Research

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10 pages, 1381 KiB

Open AccessArticle

Asperienes A–D, Bioactive Sesquiterpenes from the Marine-Derived Fungus Aspergillus flavus

by Yun-Feng Liu, Yu-Fei Yue, Li-Xi Feng, Hua-Jie Zhu and Fei Cao

Mar. Drugs 2019, 17(10), 550; https://doi.org/10.3390/md17100550 - 26 Sep 2019

Cited by 26 | Viewed by 3295

Marine-derived fungi of the genera Aspergillus could produce novel compounds with significant bioactivities. Among these fungi, the strain Aspergillus flavus is notorious for its mutagenic mycotoxins production. However, some minor components with certain toxicities from A. flavus have not been specifically surveyed and [...] Read more.

Marine-derived fungi of the genera Aspergillus could produce novel compounds with significant bioactivities. Among these fungi, the strain Aspergillus flavus is notorious for its mutagenic mycotoxins production. However, some minor components with certain toxicities from A. flavus have not been specifically surveyed and might have potent biological activities. Our investigation of the marine-derived fungus Aspergillus flavus CF13-11 cultured in solid medium led to the isolation of four C-6′/C-7′ epimeric drimane sesquiterpene esters, asperienes A–D (1–4). Their absolute configurations were assigned by electronic circular dichroism (ECD) and Snatzke’s methods. This is the first time that two pairs of C-6′/C-7′ epimeric drimane sesquiterpene esters have successfully been separated. Aperienes A–D (1–4) displayed potent bioactivities towards four cell lines with the IC₅₀ values ranging from 1.4 to 8.3 μM. Interestingly, compounds 1 and 4 exhibited lower toxicities than 2 and 3 toward normal GES-1 cells, indicating more potential for development as an antitumor agent in the future. Full article

(This article belongs to the Special Issue Bioassay-Guided Isolation of Marine Natural Products for Drug Discovery)

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27 pages, 18221 KiB

Open AccessFeature PaperArticle

Cytotoxic and Antiproliferative Effects of Preussin, a Hydroxypyrrolidine Derivative from the Marine Sponge-Associated Fungus Aspergillus candidus KUFA 0062, in a Panel of Breast Cancer Cell Lines and Using 2D and 3D Cultures

by Fernanda Malhão, Alice A. Ramos, Suradet Buttachon, Tida Dethoup, Anake Kijjoa and Eduardo Rocha

Mar. Drugs 2019, 17(8), 448; https://doi.org/10.3390/md17080448 - 30 Jul 2019

Cited by 20 | Viewed by 5416

Abstract

Preussin, a hydroxyl pyrrolidine derivative isolated from the marine sponge-associated fungus Aspergillus candidus KUFA 0062, displayed anticancer effects in some cancer cell lines, including MCF7. Preussin was investigated for its cytotoxic and antiproliferative effects in breast cancer cell lines (MCF7, SKBR3, and MDA-MB-231), [...] Read more.

Preussin, a hydroxyl pyrrolidine derivative isolated from the marine sponge-associated fungus Aspergillus candidus KUFA 0062, displayed anticancer effects in some cancer cell lines, including MCF7. Preussin was investigated for its cytotoxic and antiproliferative effects in breast cancer cell lines (MCF7, SKBR3, and MDA-MB-231), representatives of major breast cancers subtypes, and in a non-tumor cell line (MCF12A). Preussin was first tested in 2D (monolayer), and then in 3D (multicellular aggregates), cultures, using a multi-endpoint approach for cytotoxicity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), resazurin and lactate dehydrogenase (LDH)) and proliferative (5-bromo-2′-deoxyuridine (BrdU)) assays, as well as the analysis of cell morphology by optical/electron microscopy and immunocytochemistry for caspase-3 and ki67. Preussin affected cell viability and proliferation in 2D and 3D cultures in all cell lines tested. The results in the 3D culture showed the same tendency as in the 2D culture, however, cells in the 3D culture were less responsive. The effects were observed at different concentrations of preussin, depending on the cell line and assay method. Morphological study of preussin-exposed cells revealed cell death, which was confirmed by caspase-3 immunostaining. In view of the data, we recommend a multi-endpoint approach, including histological evaluation, in future assays with the tested 3D models. Our data showed cytotoxic and antiproliferative activities of preussin in breast cancer cell lines in 2D and 3D cultures, warranting further studies for its anticancer potential. Full article

