rubén L. Rodríguez-Expósito, Ines Sifaoui, Lizbeth Salazar-Villatoro, Carlos J. Bethencourt-Estrella, José J. Fernández, Ana R. Díaz-Marrero, Robert Sutak, Maritza Omaña-Molina, José E. Piñero and Jacob Lorenzo-Morales

Mar. Drugs 2024, 22(9), 423; https://doi.org/10.3390/md22090423 - 18 Sep 2024

Viewed by 4208

Abstract

Acanthamoeba is a ubiquitous genus of amoebae that can trigger a severe and progressive ocular disease known as Acanthamoeba Keratitis (AK). Furthermore, current treatment protocols are based on the combination of different compounds that are not fully effective. Therefore, an urgent need to [...] Read more.

Acanthamoeba is a ubiquitous genus of amoebae that can trigger a severe and progressive ocular disease known as Acanthamoeba Keratitis (AK). Furthermore, current treatment protocols are based on the combination of different compounds that are not fully effective. Therefore, an urgent need to find new compounds to treat Acanthamoeba infections is clear. In the present study, we evaluated staurosporine as a potential treatment for Acanthamoeba keratitis using mouse cornea as an ex vivo model, and a comparative proteomic analysis was conducted to elucidate a mechanism of action. The obtained results indicate that staurosporine altered the conformation of actin and tubulin in treated trophozoites of A. castellanii. In addition, proteomic analysis of treated trophozoites revealed that this molecule induced overexpression and a downregulation of proteins related to key functions for Acanthamoeba infection pathways. Additionally, the ex vivo assay used validated this model for the study of the pathogenesis and therapies of AK. Finally, staurosporine eliminated the entire amoebic population and prevented the adhesion and infection of amoebae to the epithelium of treated mouse corneas. Full article

(This article belongs to the Special Issue Marine-Derived Bioactive Substances and Their Mechanisms of Action)

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27 pages, 7852 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Anti-Inflammatory Compounds from Marine Microorganisms

by Guihua Yang, Miaoping Lin, Kumaravel Kaliaperumal, Yaqi Lu, Xin Qi, Xiaodong Jiang, Xinya Xu, Chenghai Gao, Yonghong Liu and Xiaowei Luo

Mar. Drugs 2024, 22(9), 424; https://doi.org/10.3390/md22090424 - 18 Sep 2024

Cited by 1 | Viewed by 2426

Abstract

Marine microbial secondary metabolites with diversified structures have been found as promising sources of anti-inflammatory lead compounds. This review summarizes the sources, chemical structures, and pharmacological properties of anti-inflammatory natural products reported from marine microorganisms in the past three years (2021–2023). Approximately 252 [...] Read more.

Marine microbial secondary metabolites with diversified structures have been found as promising sources of anti-inflammatory lead compounds. This review summarizes the sources, chemical structures, and pharmacological properties of anti-inflammatory natural products reported from marine microorganisms in the past three years (2021–2023). Approximately 252 anti-inflammatory compounds, including 129 new ones, were predominantly obtained from marine fungi and they are structurally divided into polyketides (51.2%), terpenoids (21.0%), alkaloids (18.7%), amides or peptides (4.8%), and steroids (4.3%). This review will shed light on the development of marine microbial secondary metabolites as potential anti-inflammatory lead compounds with promising clinical applications in human health. Full article

(This article belongs to the Special Issue Marine Anti-Inflammatory and Antioxidant Agents, 4th Edition)

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80 pages, 28457 KiB

Open AccessEditor’s ChoiceReview

A Chemical Toolbox to Unveil Synthetic Nature-Inspired Antifouling (NIAF) Compounds

by Ana Rita Neves, Sara Godinho, Catarina Gonçalves, Ana Sara Gomes, Joana R. Almeida, Madalena Pinto, Emília Sousa and Marta Correia-da-Silva

Mar. Drugs 2024, 22(9), 416; https://doi.org/10.3390/md22090416 - 12 Sep 2024

Cited by 4 | Viewed by 4064

Abstract

The current scenario of antifouling (AF) strategies to prevent the natural process of marine biofouling is based in the use of antifouling paints containing different active ingredients, believed to be harmful to the marine environment. Compounds called booster biocides are being used with [...] Read more.

The current scenario of antifouling (AF) strategies to prevent the natural process of marine biofouling is based in the use of antifouling paints containing different active ingredients, believed to be harmful to the marine environment. Compounds called booster biocides are being used with copper as an alternative to the traditionally used tributyltin (TBT); however, some of them were recently found to accumulate in coastal waters at levels that are deleterious for marine organisms. More ecological alternatives were pursued, some of them based on the marine organism mechanisms’ production of specialized metabolites with AF activity. However, despite the investment in research on AF natural products and their synthetic analogues, many studies showed that natural AF alternatives do not perform as well as the traditional metal-based ones. In the search for AF agents with better performance and to understand which molecular motifs were responsible for the AF activity of natural compounds, synthetic analogues were produced and investigated for structure–AF activity relationship studies. This review is a comprehensive compilation of AF compounds synthesized in the last two decades with highlights on the data concerning their structure–activity relationship, providing a chemical toolbox for researchers to develop efficient nature-inspired AF agents. Full article

(This article belongs to the Special Issue Marine Natural Products with Antifouling Activity, 3rd Edition)

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17 pages, 2715 KiB

Open AccessEditor’s ChoiceArticle

Sphaerococcenol A Derivatives: Design, Synthesis, and Cytotoxicity

by Dídia Sousa, Milene A. G. Fortunato, Joana Silva, Mónica Pingo, Alice Martins, Carlos A. M. Afonso, Rui Pedrosa, Filipa Siopa and Celso Alves

Mar. Drugs 2024, 22(9), 408; https://doi.org/10.3390/md22090408 - 5 Sep 2024

Viewed by 1518

Abstract

Sphaerococcenol A is a cytotoxic bromoditerpene biosynthesized by the red alga Sphaerococcus coronopifolius. A series of its analogues (1–6) was designed and semi-synthesized using thiol-Michael additions and enone reduction, and the structures of these analogues were characterized by [...] Read more.

Sphaerococcenol A is a cytotoxic bromoditerpene biosynthesized by the red alga Sphaerococcus coronopifolius. A series of its analogues (1–6) was designed and semi-synthesized using thiol-Michael additions and enone reduction, and the structures of these analogues were characterized by spectroscopic methods. Cytotoxic analyses (1–100 µM; 24 h) were accomplished on A549, DU-145, and MCF-7 cells. The six novel sphaerococcenol A analogues displayed an IC₅₀ range between 14.31 and 70.11 µM on A549, DU-145, and MCF-7 malignant cells. Compound 1, resulting from the chemical addition of 4-methoxybenzenethiol, exhibited the smallest IC₅₀ values on the A549 (18.70 µM) and DU-145 (15.82 µM) cell lines, and compound 3, resulting from the chemical addition of propanethiol, exhibited the smallest IC₅₀ value (14.31 µM) on MCF-7 cells. The highest IC₅₀ values were exhibited by compound 4, suggesting that the chemical addition of benzylthiol led to a loss of cytotoxic activity. The remaining chemical modifications were not able to potentiate the cytotoxicity of the original compounds. Regarding A549 cell viability, analogue 1 exhibited a marked effect on mitochondrial function, which was accompanied by an increase in ROS levels, Caspase-3 activation, and DNA fragmentation and condensation. This study opens new avenues for research by exploring sphaerococcenol A as a scaffold for the synthesis of novel bioactive molecules. Full article

(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents 3.0)

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24 pages, 2152 KiB

Open AccessEditor’s ChoiceReview

New Secondary Metabolites of Mangrove-Associated Strains

by Yunxia Yu, Zimin Wang, Dingmi Xiong, Liman Zhou, Fandong Kong and Qi Wang

Mar. Drugs 2024, 22(8), 372; https://doi.org/10.3390/md22080372 - 16 Aug 2024

Cited by 4 | Viewed by 2092

Abstract

Positioned at the dynamic interface between terrestrial and marine realms, mangroves embody a vibrant tapestry of biodiversity, encompassing an array of plants, animals, and microorganisms. These microbial inhabitants of mangrove habitats have emerged as a pivotal resource for antimicrobials and a plethora of [...] Read more.

Positioned at the dynamic interface between terrestrial and marine realms, mangroves embody a vibrant tapestry of biodiversity, encompassing an array of plants, animals, and microorganisms. These microbial inhabitants of mangrove habitats have emerged as a pivotal resource for antimicrobials and a plethora of pharmaceutically valuable compounds, spanning enzymes, antineoplastic agents, pesticides, immunosuppressants, and immunomodulators. This review delves into the recent landscape (January 2021 to May 2024, according to the time of publication) of novel secondary metabolites isolated from mangrove-associated microorganisms, analyzing 41 microbial strains that collectively yielded 165 distinct compounds. Our objective is to assess the productivity and potential of natural products derived from microbial populations within mangrove ecosystems in recent times. Notably, fungi stand out as the preeminent contributors to the emergence of these novel natural products, underscoring their pivotal role in the bioprospecting endeavors within these unique environments. Full article

(This article belongs to the Special Issue Bio-Active Products from Mangrove Ecosystems 2.0)

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11 pages, 1357 KiB

Open AccessEditor’s ChoiceArticle

From Sea Sponge to Clinical Trials: Starting the Journey of the Novel Compound PM742

by Patricia G. Cruz, Rogelio Fernández, Raquel Rodríguez-Acebes, Marta Martínez-Díez, Gema Santamaría-Núñez, Marta Pérez and Carmen Cuevas

Mar. Drugs 2024, 22(8), 339; https://doi.org/10.3390/md22080339 - 26 Jul 2024

Viewed by 3225

Abstract

PM742 (1), a new chemical entity, has been isolated from the sponge Discodermia du Bocage collected in the Pacific Ocean. This compound showed strong in vitro cytotoxicity against several human tumor cell lines as well as a tubulin depolymerization mechanism of [...] Read more.

PM742 (1), a new chemical entity, has been isolated from the sponge Discodermia du Bocage collected in the Pacific Ocean. This compound showed strong in vitro cytotoxicity against several human tumor cell lines as well as a tubulin depolymerization mechanism of action, which led us to conduct an extensive Structure-Activity-Relationship study through the synthesis of different analogs. As a result, a derivatively named PM534 (2) is currently in its first human Phase I clinical trial. Herein, we present a comprehensive review of the isolation, structural elucidation, and antitumor activities of the parent compound PM742. Full article

(This article belongs to the Special Issue From Seaside to Bedside: Dedicated to Professor José María Fernández Sousa-Faro)

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22 pages, 3208 KiB

Open AccessEditor’s ChoiceReview

Seaweeds as Source of Bioactive Pigments with Neuroprotective and/or Anti-Neurodegenerative Activities: Astaxanthin and Fucoxanthin

by Estela Guardado Yordi, Amaury Pérez Martínez, Matteo Radice, Laura Scalvenzi, Reinier Abreu-Naranjo, Eugenio Uriarte, Lourdes Santana and Maria Joao Matos

Mar. Drugs 2024, 22(7), 327; https://doi.org/10.3390/md22070327 - 22 Jul 2024

Cited by 4 | Viewed by 5462

Abstract

The marine kingdom is an important source of a huge variety of scaffolds inspiring the design of new drugs. The complex molecules found in the oceans present a great challenge to organic and medicinal chemists. However, the wide variety of biological activities they [...] Read more.

