Marine Drugs

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

Viewed by 4133

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

Viewed by 3443

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 1 | Viewed by 2541

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 1562

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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26 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 1 | Viewed by 1273

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

Viewed by 1279

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

Viewed by 1334

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

Viewed by 1622

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 1216

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 1462

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

Viewed by 2115

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 3 | Viewed by 2543

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 3 | Viewed by 2312

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

Viewed by 1828

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 1 | Viewed by 2225

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

Viewed by 1468

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

Viewed by 1959

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 2 | Viewed by 2052

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 1 | Viewed by 1690

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 1 | Viewed by 2130

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 1 | Viewed by 2297

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 2781

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 1 | Viewed by 2192

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 2831

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 3 | Viewed by 2034

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 3 | Viewed by 2528

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

Viewed by 3682

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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21 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 1 | Viewed by 3303

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

Viewed by 2284

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 3995

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 1 | Viewed by 4129

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 4 | Viewed by 3127

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

Viewed by 4853

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 3 | Viewed by 4584

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 1 | Viewed by 2021

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 2 | Viewed by 1724

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 4030

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 2 | Viewed by 1476

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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17 pages, 5543 KiB

Open AccessEditor’s ChoiceArticle

Talarolides Revisited: Cyclic Heptapeptides from an Australian Marine Tunicate-Associated Fungus, Talaromyces sp. CMB-TU011

by Angela A. Salim, Waleed M. Hussein, Pradeep Dewapriya, Huy N. Hoang, Yahao Zhou, Kaumadi Samarasekera, Zeinab G. Khalil, David P. Fairlie and Robert J. Capon

Mar. Drugs 2023, 21(9), 487; https://doi.org/10.3390/md21090487 - 11 Sep 2023

Cited by 2 | Viewed by 3205

Abstract

Application of a miniaturized 24-well plate system for cultivation profiling (MATRIX) permitted optimization of the cultivation conditions for the marine-derived fungus Talaromyces sp. CMB-TU011, facilitating access to the rare cycloheptapeptide talarolide A (1) along with three new analogues, B–D (2 [...] Read more.

Application of a miniaturized 24-well plate system for cultivation profiling (MATRIX) permitted optimization of the cultivation conditions for the marine-derived fungus Talaromyces sp. CMB-TU011, facilitating access to the rare cycloheptapeptide talarolide A (1) along with three new analogues, B–D (2–4). Detailed spectroscopic analysis supported by Marfey’s analysis methodology was refined to resolve N-Me-l-Ala from N-Me-d-Ala, l-allo-Ile from l-Ile and l-Leu, and partial and total syntheses of 2, and permitted unambiguous assignment of structures for 1 (revised) and 2–4. Consideration of diagnostic ROESY correlations for the hydroxamates 1 and 3–4, and a calculated solution structure for 1, revealed how cross-ring H-bonding to the hydroxamate moiety influences (defines/stabilizes) the cyclic peptide conformation. Such knowledge draws attention to the prospect that hydroxamates may be used as molecular bridges to access new cyclic peptide conformations, offering the prospect of new biological properties, including enhanced oral bioavailability. Full article

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

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20 pages, 7103 KiB

Open AccessEditor’s ChoiceArticle

Spatial Distribution and Biochemical Characterization of Serine Peptidase Inhibitors in the Venom of the Brazilian Sea Anemone Anthopleura cascaia Using Mass Spectrometry Imaging

by Daiane Laise da Silva, Rodrigo Valladão, Emidio Beraldo-Neto, Guilherme Rabelo Coelho, Oscar Bento da Silva Neto, Hugo Vigerelli, Adriana Rios Lopes, Brett R. Hamilton, Eivind A. B. Undheim, Juliana Mozer Sciani and Daniel Carvalho Pimenta

Mar. Drugs 2023, 21(9), 481; https://doi.org/10.3390/md21090481 - 30 Aug 2023

Cited by 1 | Viewed by 1853

Abstract

Sea anemones are known to produce a diverse array of toxins with different cysteine-rich peptide scaffolds in their venoms. The serine peptidase inhibitors, specifically Kunitz inhibitors, are an important toxin family that is believed to function as defensive peptides, as well as prevent [...] Read more.