(This article belongs to the Special Issue Bioassay-Guided Isolation of Marine Natural Products for Drug Discovery)

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19 pages, 1655 KiB

Open AccessArticle

In Vitro and In Silico Approaches to Generating and Identifying Angiotensin-Converting Enzyme I Inhibitory Peptides from Green Macroalga Ulva lactuca

by Marco Garcia-Vaquero, Leticia Mora and Maria Hayes

Mar. Drugs 2019, 17(4), 204; https://doi.org/10.3390/md17040204 - 30 Mar 2019

Cited by 52 | Viewed by 7482

Abstract

A protein extract was generated from the macroalga Ulva lactuca, which was subsequently hydrolysed using the food-grade enzyme papain and angiotensin-converting Enzyme I and renin inhibitory peptides identified using a combination of enrichment strategies employing molecular weight cutoff filtration and mass spectrometry [...] Read more.

A protein extract was generated from the macroalga Ulva lactuca, which was subsequently hydrolysed using the food-grade enzyme papain and angiotensin-converting Enzyme I and renin inhibitory peptides identified using a combination of enrichment strategies employing molecular weight cutoff filtration and mass spectrometry analysis. The generated hydrolysates with the most promising in vitro activity were further purified using preparative RP-HPLC and characterised. The 1 kDa hydrolysate (1 kDa-UFH), purified and collected by preparative RP-HPLC at minutes 41‒44 (Fr41‒44), displayed statistically higher ACE-I inhibitory activities ranging from 96.91% to 98.06%. A total of 48 novel peptides were identified from these four fractions by LC-MS/MS. A simulated gastrointestinal digestion of the identified peptide sequences was carried out using in silico enzyme cleavage simulation tools, resulting in 86 peptide sequences that were further assessed for their potential activity, toxicity and allergenicity using multiple predictive approaches. All the peptides obtained in this study were predicted to be non-toxic. However, 28 out of the 86 novel peptides released after the in silico gastrointestinal digestion were identified as potential allergens. The potential allergenicity of these peptides should be further explored to comply with the current labelling regulations in formulated food products containing U. lactuca protein hydrolysates. Full article

(This article belongs to the Special Issue Bioassay-Guided Isolation of Marine Natural Products for Drug Discovery)

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16 pages, 1811 KiB

Open AccessArticle

Antioxidant and Neuroprotective Potential of the Brown Seaweed Bifurcaria bifurcata in an in vitro Parkinson’s Disease Model

by Joana Silva, Celso Alves, Rafaela Freitas, Alice Martins, Susete Pinteus, Joana Ribeiro, Helena Gaspar, Amparo Alfonso and Rui Pedrosa

Mar. Drugs 2019, 17(2), 85; https://doi.org/10.3390/md17020085 - 01 Feb 2019

Cited by 58 | Viewed by 5651

Abstract

Bifurcaria bifurcata is a marine brown seaweed mainly found on the Atlantic coast. Herein, we report the antioxidant and neuroprotective activities of seven fractions (F1–F7) obtained by normal phase chromatography from the B. bifurcata dichloromethane extract, as well as of its two major [...] Read more.