The marine kingdom is an important source of a huge variety of scaffolds inspiring the design of new drugs. The complex molecules found in the oceans present a great challenge to organic and medicinal chemists. However, the wide variety of biological activities they can display is worth the effort. In this article, we present an overview of different seaweeds as potential sources of bioactive pigments with activity against neurodegenerative diseases, especially due to their neuroprotective effects. Along with a broad introduction to seaweed as a source of bioactive pigments, this review is especially focused on astaxanthin and fucoxanthin as potential neuroprotective and/or anti-neurodegenerative agents. PubMed and SciFinder were used as the main sources to search and select the most relevant scientific articles within the field. Full article

(This article belongs to the Special Issue Synthetic Chemistry in Marine Drug Discovery: Challenges and Opportunities)

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25 pages, 8776 KiB

Open AccessEditor’s ChoiceArticle

From Sea to Science: Coral Aquaculture for Sustainable Anticancer Drug Development

by Hung-Yu Lin, Tsen-Ni Tsai, Kai-Cheng Hsu, Yu-Ming Hsu, Lin-Chien Chiang, Mohamed El-Shazly, Ken-Ming Chang, Yu-Hsuan Lin, Shang-Yi Tu, Tony Eight Lin, Ying-Chi Du, Yi-Chang Liu and Mei-Chin Lu

Mar. Drugs 2024, 22(7), 323; https://doi.org/10.3390/md22070323 - 19 Jul 2024

Cited by 1 | Viewed by 4585

Abstract

Marine natural products offer immense potential for drug development, but the limited supply of marine organisms poses a significant challenge. Establishing aquaculture presents a sustainable solution for this challenge by facilitating the mass production of active ingredients while reducing our reliance on wild [...] Read more.

Marine natural products offer immense potential for drug development, but the limited supply of marine organisms poses a significant challenge. Establishing aquaculture presents a sustainable solution for this challenge by facilitating the mass production of active ingredients while reducing our reliance on wild populations and harm to local environments. To fully utilize aquaculture as a source of biologically active products, a cell-free system was established to target molecular components with protein-modulating activity, including topoisomerase II, HDAC, and tubulin polymerization, using extracts from aquaculture corals. Subsequent in vitro studies were performed, including MTT assays, flow cytometry, confocal microscopy, and Western blotting, along with in vivo xenograft models, to verify the efficacy of the active extracts and further elucidate their cytotoxic mechanisms. Regulatory proteins were clarified using NGS and gene modification techniques. Molecular docking and SwissADME assays were performed to evaluate the drug-likeness and pharmacokinetic and medicinal chemistry-related properties of the small molecules. The extract from Lobophytum crassum (LCE) demonstrated potent broad-spectrum activity, exhibiting significant inhibition of tubulin polymerization, and showed low IC₅₀ values against prostate cancer cells. Flow cytometry and Western blotting assays revealed that LCE induced apoptosis, as evidenced by the increased expression of apoptotic protein-cleaved caspase-3 and the populations of early and late apoptotic cells. In the xenograft tumor experiments, LCE significantly suppressed tumor growth and reduced the tumor volume (PC3: 43.9%; Du145: 49.2%) and weight (PC3: 48.8%; Du145: 7.8%). Additionally, LCE inhibited prostate cancer cell migration, and invasion upregulated the epithelial marker E-cadherin and suppressed EMT-related proteins. Furthermore, LCE effectively attenuated TGF-β-induced EMT in PC3 and Du145 cells. Bioactivity-guided fractionation and SwissADME validation confirmed that LCE’s main component, 13-acetoxysarcocrassolide (13-AC), holds greater potential for the development of anticancer drugs. Full article

(This article belongs to the Special Issue Marine Natural Products as Anticancer Agents 3.0)

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58 pages, 5548 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Marine Pharmacology in 2019–2021: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action

by Alejandro M. S. Mayer, Veronica A. Mayer, Michelle Swanson-Mungerson, Marsha L. Pierce, Abimael D. Rodríguez, Fumiaki Nakamura and Orazio Taglialatela-Scafati

Mar. Drugs 2024, 22(7), 309; https://doi.org/10.3390/md22070309 - 30 Jun 2024

Cited by 8 | Viewed by 4291

Abstract

The current 2019–2021 marine pharmacology literature review provides a continuation of previous reviews covering the period 1998 to 2018. Preclinical marine pharmacology research during 2019–2021 was published by researchers in 42 countries and contributed novel mechanism-of-action pharmacology for 171 structurally characterized marine compounds. [...] Read more.

The current 2019–2021 marine pharmacology literature review provides a continuation of previous reviews covering the period 1998 to 2018. Preclinical marine pharmacology research during 2019–2021 was published by researchers in 42 countries and contributed novel mechanism-of-action pharmacology for 171 structurally characterized marine compounds. The peer-reviewed marine natural product pharmacology literature reported antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral mechanism-of-action studies for 49 compounds, 87 compounds with antidiabetic and anti-inflammatory activities that also affected the immune and nervous system, while another group of 51 compounds demonstrated novel miscellaneous mechanisms of action, which upon further investigation, may contribute to several pharmacological classes. Thus, in 2019–2021, a very active preclinical marine natural product pharmacology pipeline provided novel mechanisms of action as well as new lead chemistry for the clinical marine pharmaceutical pipeline targeting the therapy of several disease categories. Full article

(This article belongs to the Section Marine Pharmacology)

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16 pages, 1224 KiB

Open AccessEditor’s ChoiceArticle

Isolation and Total Synthesis of PM170453, a New Cyclic Depsipeptide Isolated from Lyngbya sp.

by Rogelio Fernández, Marta Pérez, Alejandro Losada, Silvia Reboredo, Asier Gómez-San Juan, María Jesús Martín, Andrés Francesch, Simon Munt and Carmen Cuevas

Mar. Drugs 2024, 22(7), 303; https://doi.org/10.3390/md22070303 - 28 Jun 2024

Viewed by 2098

Abstract

In our continuing search for biologically active new chemical entities from marine organisms, we have isolated a new cyclic depsipeptide, PM170453 (1), from a cyanobacterium of the genus Lyngbya sp., collected in the Indo-Pacific Ocean. Structure elucidation of the isolated compound [...] Read more.

In our continuing search for biologically active new chemical entities from marine organisms, we have isolated a new cyclic depsipeptide, PM170453 (1), from a cyanobacterium of the genus Lyngbya sp., collected in the Indo-Pacific Ocean. Structure elucidation of the isolated compound was determined by spectroscopic methods including MS, ¹H, ¹³C and 2D-NMR. To solve the supply problem for 1 and progress pharmaceutical development, the total synthesis of 1 that involves a total of 20 chemical steps in a convergent process was carried out. Its in vitro cytotoxic activity against four human tumor cell lines, as well as the inhibition of the interaction between the programmed cell death protein 1 PD-1 and its ligand PD-L1 were also evaluated. Full article

(This article belongs to the Section Synthesis and Medicinal Chemistry of Marine Natural Products)

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25 pages, 1555 KiB

Open AccessEditor’s ChoiceReview

Proof of Concept of Natural and Synthetic Antifouling Agents in Coatings

by Daniela Pereira, Joana R. Almeida, Honorina Cidade and Marta Correia-da-Silva

Mar. Drugs 2024, 22(7), 291; https://doi.org/10.3390/md22070291 - 24 Jun 2024

Cited by 5 | Viewed by 2218

Abstract

Marine biofouling, caused by the deposition and accumulation of marine organisms on submerged surfaces, represents a huge concern for the maritime industries and also contributes to environmental pollution and health concerns. The most effective way to prevent this phenomenon is the use of [...] Read more.

Marine biofouling, caused by the deposition and accumulation of marine organisms on submerged surfaces, represents a huge concern for the maritime industries and also contributes to environmental pollution and health concerns. The most effective way to prevent this phenomenon is the use of biocide-based coatings which have proven to cause serious damage to marine ecosystems. Several research groups have focused on the search for new environmentally friendly antifoulants, including marine and terrestrial natural products and synthetic analogues. Some of these compounds have been incorporated into marine coatings and display interesting antifouling activities caused by the interference with the biofilm-forming species as well as by the inhibition of the settlement of macroorganisms. This review highlights the proof-of-concept studies of emerging natural or synthetic antifouling compounds in coatings, from lab-made to commercial ones, performed between 2019 and 2023 and their results in the field or in in vivo laboratorial tests. Full article

(This article belongs to the Special Issue Marine Anti-Biofilm Compounds from Natural to Synthetic Compounds)

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10 pages, 1078 KiB

Open AccessEditor’s ChoiceArticle

New Cyclic Pentapeptides from the Mangrove-Derived Aspergillus fumigatus GXIMD 03099

by Yu Wang, Guangping Cao, Yuman Gan, Xiao Lin, Xiangxi Yi, Longyan Zhao, Yonghong Liu, Chenghai Gao and Meng Bai

Mar. Drugs 2024, 22(6), 282; https://doi.org/10.3390/md22060282 - 16 Jun 2024

Cited by 7 | Viewed by 1821

Abstract

Four new cyclic pentapeptides, avellanins D–G (1–4), together with four known compounds (5–8), were isolated from a mangrove-derived Aspergillus fumigatus GXIMD 03099 fungus from Acanthus ilicifolius L. Their structures were elucidated by analysis of HRESIMS, [...] Read more.