Sea anemones are known to produce a diverse array of toxins with different cysteine-rich peptide scaffolds in their venoms. The serine peptidase inhibitors, specifically Kunitz inhibitors, are an important toxin family that is believed to function as defensive peptides, as well as prevent proteolysis of other secreted anemone toxins. In this study, we isolated three serine peptidase inhibitors named Anthopleura cascaia peptide inhibitors I, II, and III (ACPI-I, ACPI-II, and ACPI-III) from the venom of the endemic Brazilian sea anemone A. cascaia. The venom was fractionated using RP-HPLC, and the inhibitory activity of these fractions against trypsin was determined and found to range from 59% to 93%. The spatial distribution of the anemone peptides throughout A. cascaia was observed using mass spectrometry imaging. The inhibitory peptides were found to be present in the tentacles, pedal disc, and mesenterial filaments. We suggest that the three inhibitors observed during this study belong to the venom Kunitz toxin family on the basis of their similarity to PI-actitoxin-aeq3a-like and the identification of amino acid residues that correspond to a serine peptidase binding site. Our findings expand our understanding of the diversity of toxins present in sea anemone venom and shed light on their potential role in protecting other venom components from proteolysis. Full article

(This article belongs to the Section Marine Toxins)

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20 pages, 2442 KiB

Open AccessEditor’s ChoiceArticle

An Investigation of Structure–Activity Relationships and Cell Death Mechanisms of the Marine Alkaloids Discorhabdins in Merkel Cell Carcinoma Cells

by Maria Orfanoudaki, Emily A. Smith, Natasha T. Hill, Khalid A. Garman, Isaac Brownell, Brent R. Copp, Tanja Grkovic and Curtis J. Henrich

Mar. Drugs 2023, 21(9), 474; https://doi.org/10.3390/md21090474 - 29 Aug 2023

Cited by 5 | Viewed by 3500

Abstract

A library of naturally occurring and semi-synthetic discorhabdins was assessed for their effects on Merkel cell carcinoma (MCC) cell viability. The set included five new natural products and semi-synthetic compounds whose structures were elucidated with NMR, HRMS, and ECD techniques. Several discorhabdins averaged [...] Read more.

A library of naturally occurring and semi-synthetic discorhabdins was assessed for their effects on Merkel cell carcinoma (MCC) cell viability. The set included five new natural products and semi-synthetic compounds whose structures were elucidated with NMR, HRMS, and ECD techniques. Several discorhabdins averaged sub-micromolar potency against the MCC cell lines tested and most of the active compounds showed selectivity towards virus-positive MCC cell lines. An investigation of structure–activity relationships resulted in an expanded understanding of the crucial structural features of the discorhabdin scaffold. Mechanistic cell death assays suggested that discorhabdins, unlike many other MCC-active small molecules, do not induce apoptosis, as shown by the lack of caspase activation, annexin V staining, and response to caspase inhibition. Similarly, discorhabdin treatment failed to increase MCC intracellular calcium and ROS levels. In contrast, the rapid loss of cellular reducing potential and mitochondrial membrane potential suggested that discorhabdins induce mitochondrial dysfunction leading to non-apoptotic cell death. Full article

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

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13 pages, 2613 KiB

Open AccessEditor’s ChoiceArticle

Butanolides and Butenolides from a Marine-Derived Streptomyces sp. Exert Neuroprotective Activity through Activation of the TrkB Neurotrophin Receptor

by Paolo Giaccio, Despoina Charou, Dafni-Ioanna Diakaki, Anna Chita, Achille Gravanis, Ioannis Charalampopoulos, Vassilios Roussis and Efstathia Ioannou

Mar. Drugs 2023, 21(9), 465; https://doi.org/10.3390/md21090465 - 25 Aug 2023

Viewed by 2880

Abstract

Neurodegenerative diseases are incurable and debilitating conditions, characterized by progressive loss and degeneration of vulnerable neuronal populations. Currently, there are no effective therapies available for the treatment of most neurodegenerative disorders. A panel of extracts exhibiting interesting chemical profiles among a high number [...] Read more.