Bifurcaria bifurcata is a marine brown seaweed mainly found on the Atlantic coast. Herein, we report the antioxidant and neuroprotective activities of seven fractions (F1–F7) obtained by normal phase chromatography from the B. bifurcata dichloromethane extract, as well as of its two major isolated diterpenes. Total phenolic content of fractions was determined by the Folin–Ciocalteu method, while antioxidant activity was evaluated by the DPPH, ORAC, and FRAP assays. Neuroprotective effects were evaluated in a neurotoxic model induced by 6-hydroxydopamine (6-OHDA) in a human neuroblastoma cell line (SH-SY5Y), while the mechanisms associated to neuroprotection were investigated by the determination of mitochondrial membrane potential, H₂O₂ production, Caspase-3 activity, and by observation of DNA fragmentation. Fractions F4 and F5 exhibited the best neuroprotective and antioxidant activities, respectively. F4 fraction prevented changes in mitochondrial potential, and induced a reduction of H₂O₂ levels production and an increase in cell viability, suggesting that it may contain multi-target compounds acting on different pathways. Hence, this fraction was subjected to purification steps, affording the known diterpenes eleganolone and eleganonal. Both compounds exhibited antioxidant potential, being interesting candidates for further neuroprotective studies. Full article

(This article belongs to the Special Issue Bioassay-Guided Isolation of Marine Natural Products for Drug Discovery)

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12 pages, 1745 KiB

Open AccessArticle

Anti-Acanthamoeba Activity of Brominated Sesquiterpenes from Laurencia johnstonii

by Sara García-Davis, Ines Sifaoui, María Reyes-Batlle, Ezequiel Viveros-Valdez, José E. Piñero, Jacob Lorenzo-Morales, José J. Fernández and Ana R. Díaz-Marrero

Mar. Drugs 2018, 16(11), 443; https://doi.org/10.3390/md16110443 - 11 Nov 2018

Cited by 26 | Viewed by 4559

Abstract

Focused on our interest to develop novel antiparasistic agents, the present study was aimed to evaluate the biological activity of an extract of Laurencia johnstonii collected in Baja California Sur, Mexico, against an Acantamoeba castellanii Neff strain. Bioassay-guided fractionation allowed us to identify [...] Read more.

Focused on our interest to develop novel antiparasistic agents, the present study was aimed to evaluate the biological activity of an extract of Laurencia johnstonii collected in Baja California Sur, Mexico, against an Acantamoeba castellanii Neff strain. Bioassay-guided fractionation allowed us to identify the amoebicidal diastereoisomers α-bromocuparane (4) and α-isobromocuparane (5). Furthermore, bromination of the inactive laurinterol (1) and isolaurinterol (2) yielded four halogenated derivatives, (6)–(9), which improved the activity of the natural sesquiterpenes. Among them, the most active compound was 3α-bromojohnstane (7), a sesquiterpene derivative which possesses a novel carbon skeleton johnstane. Full article

(This article belongs to the Special Issue Bioassay-Guided Isolation of Marine Natural Products for Drug Discovery)

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8 pages, 788 KiB

Open AccessArticle

Anti-MRSA Sesquiterpenes from the Semi-Mangrove Plant Myoporum bontioides A. Gray

by Li-Mei Dong, Li-Lan Huang, Hang Dai, Qiao-Lin Xu, Jin-Kui Ouyang, Xu-Chao Jia, Wen-Xiang Gu and Jian-Wen Tan

Mar. Drugs 2018, 16(11), 438; https://doi.org/10.3390/md16110438 - 08 Nov 2018

Cited by 22 | Viewed by 3401

Abstract

The striking rise of methicillin-resistant Staphylococcus aureus (MRSA) infections has become a serious threat to public health worldwide. In an effort to search for new anti-MRSA agents from natural products, a bioassay-guided phytochemical study was conducted on the semi-mangrove plant Myoporum bontioides A. [...] Read more.