Four new cyclic pentapeptides, avellanins D–G (1–4), together with four known compounds (5–8), were isolated from a mangrove-derived Aspergillus fumigatus GXIMD 03099 fungus from Acanthus ilicifolius L. Their structures were elucidated by analysis of HRESIMS, NMR, and ESI-MS/MS data. Their absolute configurations were determined by X-ray diffraction analysis and Marfey’s method. Compounds 1–8 were screened for insecticidal and antibacterial activities. Compound 2 showed insecticidal activity against newly hatched larvae of Culex quinquefasciatus with an LC₅₀ value of 86.6 µM; compound 4 had weak activity against Vibrio harveyi with an MIC value of 5.85 µM. Full article

(This article belongs to the Special Issue Bioactive Secondary Metabolites of Marine Fungi 2.0)

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10 pages, 2011 KiB

Open AccessEditor’s ChoiceCommunication

Cytotoxic Pentaketide-Sesquiterpenes from the Marine-Derived Fungus Talaromyces variabilis M22734

by Lingzhi Tang, Jinmei Xia, Zhongwei Chen, Xiaohui Wu, Guangyu Li, Qiliang Lai, Zongze Shao, Weiyi Wang and Xuan Hong

Mar. Drugs 2024, 22(6), 274; https://doi.org/10.3390/md22060274 - 13 Jun 2024

Cited by 1 | Viewed by 1873

Abstract

Talaromyces, a filamentous fungus widely distributed across terrestrial and marine environments, can produce a diverse array of natural products, including alkaloids, polyketones, and polyketide-terpenoids. Among these, chrodrimanins represented a typical class of natural products. In this study, we isolated three previously undescribed [...] Read more.

Talaromyces, a filamentous fungus widely distributed across terrestrial and marine environments, can produce a diverse array of natural products, including alkaloids, polyketones, and polyketide-terpenoids. Among these, chrodrimanins represented a typical class of natural products. In this study, we isolated three previously undescribed pentaketide-sesquiterpenes, 8,9-epi-chrodrimanins (1–3), along with eight known compounds (4–11). The structures of compounds 1–3 were elucidated using nuclear magnetic resonance (NMR) and mass spectrometry (MS), while their absolute configurations were determined through X-ray crystallography and electronic circular dichroism (ECD) computations. The biosynthetic pathways of compounds 1–3 initiate with 6-hydroxymellein and involve multiple stages of isoprenylation, cyclization, oxidation, and acetylation. We selected four strains of gastrointestinal cancer cells for activity evaluation. We found that compound 3 selectively inhibited MKN-45, whereas compounds 1 and 2 exhibited no significant inhibitory activity against the four cell lines. These findings suggested that 8,9-epi-chrodrimanins could serve as scaffold compounds for further structural modifications, potentially leading to the development of targeted therapies for gastric cancer. Full article

(This article belongs to the Special Issue Marine-Derived Terpenes: Chemistry, Synthesis and Their Therapeutic Potential)

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13 pages, 1539 KiB

Open AccessEditor’s ChoiceArticle

Cellulamides: A New Family of Marine-Sourced Linear Peptides from the Underexplored Cellulosimicrobium Genus

by Mariana Girão, José Murillo-Alba, Jesús Martín, Ignacio Pérez-Victoria, Ricardo B. Leite, Ralph Urbatzka, Pedro N. Leão, Maria F. Carvalho and Fernando Reyes

Mar. Drugs 2024, 22(6), 268; https://doi.org/10.3390/md22060268 - 11 Jun 2024

Cited by 1 | Viewed by 2230

Abstract

Bioprospecting the secondary metabolism of underexplored Actinomycetota taxa is a prolific route to uncover novel chemistry. In this work, we report the isolation, structure elucidation, and bioactivity screening of cellulamides A and B (1 and 2), two novel linear peptides obtained [...] Read more.

Bioprospecting the secondary metabolism of underexplored Actinomycetota taxa is a prolific route to uncover novel chemistry. In this work, we report the isolation, structure elucidation, and bioactivity screening of cellulamides A and B (1 and 2), two novel linear peptides obtained from the culture of the macroalga-associated Cellulosimicrobium funkei CT-R177. The host of this microorganism, the Chlorophyta Codium tomentosum, was collected in the northern Portuguese coast and, in the scope of a bioprospecting study focused on its associated actinobacterial community, strain CT-R177 was isolated, taxonomically identified, and screened for the production of antimicrobial and anticancer compounds. Dereplication of a crude extract of this strain using LC-HRMS(/MS) analysis unveiled a putative novel natural product, cellulamide A (1), that was isolated following mass spectrometry-guided fractionation. An additional analog, cellulamide B (2) was obtained during the chromatographic process and chemically characterized. The chemical structures of the novel linear peptides, including their absolute configurations, were elucidated using a combination of HRMS, 1D/2D NMR spectroscopy, and Marfey’s analysis. Cellulamide A (1) was subjected to a set of bioactivity screenings, but no significant biological activity was observed. The cellulamides represent the first family of natural products reported from the Actinomycetota genus Cellulosimicrobium, showcasing not only the potential of less-explored taxa but also of host-associated marine strains for novel chemistry discovery. Full article

(This article belongs to the Special Issue From Seaside to Bedside: Dedicated to Professor José María Fernández Sousa-Faro)

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10 pages, 602 KiB

Open AccessEditor’s ChoiceArticle

New Secondary Metabolites from Marine-Derived Fungus Talaromyces minnesotensis BTBU20220184

by Weiliang Wang, Jingjing Wang, Fuhang Song, Renming Jia, Long Wang, Xiuli Xu and Na Yang

Mar. Drugs 2024, 22(6), 237; https://doi.org/10.3390/md22060237 - 23 May 2024

Viewed by 1721

Abstract

Six new compounds, talamitones A and B (1 and 2), demethyltalamitone B (3), talamiisocoumaringlycosides A and B (4 and 5), and talaminaphtholglycoside (6), together with six known compounds (7–12), were isolated [...] Read more.

Six new compounds, talamitones A and B (1 and 2), demethyltalamitone B (3), talamiisocoumaringlycosides A and B (4 and 5), and talaminaphtholglycoside (6), together with six known compounds (7–12), were isolated from the marine-derived fungus Talaromyces minnesotensis BTBU20220184. The new structures were characterized by using HRESIMS and NMR. This is the first report of isocoumaringlycoside derivatives from a fungus of the Talaromyces genus. Compounds 5, 6, and 9 showed synergistic antibacterial activity against Staphylococcus aureus. Full article

(This article belongs to the Special Issue Bioactive Secondary Metabolites of Marine Fungi 2.0)

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20 pages, 2736 KiB

Open AccessEditor’s ChoiceArticle

Chemical Investigation of the Calcareous Marine Sponge Pericharax heteroraphis, Clathridine-A Related Derivatives Isolation, Synthesis and Osteogenic Activity

by Capucine Jourdain de Muizon, Céline Moriou, Marceau Levasseur, David Touboul, Bogdan I. Iorga, Hristo Nedev, Elsa Van Elslande, Pascal Retailleau, Sylvain Petek, Eric Folcher, Arnaud Bianchi, Mireille Thomas, Solène Viallon, Sylvie Peyroche, Sarah Nahle, Marthe Rousseau and Ali Al-Mourabit

Mar. Drugs 2024, 22(5), 196; https://doi.org/10.3390/md22050196 - 25 Apr 2024

Viewed by 1970

Abstract

As a result of screening a panel of marine organisms to identify lead molecules for the stimulation of endochondral bone formation, the calcareous sponge Pericharax heteroraphis was identified to exhibit significant activity during endochondral differentiation. On further molecular networking analysis, dereplication and chemical [...] Read more.

As a result of screening a panel of marine organisms to identify lead molecules for the stimulation of endochondral bone formation, the calcareous sponge Pericharax heteroraphis was identified to exhibit significant activity during endochondral differentiation. On further molecular networking analysis, dereplication and chemical fractionation yielded the known clathridine A-related metabolites 3–6 and the homodimeric complex (clathridine A)₂ Zn²⁺ (9), together with the new unstable heterodimeric complex (clathridine A–clathridimine)Zn²⁺ (10). With the presence of the zinc complexes annotated through the LC-MS analysis of the crude extract changing due to the instability of some metabolites and complexes constituting the mixture, we combined the isolation of the predicted molecules with their synthesis in order to confirm their structure and to understand their reactivity. Interestingly, we also found a large quantity of the contaminant benzotriazoles BTZ (7) and its semi-dimer (BTZ)₂CH₂ (8), which are known to form complexes with transition metals and are used for preventing corrosion in water. All isolated 2-aminoimidazole derivatives and complexes were synthesized not only for structural confirmation and chemical understanding but to further study their bioactivity during endochondral differentiation, particularly the positively screened imidazolone derivatives. Compounds leucettamine B, clathridine A and clathridimine were found to increase type X collagen transcription and stimulate endochondral ossification in the ATDC5 micromass model. Full article

(This article belongs to the Special Issue Bio-Active Components from Marine Sponges)

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14 pages, 2390 KiB

Open AccessEditor’s ChoiceArticle

The Discovery of Weddellamycin, a Tricyclic Polyene Macrolactam Antibiotic from an Antarctic Deep-Sea-Derived Streptomyces sp. DSS69, by Heterologous Expression

by Lu Chen, Kai Liu, Jiali Hong, Zhanzhao Cui, Weijun He, Yemin Wang, Zixin Deng and Meifeng Tao

Mar. Drugs 2024, 22(4), 189; https://doi.org/10.3390/md22040189 - 21 Apr 2024

Cited by 2 | Viewed by 2787

Abstract

Polyene macrolactams are a special group of natural products with great diversity, unique structural features, and a wide range of biological activities. Herein, a cryptic gene cluster for the biosynthesis of putative macrolactams was disclosed from a sponge-associated bacterium, Streptomyces sp. DSS69, by [...] Read more.

Polyene macrolactams are a special group of natural products with great diversity, unique structural features, and a wide range of biological activities. Herein, a cryptic gene cluster for the biosynthesis of putative macrolactams was disclosed from a sponge-associated bacterium, Streptomyces sp. DSS69, by genome mining. Cloning and heterologous expression of the whole biosynthetic gene cluster led to the discovery of weddellamycin, a polyene macrolactam bearing a 23/5/6 ring skeleton. A negative regulator, WdlO, and two positive regulators, WdlA and WdlB, involved in the regulation of weddellamycin production were unraveled. The fermentation titer of weddellamycin was significantly improved by overexpression of wdlA and wdlB and deletion of wdlO. Notably, weddellamycin showed remarkable antibacterial activity against various Gram-positive bacteria including MRSA, with MIC values of 0.10–0.83 μg/mL, and antifungal activity against Candida albicans, with an MIC value of 3.33 μg/mL. Weddellamycin also displayed cytotoxicity against several cancer cell lines, with IC₅₀ values ranging from 2.07 to 11.50 µM. Full article

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15 pages, 3281 KiB

Open AccessEditor’s ChoiceArticle

Zeaxanthin epoxidase 3 Knockout Mutants of the Model Diatom Phaeodactylum tricornutum Enable Commercial Production of the Bioactive Carotenoid Diatoxanthin

by Cecilie Græsholt, Tore Brembu, Charlotte Volpe, Zdenka Bartosova, Manuel Serif, Per Winge and Marianne Nymark

Mar. Drugs 2024, 22(4), 185; https://doi.org/10.3390/md22040185 - 19 Apr 2024

Cited by 9 | Viewed by 3464

Abstract

Carotenoids are pigments that have a range of functions in human health. The carotenoid diatoxanthin is suggested to have antioxidant, anti-inflammatory and chemo-preventive properties. Diatoxanthin is only produced by a few groups of microalgae, where it functions in photoprotection. Its large-scale production in [...] Read more.