Neurodegenerative diseases are incurable and debilitating conditions, characterized by progressive loss and degeneration of vulnerable neuronal populations. Currently, there are no effective therapies available for the treatment of most neurodegenerative disorders. A panel of extracts exhibiting interesting chemical profiles among a high number of bacterial strains isolated from East Mediterranean marine sediments and macroorganisms were evaluated for their activity on TrkB-expressing cells. Among them, the actinobacterial strain Streptomyces sp. BI0788, exhibiting neuroprotective activity in vitro, was selected and cultivated in large-scale. The chemical analysis of its organic extract resulted in the isolation of four new butanolides (1, 4–6), along with two previously reported butanolides (2 and 3) and eight previously reported butenolides (7–14). Compounds 2–4 and 7–14 were evaluated for their neuroprotective effects on TrkB-expressing NIH-3T3 cells. Among them, metabolites 3, 4, 7, 10, 11, 13 and 14 exhibited significant protective activity on the aforementioned cells through the activation of TrkB, the high-affinity receptor for the Brain-Derived Neurotrophic Factor (BDNF), which is well known to play a crucial role in neuronal cell survival and maintenance. Full article

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14 pages, 2935 KiB

Open AccessEditor’s ChoiceArticle

Lobosteroids A–F: Six New Highly Oxidized Steroids from the Chinese Soft Coral Lobophytum sp.

by Zi-Yi Xia, Man-Man Sun, Yang Jin, Li-Gong Yao, Ming-Zhi Su, Lin-Fu Liang, Hong Wang and Yue-Wei Guo

Mar. Drugs 2023, 21(8), 457; https://doi.org/10.3390/md21080457 - 19 Aug 2023

Cited by 1 | Viewed by 3142

Abstract

To explore the steroidal constituents of the soft coral Lobophytum sp. at the coast of Xuwen County, Guangdong Province, China, a chemical investigation of the above-mentioned soft coral was carried out. After repeated column chromatography over silica gel, Sephadex LH-20, and reversed-phase HPLC, [...] Read more.

To explore the steroidal constituents of the soft coral Lobophytum sp. at the coast of Xuwen County, Guangdong Province, China, a chemical investigation of the above-mentioned soft coral was carried out. After repeated column chromatography over silica gel, Sephadex LH-20, and reversed-phase HPLC, six new steroids, namely lobosteroids A–F (1–6), along with four known compounds 7–10, were obtained. Their structures were determined by extensive spectroscopic analysis and comparison with the spectral data reported in the literature. Among them, the absolute configuration of 1 was determined by X-ray diffraction analysis using Cu Kα radiation. These steroids were characterized by either the presence of an α,β-α′,β′-unsaturated carbonyl, or an α,β-unsaturated carbonyl moiety in ring A, or the existence of a 5α,8α-epidioxy system in ring B, as well as diverse oxidation of side chains. The antibacterial bioassays showed that all isolated steroids exhibited significant inhibitory activities against the fish pathogenic bacteria Streptococcus parauberis FP KSP28, Phoyobacterium damselae FP2244, and Streptococcus parauberis SPOF3K, with IC₉₀ values ranging from 0.1 to 11.0 µM. Meanwhile, compounds 2 and 6–10 displayed potent inhibitory effects against the vancomycin-resistant Enterococcus faecium bacterium G7 with IC₉₀ values ranging from 4.4 to 18.3 µM. Therefore, ten highly oxidized steroids with strong antibacterial activities were isolated from the Chinese soft coral Lobophytum sp., which could be developed as new chemotypes of antibacterial drug leads. Full article

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

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13 pages, 1588 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

MariClus: Your One-Stop Platform for Information on Marine Natural Products, Their Gene Clusters and Producing Organisms

by Cedric Hermans, Maarten Lieven De Mol, Marieke Mispelaere, Anne-Sofie De Rop, Jeltien Rombaut, Tesneem Nusayr, Rebecca Creamer, Sofie L. De Maeseneire, Wim K. Soetaert and Paco Hulpiau

Mar. Drugs 2023, 21(8), 449; https://doi.org/10.3390/md21080449 - 15 Aug 2023

Cited by 1 | Viewed by 3715

Abstract

Background: The marine environment hosts the vast majority of living species and marine microbes that produce natural products with great potential in providing lead compounds for drug development. With over 70% of Earth’s surface covered in water and the high interaction rate associated [...] Read more.