The striking rise of methicillin-resistant Staphylococcus aureus (MRSA) infections has become a serious threat to public health worldwide. In an effort to search for new anti-MRSA agents from natural products, a bioassay-guided phytochemical study was conducted on the semi-mangrove plant Myoporum bontioides A. Gray, which led to the isolation of two new sesquiterpene alkaloids (1 and 2) and six known furanosesquiterpenes (3–8). Their structures were elucidated on the basis of extensive analysis of their 1D, 2D NMR and mass spectroscopic data. These two new alkaloids (1 and 2) displayed potent anti-MRSA activity with MIC value of 6.25 μg/mL. This is the first report of sesquiterpene alkaloids from the plants of Myoporum genus and their anti-MRSA activity. Full article

(This article belongs to the Special Issue Bioassay-Guided Isolation of Marine Natural Products for Drug Discovery)

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8 pages, 1445 KiB

Open AccessArticle

Cytotoxic Tetrahydroxanthone Dimers from the Mangrove-Associated Fungus Aspergillus versicolor HDN1009

by Guihong Yu, Guangwei Wu, Zichao Sun, Xiaomin Zhang, Qian Che, Qianqun Gu, Tianjiao Zhu, Dehai Li and Guojian Zhang

Mar. Drugs 2018, 16(9), 335; https://doi.org/10.3390/md16090335 - 14 Sep 2018

Cited by 33 | Viewed by 3543

Abstract

Three new tetrahydroxanthone dimers, 5-epi-asperdichrome (1), versixanthones N (2), and O (3), were isolated from the mangrove-derived fungus Aspergillus versicolor HDN1009. Their structures, including the absolute configurations, were elucidated by NMR, HRMS, and circular dichroism [...] Read more.

Three new tetrahydroxanthone dimers, 5-epi-asperdichrome (1), versixanthones N (2), and O (3), were isolated from the mangrove-derived fungus Aspergillus versicolor HDN1009. Their structures, including the absolute configurations, were elucidated by NMR, HRMS, and circular dichroism (CD) experiments. Among them, compound 1 was the second example of tetrahydroxanthone dimers, which dimerized by a rare diaryl ether linkage and showed promising antibacterial activities against Vibrio parahemolyticus, Bacillus subtilis, Mycobacterium phlei, and Pseudomonas aeruginosa, with MIC values ranging from 100 μM to 200 μM; whilst compounds 2 and 3 exhibited extensive cytotoxicities against five cancer cell lines (HL-60, K562, H1975, MGC803, and HO-8910), with IC₅₀ values ranging from 1.7 μM to 16.1 μM. Full article

(This article belongs to the Special Issue Bioassay-Guided Isolation of Marine Natural Products for Drug Discovery)

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10 pages, 1363 KiB

Open AccessArticle

Mycophenolic Acid Derivatives with Immunosuppressive Activity from the Coral-Derived Fungus Penicillium bialowiezense

by Qing Zhang, Beiye Yang, Fengli Li, Mengting Liu, Shuang Lin, Jianping Wang, Yongbo Xue, Hucheng Zhu, Weiguang Sun, Zhengxi Hu and Yonghui Zhang

Mar. Drugs 2018, 16(7), 230; https://doi.org/10.3390/md16070230 - 07 Jul 2018

Cited by 16 | Viewed by 5445

Abstract

Mycophenolic acid (MPA) is a potent inosine-5′-monophosphate dehydrogenase (IMPDH) inhibitor for immunosuppressive chemotherapy. Most importantly, as the 2-morpholinoethyl ester prodrug of MPA, mycophenolate mofetil (MMF) is a well-known immunosuppressant used to prevent rejection in organ transplantations. Nevertheless, due to its frequently occurred side [...] Read more.

Mycophenolic acid (MPA) is a potent inosine-5′-monophosphate dehydrogenase (IMPDH) inhibitor for immunosuppressive chemotherapy. Most importantly, as the 2-morpholinoethyl ester prodrug of MPA, mycophenolate mofetil (MMF) is a well-known immunosuppressant used to prevent rejection in organ transplantations. Nevertheless, due to its frequently occurred side effects, searching for new therapeutic agents is ongoing. In our current work, by virtue of efficient bioassay-guided fractionation and purification, eleven mycophenolic acid derivatives, including five previously unreported metabolites (3–7) and six known compounds (1, 2, and 8–11), were obtained from the coral-derived fungus Penicillium bialowiezense. Their structures were elucidated by means of extensive spectroscopic analyses (including 1D and 2D NMR and HRESIMS data) and comparison of the NMR and other physical data with those reported in the literature in the case of the known compounds. All the isolates 1–11 were evaluated for the immunosuppressive activity, and 1–3 showed potent IMPDH2 inhibitory potency with IC₅₀ values of 0.84–0.95 μM, which were comparable to that of MPA (the positive control), while 4–10 showed significant inhibitory potency with IC₅₀ values of 3.27–24.68 μM. All the MPA derivatives showed promising immunosuppressive activity, endowing them as potential drug leads for organ transplantations and autoimmune related diseases. Full article