Carotenoids are pigments that have a range of functions in human health. The carotenoid diatoxanthin is suggested to have antioxidant, anti-inflammatory and chemo-preventive properties. Diatoxanthin is only produced by a few groups of microalgae, where it functions in photoprotection. Its large-scale production in microalgae is currently not feasible. In fact, rapid conversion into the inactive pigment diadinoxanthin is triggered when cells are removed from a high-intensity light source, which is the case during large-scale harvesting of microalgae biomass. Zeaxanthin epoxidase (ZEP) 2 and/or ZEP3 have been suggested to be responsible for the back-conversion of high-light accumulated diatoxanthin to diadinoxanthin in low-light in diatoms. Using CRISPR/Cas9 gene editing technology, we knocked out the ZEP2 and ZEP3 genes in the marine diatom Phaeodactylum tricornutum to investigate their role in the diadinoxanthin–diatoxanthin cycle and determine if one of the mutant strains could function as a diatoxanthin production line. Light-shift experiments proved that ZEP3 encodes the enzyme converting diatoxanthin to diadinoxanthin in low light. Loss of ZEP3 caused the high-light-accumulated diatoxanthin to be stable for several hours after the cultures had been returned to low light, suggesting that zep3 mutant strains could be suitable as commercial production lines of diatoxanthin. Full article

(This article belongs to the Special Issue Marine Anti-inflammatory and Antioxidant Agents 3.0)

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28 pages, 5918 KiB

Open AccessEditor’s ChoiceReview

Marine-Derived Metabolites Act as Promising Antifungal Agents

by Sijin Hang, Hui Lu and Yuanying Jiang

Mar. Drugs 2024, 22(4), 180; https://doi.org/10.3390/md22040180 - 17 Apr 2024

Cited by 6 | Viewed by 3350

Abstract

The incidence of invasive fungal diseases (IFDs) is on the rise globally, particularly among immunocompromised patients, leading to significant morbidity and mortality. Current clinical antifungal agents, such as polyenes, azoles, and echinocandins, face increasing resistance from pathogenic fungi. Therefore, there is a pressing [...] Read more.

The incidence of invasive fungal diseases (IFDs) is on the rise globally, particularly among immunocompromised patients, leading to significant morbidity and mortality. Current clinical antifungal agents, such as polyenes, azoles, and echinocandins, face increasing resistance from pathogenic fungi. Therefore, there is a pressing need for the development of novel antifungal drugs. Marine-derived secondary metabolites represent valuable resources that are characterized by varied chemical structures and pharmacological activities. While numerous compounds exhibiting promising antifungal activity have been identified, a comprehensive review elucidating their specific underlying mechanisms remains lacking. In this review, we have compiled a summary of antifungal compounds derived from marine organisms, highlighting their diverse mechanisms of action targeting various fungal cellular components, including the cell wall, cell membrane, mitochondria, chromosomes, drug efflux pumps, and several biological processes, including vesicular trafficking and the growth of hyphae and biofilms. This review is helpful for the subsequent development of antifungal drugs due to its summary of the antifungal mechanisms of secondary metabolites from marine organisms. Full article

(This article belongs to the Topic Antimicrobial Agents and Nanomaterials)

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15 pages, 1736 KiB

Open AccessEditor’s ChoiceArticle

Structural Insights into the Marine Alkaloid Discorhabdin G as a Scaffold towards New Acetylcholinesterase Inhibitors

by Andrea Defant, Giacomo Carloni, Nicole Innocenti, Tomaž Trobec, Robert Frangež, Kristina Sepčić and Ines Mancini

Mar. Drugs 2024, 22(4), 173; https://doi.org/10.3390/md22040173 - 12 Apr 2024

Cited by 1 | Viewed by 2407

Abstract

In this study, Antarctic Latrunculia sponge-derived discorhabdin G was considered a hit for developing potential lead compounds acting as cholinesterase inhibitors. The hypothesis on the pharmacophore moiety suggested through molecular docking allowed us to simplify the structure of the metabolite. ADME prediction and [...] Read more.

In this study, Antarctic Latrunculia sponge-derived discorhabdin G was considered a hit for developing potential lead compounds acting as cholinesterase inhibitors. The hypothesis on the pharmacophore moiety suggested through molecular docking allowed us to simplify the structure of the metabolite. ADME prediction and drug-likeness consideration provided valuable support in selecting 5-methyl-2H-benzo[h]imidazo[1,5,4-de]quinoxalin-7(3H)-one as a candidate molecule. It was synthesized in a four-step sequence starting from 2,3-dichloronaphthalene-1,4-dione and evaluated as an inhibitor of electric eel acetylcholinesterase (eeAChE), human recombinant AChE (hAChE), and horse serum butyrylcholinesterase (BChE), together with other analogs obtained by the same synthesis. The candidate molecule showed a slightly lower inhibitory potential against eeAChE but better inhibitory activity against hAChE than discorhabdin G, with a higher selectivity for AChEs than for BChE. It acted as a reversible competitive inhibitor, as previously observed for the natural alkaloid. The findings from the in vitro assay were relatively consistent with the data available from the AutoDock Vina and Protein-Ligand ANTSystem (PLANTS) calculations. Full article

(This article belongs to the Special Issue Marine Drug Discovery through Molecular Docking)

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15 pages, 4793 KiB

Open AccessEditor’s ChoiceArticle

Equinins as Novel Broad-Spectrum Antimicrobial Peptides Isolated from the Cnidarian Actinia equina (Linnaeus, 1758)

by Claudia La Corte, Valentina Catania, Mariano Dara, Daniela Parrinello, Mariele Staropoli, Maria Rosa Trapani, Matteo Cammarata and Maria Giovanna Parisi

Mar. Drugs 2024, 22(4), 172; https://doi.org/10.3390/md22040172 - 12 Apr 2024

Cited by 6 | Viewed by 2946

Abstract

Sea anemones are valuable for therapeutic research as a diversified source of bioactive molecules, due to their diverse bioactive molecules linked to predation and defence mechanisms involving toxins and antimicrobial peptides. Acid extracts from Actinia equina tentacles and body were examined for antibacterial [...] Read more.

Sea anemones are valuable for therapeutic research as a diversified source of bioactive molecules, due to their diverse bioactive molecules linked to predation and defence mechanisms involving toxins and antimicrobial peptides. Acid extracts from Actinia equina tentacles and body were examined for antibacterial activity against Gram-positive, Gram-negative bacteria, and fungi. The peptide fractions showed interesting minimum inhibitory concentration (MIC) values (up to 0.125 µg/mL) against the tested pathogens. Further investigation and characterization of tentacle acid extracts with significant antimicrobial activity led to the purification of peptides through reverse phase chromatography on solid phase and HPLC. Broad-spectrum antimicrobial peptide activity was found in 40% acetonitrile fractions. The resulting peptides had a molecular mass of 2612.91 and 3934.827 Da and MIC ranging from 0.06 to 0.20 mg/mL. Sequencing revealed similarities to AMPs found in amphibians, fish, and Cnidaria, with anti-Gram+, Gram-, antifungal, candidacidal, anti-methicillin-resistant Staphylococcus aureus, carbapenemase-producing, vancomycin-resistant bacteria, and multi-drug resistant activity. Peptides 6.2 and 7.3, named Equinin A and B, respectively, were synthesized and evaluated in vitro towards the above-mentioned bacterial pathogens. Equinin B exerted interesting antibacterial activity (MIC and bactericidal concentrations of 1 mg/mL and 0.25 mg/mL, respectively) and gene organization supporting its potential in applied research. Full article

(This article belongs to the Section Marine Pharmacology)

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11 pages, 2179 KiB

Open AccessEditor’s ChoiceArticle

Lemneolemnanes A–D, Four Uncommon Sesquiterpenoids from the Soft Coral Lemnalia sp.

by Yuan Zong, Tian-Yun Jin, Jun-Jie Yang, Kun-Ya Wang, Xing Shi, Yue Zhang and Ping-Lin Li

Mar. Drugs 2024, 22(4), 145; https://doi.org/10.3390/md22040145 - 26 Mar 2024

Cited by 2 | Viewed by 1847

Abstract

Four undescribed sesquiterpenoids, lemneolemnanes A–D (1–4), have been isolated from the marine soft coral Lemnalia sp. The absolute configurations of the stereogenic carbons of 1–4 were determined by single-crystal X-ray crystallographic analysis. Compounds 1 and 2 are [...] Read more.

Four undescribed sesquiterpenoids, lemneolemnanes A–D (1–4), have been isolated from the marine soft coral Lemnalia sp. The absolute configurations of the stereogenic carbons of 1–4 were determined by single-crystal X-ray crystallographic analysis. Compounds 1 and 2 are epimers at C-3 and have an unusual skeleton with a formyl group on C-6. Compound 3 possesses an uncommonly rearranged carbon skeleton, while 4 has a 6/5/5 tricyclic system. Compound 1 showed significant anti-Alzheimer’s disease (AD) activity in a humanized Caenorhabditis elegans AD pathological model. Full article

(This article belongs to the Special Issue Bioactive Compounds from Soft Corals and Their Derived Microorganisms)

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21 pages, 8244 KiB

Open AccessEditor’s ChoiceReview

Towards the Exploration and Evolution of Insulin-like Venoms in Actiniaria (Sea anemones)

by Alonso Delgado, Kyle S. Sozanski and Marymegan Daly

Mar. Drugs 2024, 22(3), 136; https://doi.org/10.3390/md22030136 - 20 Mar 2024

Cited by 2 | Viewed by 2519

Abstract

Recent studies have elucidated the diversity of genes encoding venom in Sea anemones. However, most of those genes are yet to be explored in an evolutionary context. Insulin is a common peptide across metazoans and has been coopted into a predatory venom [...] Read more.