Background: The marine environment hosts the vast majority of living species and marine microbes that produce natural products with great potential in providing lead compounds for drug development. With over 70% of Earth’s surface covered in water and the high interaction rate associated with liquid environments, this has resulted in many marine natural product discoveries. Our improved understanding of the biosynthesis of these molecules, encoded by gene clusters, along with increased genomic information will aid us in uncovering even more novel compounds. Results: We introduce MariClus (https://www.mariclus.com), an online user-friendly platform for mining and visualizing marine gene clusters. The first version contains information on clusters and the predicted molecules for over 500 marine-related prokaryotes. The user-friendly interface allows scientists to easily search by species, cluster type or molecule and visualize the information in table format or graphical representation. Conclusions: This new online portal simplifies the exploration and comparison of gene clusters in marine species for scientists and assists in characterizing the bioactive molecules they produce. MariClus integrates data from public sources, like GenBank, MIBiG and PubChem, with genome mining results from antiSMASH. This allows users to access and analyze various aspects of marine natural product biosynthesis and diversity. Full article

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11 pages, 1719 KiB

Open AccessEditor’s ChoiceArticle

Jejucarbosides B–E, Chlorinated Cycloaromatized Enediynes, from a Marine Streptomyces sp.

by Ji Hyeon Im, Yern-Hyerk Shin, Eun Seo Bae, Sang Kook Lee and Dong-Chan Oh

Mar. Drugs 2023, 21(7), 405; https://doi.org/10.3390/md21070405 - 18 Jul 2023

Cited by 2 | Viewed by 1805

Abstract

Four new chlorinated cycloaromatized enediyne compounds, jejucarbosides B–E (1–4), were discovered together with previously-identified jejucarboside A from a marine actinomycete strain. Compounds 1–4 were identified as new chlorinated cyclopenta[a]indene glycosides based on 1D and 2D [...] Read more.

Four new chlorinated cycloaromatized enediyne compounds, jejucarbosides B–E (1–4), were discovered together with previously-identified jejucarboside A from a marine actinomycete strain. Compounds 1–4 were identified as new chlorinated cyclopenta[a]indene glycosides based on 1D and 2D nuclear magnetic resonance, high-resolution mass spectrometry, and circular dichroism (CD) spectra. Jejucarbosides B and E bear a carbonate functional group whereas jejucarbosides C and D are variants possessing 1,2-diol by losing the carbonate functionality. It is proposed that the production of 1–4 occurs via Bergman cycloaromatization capturing Cl^- and H⁺ in the alternative positions of a p-benzyne intermediate derived from a 9-membered enediyne core. Jejucarboside E (4) displayed significant cytotoxicity against human cancer cell lines including SNU-638, SK-HEP-1, A549, HCT116, and MDA-MB-231, with IC₅₀ values of 0.31, 0.40, 0.25, 0.29, and 0.48 μM, respectively, while jejucarbosides B–D (1–3) showed moderate or no cytotoxic effects. Full article

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

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14 pages, 2602 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Expanding the Utility of Bioinformatic Data for the Full Stereostructural Assignments of Marinolides A and B, 24- and 26-Membered Macrolactones Produced by a Chemically Exceptional Marine-Derived Bacterium

by Min Cheol Kim, Jaclyn M. Winter, Reiko Cullum, Alexander J. Smith and William Fenical

Mar. Drugs 2023, 21(6), 367; https://doi.org/10.3390/md21060367 - 20 Jun 2023

Cited by 1 | Viewed by 1943

Abstract

Marinolides A and B, two new 24- and 26-membered bacterial macrolactones, were isolated from the marine-derived actinobacterium AJS-327 and their stereostructures initially assigned by bioinformatic data analysis. Macrolactones typically possess complex stereochemistry, the assignments of which have been one of the most difficult [...] Read more.