(This article belongs to the Special Issue Bioassay-Guided Isolation of Marine Natural Products for Drug Discovery)

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Review

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26 pages, 4467 KiB

Open AccessFeature PaperReview

Bioactive Compounds Isolated from Marine-Derived Microbes in China: 2009–2018

by Weiwei Sun, Wenhui Wu, Xueling Liu, Diana A. Zaleta-Pinet and Benjamin R. Clark

Mar. Drugs 2019, 17(6), 339; https://doi.org/10.3390/md17060339 - 06 Jun 2019

Cited by 45 | Viewed by 7668

Abstract

This review outlines the research that was carried out regarding the isolation of bioactive compounds from marine-derived bacteria and fungi by China-based research groups from 2009–2018, with 897 publications being surveyed. Endophytic organisms featured heavily, with endophytes from mangroves, marine invertebrates, and marine [...] Read more.

This review outlines the research that was carried out regarding the isolation of bioactive compounds from marine-derived bacteria and fungi by China-based research groups from 2009–2018, with 897 publications being surveyed. Endophytic organisms featured heavily, with endophytes from mangroves, marine invertebrates, and marine algae making up more than 60% of the microbial strains investigated. There was also a strong focus on fungi as a source of active compounds, with 80% of publications focusing on this area. The rapid increase in the number of publications in the field is perhaps most notable, which have increased more than sevenfold over the past decade, and suggests that China-based researchers will play a major role in marine microbial natural products drug discovery in years to come. Full article

(This article belongs to the Special Issue Bioassay-Guided Isolation of Marine Natural Products for Drug Discovery)

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31 pages, 393 KiB

Open AccessReview

Current Screening Methodologies in Drug Discovery for Selected Human Diseases

by Olga Maria Lage, María C. Ramos, Rita Calisto, Eduarda Almeida, Vitor Vasconcelos and Francisca Vicente

Mar. Drugs 2018, 16(8), 279; https://doi.org/10.3390/md16080279 - 14 Aug 2018

Cited by 76 | Viewed by 9620

Abstract

The increase of many deadly diseases like infections by multidrug-resistant bacteria implies re-inventing the wheel on drug discovery. A better comprehension of the metabolisms and regulation of diseases, the increase in knowledge based on the study of disease-born microorganisms’ genomes, the development of [...] Read more.

The increase of many deadly diseases like infections by multidrug-resistant bacteria implies re-inventing the wheel on drug discovery. A better comprehension of the metabolisms and regulation of diseases, the increase in knowledge based on the study of disease-born microorganisms’ genomes, the development of more representative disease models and improvement of techniques, technologies, and computation applied to biology are advances that will foster drug discovery in upcoming years. In this paper, several aspects of current methodologies for drug discovery of antibacterial and antifungals, anti-tropical diseases, antibiofilm and antiquorum sensing, anticancer and neuroprotectors are considered. For drug discovery, two different complementary approaches can be applied: classical pharmacology, also known as phenotypic drug discovery, which is the historical basis of drug discovery, and reverse pharmacology, also designated target-based drug discovery. Screening methods based on phenotypic drug discovery have been used to discover new natural products mainly from terrestrial origin. Examples of the discovery of marine natural products are provided. A section on future trends provides a comprehensive overview on recent advances that will foster the pharmaceutical industry. Full article

(This article belongs to the Special Issue Bioassay-Guided Isolation of Marine Natural Products for Drug Discovery)

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