Recent studies have elucidated the diversity of genes encoding venom in Sea anemones. However, most of those genes are yet to be explored in an evolutionary context. Insulin is a common peptide across metazoans and has been coopted into a predatory venom in many venomous lineages. In this study, we focus on the diversity of insulin-derived venoms in Sea anemones and on elucidating their evolutionary history. We sourced data for 34 species of Sea anemones and found sequences belonging to two venom families which have Insulin PFAM annotations. Our findings show that both families have undergone duplication events. Members of each of the independently evolving clades have consistent predicted protein structures and distinct dN/dS values. Our work also shows that sequences allied with VP302 are part of a multidomain venom contig and have experienced a secondary gain into the venom system of cuticulate Sea anemones. Full article

(This article belongs to the Section Marine Toxins)

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15 pages, 11095 KiB

Open AccessEditor’s ChoiceArticle

Study on the Anti-Mycobacterium marinum Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactone Derivatives

by Qian-Qian Jing, Jun-Na Yin, Ya-Jie Cheng, Qun Zhang, Xi-Zhen Cao, Wei-Feng Xu, Chang-Lun Shao and Mei-Yan Wei

Mar. Drugs 2024, 22(3), 135; https://doi.org/10.3390/md22030135 - 16 Mar 2024

Cited by 3 | Viewed by 2618

Abstract

With the emergence of drug-resistant strains, the treatment of tuberculosis (TB) is becoming more difficult and there is an urgent need to find new anti-TB drugs. Mycobacterium marinum, as a model organism of Mycobacterium tuberculosis, can be used for the rapid [...] Read more.

With the emergence of drug-resistant strains, the treatment of tuberculosis (TB) is becoming more difficult and there is an urgent need to find new anti-TB drugs. Mycobacterium marinum, as a model organism of Mycobacterium tuberculosis, can be used for the rapid and efficient screening of bioactive compounds. The 14-membered resorcylic acid lactones (RALs) have a wide range of bioactivities such as antibacterial, antifouling and antimalarial activity. In order to further study their bioactivities, we initially constructed a 14-membered RALs library, which contains 16 new derivatives. The anti-M. marinum activity was evaluated in vitro. Derivatives 12, 19, 20 and 22 exhibited promising activity with MIC₉₀ values of 80, 90, 80 and 80 μM, respectively. The preliminary structure–activity relationships showed that the presence of a chlorine atom at C-5 was a key factor to improve activity. Further studies showed that 12 markedly inhibited the survival of M. marinum and significantly reduced the dosage of positive drugs isoniazid and rifampicin when combined with them. These results suggest that 12 is a bioactive compound capable of enhancing the potency of existing positive drugs, and its effective properties make it a very useful leads for future drug development in combating TB resistance. Full article

(This article belongs to the Special Issue Pharmacological Potential of Marine Natural Products)

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16 pages, 1491 KiB

Open AccessEditor’s ChoiceArticle

Novel [1,3,4]Thiadiazole[3,2-a]pyrimidin-5-ones as Promising Biofilm Dispersal Agents against Relevant Gram-Positive and Gram-Negative Pathogens

by Daniela Carbone, Camilla Pecoraro, Fabio Scianò, Valentina Catania, Domenico Schillaci, Barbara Manachini, Stella Cascioferro, Patrizia Diana and Barbara Parrino

Mar. Drugs 2024, 22(3), 133; https://doi.org/10.3390/md22030133 - 15 Mar 2024

Cited by 2 | Viewed by 2200

Abstract

Biofilm-associated infections pose significant challenges in healthcare settings due to their resistance to conventional antimicrobial therapies. In the last decade, the marine environment has been a precious source of bioactive molecules, including numerous derivatives with antibiofilm activity. In this study, we reported the [...] Read more.

Biofilm-associated infections pose significant challenges in healthcare settings due to their resistance to conventional antimicrobial therapies. In the last decade, the marine environment has been a precious source of bioactive molecules, including numerous derivatives with antibiofilm activity. In this study, we reported the synthesis and the biological evaluation of a new series of twenty-two thiadiazopyrimidinone derivatives obtained by using a hybridization approach combining relevant chemical features of two important classes of marine compounds: nortopsentin analogues and Essramycin derivatives. The synthesized compounds were in vitro tested for their ability to inhibit biofilm formation and to disrupt mature biofilm in various bacterial strains. Among the tested compounds, derivative 8j exhibited remarkable dispersal activity against preformed biofilms of relevant Gram-positive and Gram-negative pathogens, as well as towards the fungus Candida albicans, showing BIC₅₀ values ranging from 17 to 40 µg/mL. Furthermore, compound 8j was in vivo assayed for its toxicity and the anti-infective effect in a Galleria mellonella model. The results revealed a promising combination of anti-infective properties and a favorable toxicity profile for the treatment of severe chronic biofilm-mediated infections. Full article

(This article belongs to the Special Issue Marine Drug Research in Italy)

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18 pages, 535 KiB

Open AccessEditor’s ChoiceReview

A Review of Cyclic Imines in Shellfish: Worldwide Occurrence, Toxicity and Assessment of the Risk to Consumers

by Sarah C. Finch, D. Tim Harwood, Michael J. Boundy and Andrew I. Selwood

Mar. Drugs 2024, 22(3), 129; https://doi.org/10.3390/md22030129 - 11 Mar 2024

Cited by 7 | Viewed by 2798

Abstract

Cyclic imines are a class of lipophilic shellfish toxins comprising gymnodimines, spirolides, pinnatoxins, portimines, pteriatoxins, prorocentrolides, spiro-prorocentrimine, symbiomines and kabirimine. They are structurally diverse, but all share an imine moiety as part of a bicyclic ring system. These compounds are produced by marine [...] Read more.

Cyclic imines are a class of lipophilic shellfish toxins comprising gymnodimines, spirolides, pinnatoxins, portimines, pteriatoxins, prorocentrolides, spiro-prorocentrimine, symbiomines and kabirimine. They are structurally diverse, but all share an imine moiety as part of a bicyclic ring system. These compounds are produced by marine microalgal species and are characterized by the rapid death that they induce when injected into mice. Cyclic imines have been detected in a range of shellfish species collected from all over the world, which raises the question as to whether they present a food safety risk. The European Food Safety Authority (EFSA) considers them to be an emerging food safety issue, and in this review, the risk posed by these toxins to shellfish consumers is assessed by collating all available occurrence and toxicity data. Except for pinnatoxins, the risk posed to human health by the cyclic imines appears low, although this is based on only a limited dataset. For pinnatoxins, two different health-based guidance values have been proposed at which the concentration should not be exceeded in shellfish (268 and 23 µg PnTX/kg shellfish flesh), with the discrepancy caused by the application of different uncertainty factors. Pinnatoxins have been recorded globally in multiple shellfish species at concentrations of up to 54 times higher than the lower guidance figure. Despite this observation, pinnatoxins have not been associated with recorded human illness, so it appears that the lower guidance value may be conservative. However, there is insufficient data to generate a more robust guidance value, so additional occurrence data and toxicity information are needed. Full article

(This article belongs to the Special Issue Emerging Toxins Accumulation in Shellfish)

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14 pages, 1716 KiB

Open AccessEditor’s ChoiceArticle

Mycosporine-like Amino Acids in Palmaria palmata (Rhodophyta): Specific Implication of Usujirene in Photoprotection

by Fanny Lalegerie, Valérie Stiger-Pouvreau and Solène Connan

Mar. Drugs 2024, 22(3), 121; https://doi.org/10.3390/md22030121 - 5 Mar 2024

Cited by 2 | Viewed by 2899

Abstract

The effect of UV radiation on the accumulation of mycosporine-like amino acids (MAAs) and pigments was investigated on red macroalga Palmaria palmata cultivated for 21 days. The data were combined with the effect of NaNO₃ to further investigate the synthesis of these [...] Read more.

The effect of UV radiation on the accumulation of mycosporine-like amino acids (MAAs) and pigments was investigated on red macroalga Palmaria palmata cultivated for 21 days. The data were combined with the effect of NaNO₃ to further investigate the synthesis of these nitrogenous compounds. A progressive decrease in both total MAA and pigment contents was observed, with a positive effect of nitrate supply. Usujirene was the only MAA exhibiting a significantly increasing content when exposed to UV radiation, changing from 9% to 24% of the total MAA’s contribution, with no variation observed with NaNO₃. This suggests a specific induction or synthesis pathway of usujirene for photoprotection, while the synthesis of other MAAs could have been limited by an insufficient amount of UV radiation and/or irradiance. The photoprotective ability of some MAAs could have been impacted by nitrogen starvation over time, resulting in a limited synthesis and/or potential use of MAAs as a nitrogen source for red macroalgae. The data confirmed the multiple effects of environmental factors on the synthesis of MAAs while providing new insights into the specific synthesis of usujirene, which could find an application in the cosmetics sector as natural sunscreen or an anti-ageing agent. Full article

(This article belongs to the Special Issue Antiphotoaging and Photoprotective Compounds from Marine Environments)

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20 pages, 4277 KiB

Open AccessEditor’s ChoiceArticle

Using Constellation Pharmacology to Characterize a Novel α-Conotoxin from Conus ateralbus

by Jorge L. B. Neves, Cristoval Urcino, Kevin Chase, Cheryl Dowell, Arik J. Hone, David Morgenstern, Victor M. Chua, Iris Bea L. Ramiro, Julita S. Imperial, Lee S. Leavitt, Jasmine Phan, Fernando A. Fisher, Maren Watkins, Shrinivasan Raghuraman, Jortan O. Tun, Beatrix M. Ueberheide, J. Michael McIntosh, Vitor Vasconcelos, Baldomero M. Olivera and Joanna Gajewiak

Mar. Drugs 2024, 22(3), 118; https://doi.org/10.3390/md22030118 - 29 Feb 2024

Cited by 1 | Viewed by 3380

Abstract

The venom of cone snails has been proven to be a rich source of bioactive peptides that target a variety of ion channels and receptors. α-Conotoxins (αCtx) interact with nicotinic acetylcholine receptors (nAChRs) and are powerful tools for investigating the structure and function [...] Read more.

The venom of cone snails has been proven to be a rich source of bioactive peptides that target a variety of ion channels and receptors. α-Conotoxins (αCtx) interact with nicotinic acetylcholine receptors (nAChRs) and are powerful tools for investigating the structure and function of the various nAChR subtypes. By studying how conotoxins interact with nAChRs, we can improve our understanding of these receptors, leading to new insights into neurological diseases associated with nAChRs. Here, we describe the discovery and characterization of a novel conotoxin from Conus ateralbus, αCtx-AtIA, which has an amino acid sequence homologous to the well-described αCtx-PeIA, but with a different selectivity profile towards nAChRs. We tested the synthetic αCtx-AtIA using the calcium imaging-based Constellation Pharmacology assay on mouse DRG neurons and found that αCtx-AtIA significantly inhibited ACh-induced calcium influx in the presence of an α7 positive allosteric modulator, PNU-120596 (PNU). However, αCtx-AtIA did not display any activity in the absence of PNU. These findings were further validated using two-electrode voltage clamp electrophysiology performed on oocytes overexpressing mouse α3β4, α6/α3β4 and α7 nAChRs subtypes. We observed that αCtx-AtIA displayed no or low potency in blocking α3β4 and α6/α3β4 receptors, respectively, but improved potency and selectivity to block α7 nAChRs when compared with αCtx-PeIA. Through the synthesis of two additional analogs of αCtx-AtIA and subsequent characterization using Constellation Pharmacology, we were able to identify residue Trp18 as a major contributor to the activity of the peptide. Full article

(This article belongs to the Section Marine Toxins)

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17 pages, 3679 KiB

Open AccessEditor’s ChoiceReview

The Role of Natural and Synthetic Flavonoids in the Prevention of Marine Biofouling

by Daniela Pereira, Madalena Pinto, Joana R. Almeida, Marta Correia-da-Silva and Honorina Cidade

Mar. Drugs 2024, 22(2), 77; https://doi.org/10.3390/md22020077 - 2 Feb 2024

Cited by 5 | Viewed by 2901

Abstract

Marine biofouling is a major concern for the maritime industry, environment, and human health. Biocides which are currently used in marine coatings to prevent this phenomenon are toxic to the marine environment, and therefore a search for antifoulants with environmentally safe properties is [...] Read more.