Marinolides A and B, two new 24- and 26-membered bacterial macrolactones, were isolated from the marine-derived actinobacterium AJS-327 and their stereostructures initially assigned by bioinformatic data analysis. Macrolactones typically possess complex stereochemistry, the assignments of which have been one of the most difficult undertakings in natural products chemistry, and in most cases, the use of X-ray diffraction methods and total synthesis have been the major methods of assigning their absolute configurations. More recently, however, it has become apparent that the integration of bioinformatic data is growing in utility to assign absolute configurations. Genome mining and bioinformatic analysis identified the 97 kb mld biosynthetic cluster harboring seven type I polyketide synthases. A detailed bioinformatic investigation of the ketoreductase and enoylreductase domains within the multimodular polyketide synthases, coupled with NMR and X-ray diffraction data, allowed for the absolute configurations of marinolides A and B to be determined. While using bioinformatics to assign the relative and absolute configurations of natural products has high potential, this method must be coupled with full NMR-based analysis to both confirm bioinformatic assignments as well as any additional modifications that occur during biosynthesis. Full article

(This article belongs to the Special Issue 20 Years Commemorative Issue in Honor of Professor Paul J. Scheuer)

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11 pages, 1223 KiB

Open AccessEditor’s ChoiceArticle

Sesquiterpenes from Streptomyces qinglanensis and Their Cytotoxic Activity

by Cao Van Anh, Jong Soon Kang, Jeong-Wook Yang, Joo-Hee Kwon, Chang-Su Heo, Hwa-Sun Lee, Chan Hong Park and Hee Jae Shin

Mar. Drugs 2023, 21(6), 361; https://doi.org/10.3390/md21060361 - 16 Jun 2023

Cited by 2 | Viewed by 1871

Abstract

Nine sesquiterpenes, including eight pentalenenes (1–8) and one bolinane derivative (9), were isolated from the culture broth of a marine-derived actinobacterium Streptomyces qinglanensis 213DD-006. Among them, 1, 4, 7, and 9 were new compounds. [...] Read more.

Nine sesquiterpenes, including eight pentalenenes (1–8) and one bolinane derivative (9), were isolated from the culture broth of a marine-derived actinobacterium Streptomyces qinglanensis 213DD-006. Among them, 1, 4, 7, and 9 were new compounds. Their planar structures were determined by spectroscopic methods (HRMS, 1D, and 2D NMR), and the absolute configuration was established by biosynthesis consideration and electronic-circular-dichroism (ECD) calculations. All the isolated compounds were screened for their cytotoxicity against six solid and seven blood cancer cell lines. Compounds 4–6 and 8 showed a moderate activity against all of the tested solid cell lines, with GI₅₀ values ranging from 1.97 to 3.46 µM. Full article

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

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68 pages, 7649 KiB

Open AccessEditor’s ChoiceReview

Cyanobacteria: A Promising Source of Antifungal Metabolites

by Samuel Cavalcante do Amaral, Luciana Pereira Xavier, Vítor Vasconcelos and Agenor Valadares Santos

Mar. Drugs 2023, 21(6), 359; https://doi.org/10.3390/md21060359 - 14 Jun 2023

Cited by 3 | Viewed by 5923

Abstract

Cyanobacteria are a rich source of secondary metabolites, and they have received a great deal of attention due to their applicability in different industrial sectors. Some of these substances are known for their notorious ability to inhibit fungal growth. Such metabolites are very [...] Read more.