Marine biofouling is a major concern for the maritime industry, environment, and human health. Biocides which are currently used in marine coatings to prevent this phenomenon are toxic to the marine environment, and therefore a search for antifoulants with environmentally safe properties is needed. A large number of scientific papers have been published showing natural and synthetic compounds with potential to prevent the attachment of macro- and microfouling marine organisms on submerged surfaces. Flavonoids are a class of compounds which are highly present in nature, including in marine organisms, and have been found in a wide range of biological activities. Some natural and synthetic flavonoids have been evaluated over the last few years for their potential to prevent the settlement and/or the growth of marine organisms on submerged structures, thereby preventing marine biofouling. This review compiles, for the first-time, natural flavonoids as well as their synthetic analogues with attributed antifouling activity against macrofouling and microfouling marine organisms. Full article

(This article belongs to the Section Marine Chemoecology for Drug Discovery)

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11 pages, 2252 KiB

Open AccessEditor’s ChoiceArticle

Carneusones A-F, Benzophenone Derivatives from Sponge-Derived Fungus Aspergillus carneus GXIMD00543

by Chun-Ju Lu, Li-Fen Liang, Geng-Si Zhang, Hai-Yan Li, Chun-Qing Fu, Qin Yu, Dong-Mei Zhou, Zhi-Wei Su, Kai Liu, Cheng-Hai Gao, Xin-Ya Xu and Yong-Hong Liu

Mar. Drugs 2024, 22(2), 63; https://doi.org/10.3390/md22020063 - 25 Jan 2024

Cited by 1 | Viewed by 3291

Abstract

Six benzophenone derivatives, carneusones A-F (1–6), along with seven known compounds (7–13) were isolated from a strain of sponge-derived marine fungus Aspergillus carneus GXIMD00543. Their chemical structures were elucidated by detailed spectroscopic data and quantum [...] Read more.

Six benzophenone derivatives, carneusones A-F (1–6), along with seven known compounds (7–13) were isolated from a strain of sponge-derived marine fungus Aspergillus carneus GXIMD00543. Their chemical structures were elucidated by detailed spectroscopic data and quantum chemical calculations. Compounds 5, 6, and 8 exhibited moderate anti-inflammatory activity on NO secretion using lipopolysaccharide (LPS)-induced RAW 264.7 cells with EC₅₀ values of 34.6 ± 0.9, 20.2 ± 1.8, and 26.8 ± 1.7 μM, while 11 showed potent effect with an EC₅₀ value of 2.9 ± 0.1 μM. Full article

(This article belongs to the Special Issue Discovery of Marine Natural Products in China: Selected Papers from the 16th National Annual Conference and 2023 International Symposium on Marine Drugs (16-NASMD) Conference)

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18 pages, 2600 KiB

Open AccessEditor’s ChoiceArticle

Nine New Antibacterial Diterpenes and Steroids from the South China Sea Soft Coral Lobophytum catalai Tixier-Durivault

by Sheng-Hui Zhu, Yuan-Min Chang, Ming-Zhi Su, Li-Gong Yao, Song-Wei Li, Hong Wang and Yue-Wei Guo

Mar. Drugs 2024, 22(1), 50; https://doi.org/10.3390/md22010050 - 20 Jan 2024

Cited by 8 | Viewed by 2570

Abstract

Five new cembrane-type diterpenes, lobocalines A–E (1–5), and four new steroids, lobocaloids A–D (9–12), along with six known related compounds (6–8 and 13–15) were isolated from the Yalong Bay [...] Read more.

Five new cembrane-type diterpenes, lobocalines A–E (1–5), and four new steroids, lobocaloids A–D (9–12), along with six known related compounds (6–8 and 13–15) were isolated from the Yalong Bay soft coral Lobophytum catalai Tixier-Durivault. The structures of the new compounds were elucidated by extensive spectroscopic analysis, NMR calculation with DP4+ analysis, time-dependent density functional theory–electronic circular dichroism (TDDFT-ECD) calculations, X-ray diffraction analyses and comparison with the reported spectroscopic data of known compounds. Further, with the aid of X-ray diffraction analysis, the structure of lobocrasol B (15) was firmly revised as 15a. In in vitro bioassays, compound 2 showed moderate antibacterial activities against fish pathogenic bacteria Streptococcus parauberis KSP28 and Phoyobacterium damselae FP2244 with minimum inhibitory concentration (MIC) values of 8.7 and 17.3 µg/mL, respectively. All the steroids exhibited antibacterial activities against the S. parauberis KSP28 with MIC values ranging from 12.3 to 53.6 µg/mL. Compounds 2, 7 and 14 have remarkable inhibitory effects on the hemolysin production of Staphylococcus aureus, while compounds 8–12 have medium inhibitory effects on the pyocyanin production in Pseudomonas aeruginosa. Full article

(This article belongs to the Section Structural Studies on Marine Natural Products)

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16 pages, 3103 KiB

Open AccessEditor’s ChoiceArticle

αO-Conotoxin GeXIVA[1,2] Reduced Neuropathic Pain and Changed Gene Expression in Chronic Oxaliplatin-Induced Neuropathy Mice Model

by Huanbai Wang, Xiaodan Li, Yamin Qiao, Meiting Wang, Wen Wang, J. Michael McIntosh, Dongting Zhangsun and Sulan Luo

Mar. Drugs 2024, 22(1), 49; https://doi.org/10.3390/md22010049 - 19 Jan 2024

Cited by 5 | Viewed by 3126

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting painful neuropathy that occurs commonly during cancer management, which often leads to the discontinuation of medication. Previous studies suggest that the α9α10 nicotinic acetylcholine receptor (nAChR)-specific antagonist αO-conotoxin GeXIVA[1,2] is effective in CIPN models; however, the [...] Read more.

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting painful neuropathy that occurs commonly during cancer management, which often leads to the discontinuation of medication. Previous studies suggest that the α9α10 nicotinic acetylcholine receptor (nAChR)-specific antagonist αO-conotoxin GeXIVA[1,2] is effective in CIPN models; however, the related mechanisms remain unclear. Here, we analyzed the preventive effect of GeXIVA[1,2] on neuropathic pain in the long-term oxaliplatin injection-induced CIPN model. At the end of treatment, lumbar (L4-L6) spinal cord was extracted, and RNA sequencing and bioinformatic analysis were performed to investigate the potential genes and pathways related to CIPN and GeXIVA[1,2]. GeXIVA[1,2] inhibited the development of mechanical allodynia induced by chronic oxaliplatin treatment. Repeated injections of GeXIVA[1,2] for 3 weeks had no effect on the mice’s normal pain threshold or locomotor activity and anxiety-like behavior, as evaluated in the open field test (OFT) and elevated plus maze (EPM). Our RNA sequencing results identified 209 differentially expressed genes (DEGs) in the CIPN model, and simultaneously injecting GeXIVA[1,2] with oxaliplatin altered 53 of the identified DEGs. These reverted genes were significantly enriched in immune-related pathways represented by the cytokine–cytokine receptor interaction pathway. Our findings suggest that GeXIVA[1,2] could be a potential therapeutic compound for chronic oxaliplatin-induced CIPN management. Full article

(This article belongs to the Special Issue Conotoxin and Conotoxin Analogues: A Pharmacy Cabinet under the Sea)

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17 pages, 2589 KiB

Open AccessEditor’s ChoiceArticle

Chlorinated Enyne Fatty Acid Amides from a Marine Cyanobacterium: Discovery of Taveuniamides L-M and Pharmacological Characterization of Taveuniamide F as a GPCR Antagonist with CNR1 Selectivity

by Lobna A. Elsadek, Emma K. Ellis, Gustavo Seabra, Valerie J. Paul and Hendrik Luesch

Mar. Drugs 2024, 22(1), 28; https://doi.org/10.3390/md22010028 - 30 Dec 2023

Cited by 2 | Viewed by 4243

Abstract

NMR and MS/MS-based metabolomics of a cyanobacterial extract from Piti Bomb Holes, Guam, indicated the presence of unique enyne-containing halogenated fatty acid amides. We isolated three new compounds of this class, taveuniamides L-N (1–3), along with the previously [...] Read more.

NMR and MS/MS-based metabolomics of a cyanobacterial extract from Piti Bomb Holes, Guam, indicated the presence of unique enyne-containing halogenated fatty acid amides. We isolated three new compounds of this class, taveuniamides L-N (1–3), along with the previously reported taveuniamide F (4), which was the most abundant analog. The planar structures of the new compounds were established using 1D and 2D NMR as well as mass spectrometry. We established the configuration of this chemical class to be R at C-8 via Mosher’s analysis of 4 after reduction of the carboxamide group. Our biological investigations with 4 revealed that the compound binds to the cannabinoid receptor CNR1, acting as an antagonist/inverse agonist in the canonical G-protein signaling pathways. In selectivity profiling against 168 GPCR targets using the β-arrestin functional assay, we found that 4 antagonizes GPR119, NPSR1b, CCR9, CHRM4, GPR120, HTR2A, and GPR103, in addition to CNR1. Interestingly, 4 showed a 6.8-fold selectivity for CNR1 over CNR2. The binding mode of 4 to CNR1 was investigated using docking and molecular dynamics simulations with both natural and unnatural stereoisomers, revealing important CNR1 residues for the interaction and also providing a possible reasoning for the observed CNR1/CNR2 selectivity. Full article

(This article belongs to the Special Issue Bioactive Product from Marine Cyanobacteria)

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19 pages, 1451 KiB

Open AccessEditor’s ChoiceReview

Alexandrium spp.: From Toxicity to Potential Biotechnological Benefits

by Eleonora Montuori, Daniele De Luca, Antonella Penna, Darta Stalberga and Chiara Lauritano

Mar. Drugs 2024, 22(1), 31; https://doi.org/10.3390/md22010031 - 30 Dec 2023

Cited by 5 | Viewed by 4440

Abstract

Many dinoflagellates of the genus Alexandrium are well known for being responsible for harmful algal blooms (HABs), producing potent toxins that cause damages to other marine organisms, aquaculture, fishery, tourism, as well as induce human intoxications and even death after consumption of contaminated [...] Read more.

Many dinoflagellates of the genus Alexandrium are well known for being responsible for harmful algal blooms (HABs), producing potent toxins that cause damages to other marine organisms, aquaculture, fishery, tourism, as well as induce human intoxications and even death after consumption of contaminated shellfish or fish. In this review, we summarize potential bioprospecting associated to the genus Alexandrium, including which Alexandrium spp. produce metabolites with anticancer, antimicrobial, antiviral, as well as anti-Alzheimer applications. When available, we report their mechanisms of action and targets. We also discuss recent progress on the identification of secondary metabolites with biological properties favorable to human health and aquaculture. Altogether, this information highlights the importance of studying which culturing conditions induce the activation of enzymatic pathways responsible for the synthesis of bioactive metabolites. It also suggests considering and comparing clones collected in different locations for toxin monitoring and marine bioprospecting. This review can be of interest not only for the scientific community, but also for the entire population and industries. Full article

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14 pages, 2208 KiB

Open AccessEditor’s ChoiceArticle

Indole Diketopiperazine Alkaloids from the Marine Sediment-Derived Fungus Aspergillus chevalieri against Pancreatic Ductal Adenocarcinoma

by Dina H. El-Kashef, Deborah D. Obidake, Katja Schiedlauske, Alina Deipenbrock, Sebastian Scharf, Hao Wang, Daniela Naumann, Daniel Friedrich, Simone Miljanovic, Takin Haj Hassani Sohi, Christoph Janiak, Klaus Pfeffer and Nicole Teusch

Mar. Drugs 2024, 22(1), 5; https://doi.org/10.3390/md22010005 - 20 Dec 2023

Cited by 3 | Viewed by 2842

Abstract

A new prenylated indole diketopiperazine alkaloid, rubrumline P (1), was isolated along with six more analogues and characterized from the fermentation culture of a marine sediment-derived fungus, Aspergillus chevalieri, collected at a depth of 15 m near the lighthouse in [...] Read more.

A new prenylated indole diketopiperazine alkaloid, rubrumline P (1), was isolated along with six more analogues and characterized from the fermentation culture of a marine sediment-derived fungus, Aspergillus chevalieri, collected at a depth of 15 m near the lighthouse in Dahab, Red Sea, Egypt. In the current study, a bioassay-guided fractionation allowed for the identification of an active fraction displaying significant cytotoxic activity against the human pancreatic adenocarcinoma cell line PANC-1 from the EtOAc extract of the investigated fungus compared to the standard paclitaxel. The structures of the isolated compounds from the active fraction were established using 1D/2D NMR spectroscopy and mass spectrometry, together with comparisons with the literature. The absolute configuration of the obtained indole diketopiperazines was established based on single-crystal X-ray diffraction analyses of rubrumline I (2) and comparisons of optical rotations and NMR data, as well as on biogenetic considerations. Genome sequencing indicated the formation of prenyltransferases, which was subsequently confirmed by the isolation of mono-, di-, tri-, and tetraprenylated compounds. Compounds rubrumline P (1) and neoechinulin D (4) confirmed preferential cytotoxic activity against PANC-1 cancer cells with IC₅₀ values of 25.8 and 23.4 µM, respectively. Although the underlying mechanism-of-action remains elusive in this study, cell cycle analysis indicated a slight increase in the sub-G1 peak after treatment with compounds 1 and 4. Full article

(This article belongs to the Special Issue A Theme Issue Honoring Professor Peter Proksch's 70th Birthday: Bioactive Compounds from the Ocean)

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15 pages, 4213 KiB

Open AccessEditor’s ChoiceArticle

Karenia brevis Extract Induces Cellular Entry through Distinct Mechanisms in Phagocytic RAW 264.7 Macrophages versus Non-Phagocytic Vero Cells

by Laurie A. Minns, Kathryn T. Sausman, Ariel P. Brown, Robert A. York and Jennifer R. McCall

Mar. Drugs 2024, 22(1), 4; https://doi.org/10.3390/md22010004 - 19 Dec 2023

Viewed by 4403

Abstract

Marine algae extracts are an important area of potential drug discovery; however, nearly all studies to date have used non-fluorescent-based methods to determine changes in target cell activity. Many of the most robust immunological and cellular analyses rely on fluorescent probes and readouts, [...] Read more.

Marine algae extracts are an important area of potential drug discovery; however, nearly all studies to date have used non-fluorescent-based methods to determine changes in target cell activity. Many of the most robust immunological and cellular analyses rely on fluorescent probes and readouts, which can be problematic when the algae extract is fluorescent itself. In this study, we identified the fluorescent spectrum of an isolated extract from the marine dinoflagellate Karenia brevis, which included two fluorescing components: chlorophyll α and pheophytin α. When excited at 405 nm and 664 nm, the extract emitted fluorescence at 676 nm and 696 nm, respectively. The extract and its fluorescing components, chlorophyll α and pheophytin α, entered phagocytic RAW 264.7 macrophages and non-phagocytic Vero kidney cells through distinct mechanisms. When incubated with the extract and its main components, both the RAW 264.7 macrophages and the Vero cells accumulated fluorescence as early as 30 min and continued through 48 h. Vero kidney cells accumulated the K. brevis fluorescent extract through a dynamin-independent and acidified endosomal-dependent mechanism. RAW 264.7 macrophages accumulated fluorescent extract through a dynamin-independent, acidified endosomal-independent mechanism, which supports accumulation through phagocytosis. Furthermore, RAW 264.7 macrophages downregulated cell-surface expression of CD206 in response to extract stimulation indicating activation of phagocytic responses and potential immunosuppression of these immune cells. This study represents the first characterization of the cellular update of K. brevis extracts in phagocytic versus non-phagocytic cells. The data suggest the importance of understanding cellular uptake of fluorescing algae extracts and their mechanism of action for future drug discovery efforts. Full article

(This article belongs to the Section Marine Pharmacology)

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15 pages, 5294 KiB

Open AccessEditor’s ChoiceArticle

Rapid Discovery of Substances with Anticancer Potential from Marine Fungi Based on a One Strain–Many Compounds Strategy and UPLC-QTOF-MS

by Yu-Ting Wu, Xiao-Na Zhao, Pei-Xi Zhang, Cui-Fang Wang, Jing Li, Xiao-Yue Wei, Jia-Qi Shi, Wang Dai, Qi Zhang and Jie-Qing Liu

Mar. Drugs 2023, 21(12), 646; https://doi.org/10.3390/md21120646 - 18 Dec 2023

Cited by 2 | Viewed by 4702

Abstract

The secondary metabolites of marine fungi with rich chemical diversity and biological activity are an important and exciting target for natural product research. This study aimed to investigate the fungal community in Quanzhou Bay, Fujian, and identified 28 strains of marine fungi. A [...] Read more.

The secondary metabolites of marine fungi with rich chemical diversity and biological activity are an important and exciting target for natural product research. This study aimed to investigate the fungal community in Quanzhou Bay, Fujian, and identified 28 strains of marine fungi. A total of 28 strains of marine fungi were screened for small-scale fermentation by the OSMAC (One Strain-Many Compounds) strategy, and 77 EtOAc crude extracts were obtained and assayed for cancer cell inhibition rate. A total of six strains of marine fungi (P-WZ-2, P-WZ-3-2, P-WZ-4, P-WZ-5, P56, and P341) with significant changes in cancer cell inhibition induced by the OSMAC strategy were analysed by UPLC-QTOF-MS. The ACD/MS Structure ID Suite software was used to predict the possible structures with inhibitory effects on cancer cells. A total of 23 compounds were identified, of which 10 compounds have been reported to have potential anticancer activity or cytotoxicity. In this study, the OSMAC strategy was combined with an untargeted metabolomics approach based on UPLC-QTOF-MS to efficiently analyse the effect of changes in culture conditions on anticancer potentials and to rapidly find active substances that inhibit cancer cell growth. Full article

(This article belongs to the Special Issue Bioactive Metabolites from Marine-Derived Penicillium or Aspergillus Species)

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15 pages, 2539 KiB

Open AccessEditor’s ChoiceArticle

New Eremophilane-Type Sesquiterpenes from the Marine Sediment-Derived Fungus Emericellopsis maritima BC17 and Their Cytotoxic and Antimicrobial Activities

by Jorge R. Virués-Segovia, Carlos Millán, Cristina Pinedo, Victoria E. González-Rodríguez, Sokratis Papaspyrou, David Zorrilla, Thomas A. Mackenzie, María C. Ramos, Mercedes de la Cruz, Josefina Aleu and Rosa Durán-Patrón

Mar. Drugs 2023, 21(12), 634; https://doi.org/10.3390/md21120634 - 11 Dec 2023

Cited by 8 | Viewed by 3686

Abstract

The fungal strain BC17 was isolated from sediments collected in the intertidal zone of the inner Bay of Cadiz and characterized as Emericellopsis maritima. On the basis of the one strain–many compounds (OSMAC) approach, four new eremophilane-type sesquiterpenes (1–4 [...] Read more.

The fungal strain BC17 was isolated from sediments collected in the intertidal zone of the inner Bay of Cadiz and characterized as Emericellopsis maritima. On the basis of the one strain–many compounds (OSMAC) approach, four new eremophilane-type sesquiterpenes (1–4), together with thirteen known derivatives (5–17) and two reported diketopiperazines (18, 19), were isolated from this strain. The chemical structures and absolute configurations of the new compounds were determined through extensive NMR and HRESIMS spectroscopic studies and ECD calculation. Thirteen of the isolated eremophilanes were examined for cytotoxic and antimicrobial activities. PR toxin (16) exhibited cytotoxic activity against HepG2, MCF-7, A549, A2058, and Mia PaCa-2 human cancer cell lines with IC₅₀ values ranging from 3.75 to 33.44 µM. (+)-Aristolochene (10) exhibited selective activity against the fungal strains Aspergillus fumigatus ATCC46645 and Candida albicans ATCC64124 at 471 µM. Full article

(This article belongs to the Special Issue Marine Drugs Research in Spain 2nd Edition)

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20 pages, 5632 KiB

Open AccessEditor’s ChoiceReview

Biotechnological Potential of Macroalgae during Seasonal Blooms for Sustainable Production of UV-Absorbing Compounds

by Nedeljka Rosic and Carol Thornber

Mar. Drugs 2023, 21(12), 633; https://doi.org/10.3390/md21120633 - 8 Dec 2023

Cited by 3 | Viewed by 5640

Abstract

Marine macroalgae (seaweeds) are important primary global producers, with a wide distribution in oceans around the world from polar to tropical regions. Most of these species are exposed to variable environmental conditions, such as abiotic (e.g., light irradiance, temperature variations, nutrient availability, salinity [...] Read more.