Cyanobacteria are a rich source of secondary metabolites, and they have received a great deal of attention due to their applicability in different industrial sectors. Some of these substances are known for their notorious ability to inhibit fungal growth. Such metabolites are very chemically and biologically diverse. They can belong to different chemical classes, including peptides, fatty acids, alkaloids, polyketides, and macrolides. Moreover, they can also target different cell components. Filamentous cyanobacteria have been the main source of these compounds. This review aims to identify the key features of these antifungal agents, as well as the sources from which they are obtained, their major targets, and the environmental factors involved when they are being produced. For the preparation of this work, a total of 642 documents dating from 1980 to 2022 were consulted, including patents, original research, review articles, and theses. Full article

(This article belongs to the Section Marine Pharmacology)

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21 pages, 1939 KiB

Open AccessEditor’s ChoiceArticle

Pentaketides and 5-p-Hydroxyphenyl-2-pyridone Derivative from the Culture Extract of a Marine Sponge-Associated Fungus Hamigera avellanea KUFA0732

by Rotchana Klaram, Tida Dethoup, Fátima P. Machado, Luís Gales, Decha Kumla, Salar Hafez Ghoran, Emília Sousa, Sharad Mistry, Artur M. S. Silva and Anake Kijjoa

Mar. Drugs 2023, 21(6), 344; https://doi.org/10.3390/md21060344 - 2 Jun 2023

Cited by 3 | Viewed by 2034

Abstract

Five undescribed pentaketide derivatives, (R)-6,8-dihydroxy-4,5-dimethyl-3-methylidene-3,4-dihydro-1H-2-benzopyran-1-one (1), [(3S,4R)-3,8-dihydroxy-6-methoxy-4,5-dimethyl-1-oxo-3,4-dihydro-1H-isochromen-3-yl]methyl acetate (2), (R)-5, 7-dimethoxy-3-((S)-(1-hydroxyethyl)-3,4-dimethylisobenzofuran-1(3H)-one (4b), (S)-7-hydroxy-3-((S)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran 1(3H)-one ( [...] Read more.

Five undescribed pentaketide derivatives, (R)-6,8-dihydroxy-4,5-dimethyl-3-methylidene-3,4-dihydro-1H-2-benzopyran-1-one (1), [(3S,4R)-3,8-dihydroxy-6-methoxy-4,5-dimethyl-1-oxo-3,4-dihydro-1H-isochromen-3-yl]methyl acetate (2), (R)-5, 7-dimethoxy-3-((S)-(1-hydroxyethyl)-3,4-dimethylisobenzofuran-1(3H)-one (4b), (S)-7-hydroxy-3-((S)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran 1(3H)-one (5), and a p-hydroxyphenyl-2-pyridone derivative, avellaneanone (6), were isolated together with the previously reported (R)-3-acetyl-7-hydroxy-5-methoxy-3,4-dimethylisobenzofuran-1(3H)-one (3), (R)-7-hydroxy-3-((S)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran-1(3H)-one (4a) and isosclerone (7), from the ethyl acetate extract of a culture of a marine sponge-derived fungus, Hamigera avellanea KUFA0732. The structures of the undescribed compounds were elucidated using 1D and 2D NMR, as well as high-resolution mass spectral analyses. The absolute configurations of the stereogenic carbons in 1, 4b, 5, and 6 were established by X-ray crystallographic analysis. The absolute configurations of C-3 and C-4 in 2 were determined by ROESY correlations and on the basis of their common biosynthetic origin with 1. The crude fungal extract and the isolated compounds 1, 3, 4b, 5, 6, and 7 were assayed for their growth inhibitory activity against various plant pathogenic fungi viz. Alternaria brassicicola, Bipolaris oryzae, Colletotrichum capsici, C. gloeosporiodes, Curvularia oryzae, Fusarium semitectum, Lasiodiplodia theobromae, Phytophthora palmivora, Pyricularia oryzae, Rhizoctonia oryzae and Sclerotium rolfsii. 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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11 pages, 1026 KiB

Open AccessEditor’s ChoiceArticle

Synthesis and Antimalarial Evaluation of Halogenated Analogues of Thiaplakortone A

by Folake A. Egbewande, Brett D. Schwartz, Sandra Duffy, Vicky M. Avery and Rohan A. Davis

Mar. Drugs 2023, 21(5), 317; https://doi.org/10.3390/md21050317 - 22 May 2023

Viewed by 1819

Abstract

The incorporation of bromine, iodine or fluorine into the tricyclic core structure of thiaplakortone A (1), a potent antimalarial marine natural product, is reported. Although yields were low, it was possible to synthesise a small nine-membered library using the previously synthesised [...] Read more.

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

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

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