Marine macroalgae (seaweeds) are important primary global producers, with a wide distribution in oceans around the world from polar to tropical regions. Most of these species are exposed to variable environmental conditions, such as abiotic (e.g., light irradiance, temperature variations, nutrient availability, salinity levels) and biotic factors (e.g., grazing and pathogen exposure). As a result, macroalgae developed numerous important strategies to increase their adaptability, including synthesizing secondary metabolites, which have promising biotechnological applications, such as UV-absorbing Mycosporine-Like Amino Acid (MAAs). MAAs are small, water-soluble, UV-absorbing compounds that are commonly found in many marine organisms and are characterized by promising antioxidative, anti-inflammatory and photoprotective properties. However, the widespread use of MAAs by humans is often restricted by their limited bioavailability, limited success in heterologous expression systems, and low quantities recovered from the natural environment. In contrast, bloom-forming macroalgal species from all three major macroalgal clades (Chlorophyta, Phaeophyceae, and Rhodophyta) occasionally form algal blooms, resulting in a rapid increase in algal abundance and high biomass production. This review focuses on the bloom-forming species capable of producing pharmacologically important compounds, including MAAs, and the application of proteomics in facilitating macroalgal use in overcoming current environmental and biotechnological challenges. Full article

(This article belongs to the Special Issue Proteomic Studies for the Identification and Characterization of Marine Bioactive Molecules)

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27 pages, 4278 KiB

Open AccessEditor’s ChoiceReview

Therapeutic Potential of Marine-Derived Cyclic Peptides as Antiparasitic Agents

by Ricardo Ribeiro, Lia Costa, Eugénia Pinto, Emília Sousa and Carla Fernandes

Mar. Drugs 2023, 21(12), 609; https://doi.org/10.3390/md21120609 - 25 Nov 2023

Cited by 8 | Viewed by 5306

Abstract

Parasitic diseases still compromise human health. Some of the currently available therapeutic drugs have limitations considering their adverse effects, questionable efficacy, and long treatment, which have encouraged drug resistance. There is an urgent need to find new, safe, effective, and affordable antiparasitic drugs. [...] Read more.

Parasitic diseases still compromise human health. Some of the currently available therapeutic drugs have limitations considering their adverse effects, questionable efficacy, and long treatment, which have encouraged drug resistance. There is an urgent need to find new, safe, effective, and affordable antiparasitic drugs. Marine-derived cyclic peptides have been increasingly screened as candidates for developing new drugs. Therefore, in this review, a systematic analysis of the scientific literature was performed and 25 marine-derived cyclic peptides with antiparasitic activity (1–25) were found. Antimalarial activity is the most reported (51%), followed by antileishmanial (27%) and antitrypanosomal (20%) activities. Some compounds showed promising antiparasitic activity at the nM scale, being active against various parasites. The mechanisms of action and targets for some of the compounds have been investigated, revealing different strategies against parasites. Full article

(This article belongs to the Special Issue Marine Antiparasitic Agents)

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14 pages, 1412 KiB

Open AccessEditor’s ChoiceArticle

Lecanicilliums A–F, Thiodiketopiperazine-Class Alkaloids from a Mangrove Sediment-Derived Fungus Lecanicillium kalimantanense

by Lin-Fang Zhong, Juan Ling, Lian-Xiang Luo, Chang-Nian Yang, Xiao Liang and Shu-Hua Qi

Mar. Drugs 2023, 21(11), 575; https://doi.org/10.3390/md21110575 - 31 Oct 2023

Cited by 9 | Viewed by 2467

Abstract

Six new thiodiketopiperazine-class alkaloids lecanicilliums A–F were isolated from the mangrove sediment-derived fungus Lecanicillium kalimantanense SCSIO41702, together with thirteen known analogues. Their structures were determined by spectroscopic analysis. The absolute configurations were determined by quantum chemical calculations. Electronic circular dichroism (ECD) spectra and [...] Read more.

Six new thiodiketopiperazine-class alkaloids lecanicilliums A–F were isolated from the mangrove sediment-derived fungus Lecanicillium kalimantanense SCSIO41702, together with thirteen known analogues. Their structures were determined by spectroscopic analysis. The absolute configurations were determined by quantum chemical calculations. Electronic circular dichroism (ECD) spectra and the structure of Lecanicillium C were further confirmed by a single-crystal X-ray diffraction analysis. Lecanicillium A contained an unprecedented 6/5/6/5/7/6 cyclic system with a spirocyclic center at C-2′. Biologically, lecanicillium E, emethacin B, and versicolor A displayed significant cytotoxicity against human lung adenocarcinoma cell line H1975, with IC₅₀ values of 7.2~16.9 μM, and lecanicillium E also showed antibacterial activity against four pathogens with MIC values of 10~40 μg/mL. Their structure–activity relationship is also discussed. Full article

(This article belongs to the Special Issue Natural Products Isolated from Marine Sediment)

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12 pages, 1083 KiB

Open AccessEditor’s ChoiceArticle

Chemical Constituents from Soft Coral Clavularia spp. Demonstrate Antiproliferative Effects on Oral Cancer Cells

by Ming-Ya Cheng, Ya-Ting Chuang, Hsueh-Wei Chang, Zheng-Yu Lin, Ching-Yeu Chen and Yuan-Bin Cheng

Mar. Drugs 2023, 21(10), 529; https://doi.org/10.3390/md21100529 - 8 Oct 2023

Cited by 6 | Viewed by 2097

Abstract

Five new eudensamane-type sesquiterpene lactones, clasamanes A–E (1–5), three new dolabellane-type diterpenes, clabellanes A–C (6–8), and fifteen known compounds (9–23) were isolated from the ethanolic extract of Taiwanese soft coral Clavularia [...] Read more.

Five new eudensamane-type sesquiterpene lactones, clasamanes A–E (1–5), three new dolabellane-type diterpenes, clabellanes A–C (6–8), and fifteen known compounds (9–23) were isolated from the ethanolic extract of Taiwanese soft coral Clavularia spp. The structures of all undescribed components (1–8) were determined by analysis of IR, mass, NMR, and UV spectroscopic data. The absolute configuration of new compounds was determined by using circular dichroism and DP4+ calculations. The cytotoxic activities of all isolated marine natural products were evaluated. Compound 7 showed a significant cytotoxic effect against oral cancer cell line (Ca9-22) with an IC₅₀ value of 7.26 ± 0.17 μg/mL. Full article

(This article belongs to the Section Structural Studies on Marine Natural Products)

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19 pages, 5983 KiB

Open AccessEditor’s ChoiceArticle

Structural Diversity and Biological Activity of Cyanopeptolins Produced by Nostoc edaphicum CCNP1411

by Robert Konkel, Marta Cegłowska, Karolina Szubert, Ewa Wieczerzak, Sofia Iliakopoulou, Triantafyllos Kaloudis and Hanna Mazur-Marzec

Mar. Drugs 2023, 21(10), 508; https://doi.org/10.3390/md21100508 - 26 Sep 2023

Cited by 4 | Viewed by 4618

Abstract

Cyanopeptolins (CPs) are one of the most commonly occurring class of cyanobacterial nonribosomal peptides. For the majority of these compounds, protease inhibition has been reported. In the current work, the structural diversity of cyanopeptolins produced by Nostoc edaphicum CCNP1411 was explored. As a [...] Read more.

Cyanopeptolins (CPs) are one of the most commonly occurring class of cyanobacterial nonribosomal peptides. For the majority of these compounds, protease inhibition has been reported. In the current work, the structural diversity of cyanopeptolins produced by Nostoc edaphicum CCNP1411 was explored. As a result, 93 CPs, including 79 new variants, were detected and structurally characterized based on their mass fragmentation spectra. CPs isolated in higher amounts were additionally characterized by NMR. To the best of our knowledge, this is the highest number of cyanopeptides found in one strain. The biological assays performed with the 34 isolated CPs confirmed the significance of the amino acid located between Thr and the unique 3-amino-6-hydroxy-2-piperidone (Ahp) on the activity of the compounds against serine protease and HeLa cancer cells. Full article

(This article belongs to the Section Marine Biotechnology Related to Drug Discovery or Production)

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20 pages, 3636 KiB

Open AccessEditor’s ChoiceArticle

A Chemo-Ecological Investigation of Dendrilla antarctica Topsent, 1905: Identification of Deceptionin and the Effects of Heat Stress and Predation Pressure on Its Terpene Profiles

by Paula De Castro-Fernández, Carlos Angulo-Preckler, Cristina García-Aljaro, Conxita Avila and Adele Cutignano

Mar. Drugs 2023, 21(9), 499; https://doi.org/10.3390/md21090499 - 19 Sep 2023

Cited by 3 | Viewed by 1835

Abstract

Marine sponges usually host a wide array of secondary metabolites that play crucial roles in their biological interactions. The factors that influence the intraspecific variability in the metabolic profile of organisms, their production or ecological function remain generally unknown. Understanding this may help [...] Read more.

Marine sponges usually host a wide array of secondary metabolites that play crucial roles in their biological interactions. The factors that influence the intraspecific variability in the metabolic profile of organisms, their production or ecological function remain generally unknown. Understanding this may help predict changes in biological relationships due to environmental variations as a consequence of climate change. The sponge Dendrilla antarctica is common in shallow rocky bottoms of the Antarctic Peninsula and is known to produce diterpenes that are supposed to have defensive roles. Here we used GC-MS to determine the major diterpenes in two populations of D. antarctica from two islands, Livingston and Deception Island (South Shetland Islands). To assess the potential effect of heat stress, we exposed the sponge in aquaria to a control temperature (similar to local), heat stress (five degrees higher) and extreme heat stress (ten degrees higher). To test for defence induction by predation pressure, we exposed the sponges to the sea star Odontaster validus and the amphipod Cheirimedon femoratus. Seven major diterpenes were isolated and identified from the samples. While six of them were already reported in the literature, we identified one new aplysulphurane derivative that was more abundant in the samples from Deception Island, so we named it deceptionin (7). The samples were separated in the PCA space according to the island of collection, with 9,11-dihydrogracilin A (1) being more abundant in the samples from Livingston, and deceptionin (7) in the samples from Deception. We found a slight effect of heat stress on the diterpene profiles of D. antarctica, with tetrahydroaplysulphurin-1 (6) and the gracilane norditerpene 2 being more abundant in the group exposed to heat stress. Predation pressure did not seem to influence the metabolite production. Further research on the bioactivity of D. antarctica secondary metabolites, and their responses to environmental changes will help better understand the functioning and fate of the Antarctic benthos. Full article

(This article belongs to the Special Issue Commemorating the Launch of the Section “Marine Chemoecology for Drug Discovery”)

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