Isolation, Synthesis and Absolute Configuration of the Pericharaxins A and B, Epimeric Hydroxy-Polyene Glycerol Ethers from the Calcarean Sponge Pericharax heteroraphis.

Naturally occurring epimeric hydroxy-polyene glycerol ether pericharaxins A (1a) and B (1b) were isolated from the calcarean sponge Pericharax heteroraphis. The structural and stereochemical characterization of both diastereoisomers were established on the basis of spectroscopic data analysis and total synthesis in seven steps. The mixture of pericharaxins A (1a) and B (1b) was proven to be epimeric by chiral-phase HPLC analysis of both synthetic and natural samples. Further separation of the epimers and application of Mosher's method to the synthetic compounds allowed unequivocal absolute configuration assignment. While natural products and the synthetic intermediates were shown to be non-cytotoxic on the HCT116 cell line, the endochondral differentiation activity using human type X collagen transcription activity in ATDC5 cells is interesting.

Focus on Marine Animal Safety and Marine Bioresources in Response to the SARS-CoV-2 Crisis.

SARS-CoV-2 as a zoonotic virus has significantly affected daily life and social behavior since its outbreak in late 2019. The concerns over its transmission through different media directly or indirectly have evoked great attention about the survival of SARS-CoV-2 virions in the environment and its potential infection of other animals. To evaluate the risk of infection by SARS-CoV-2 and to counteract the COVID-19 disease, extensive studies have been performed to understand SARS-CoV-2 biogenesis and its pathogenesis. This review mainly focuses on the molecular architecture of SARS-CoV-2, its potential for infecting marine animals, and the prospect of drug discovery using marine natural products to combat SARS-CoV-2. The main purposes of this review are to piece together progress in SARS-CoV-2 functional genomic studies and antiviral drug development, and to raise our awareness of marine animal safety on exposure to SARS-CoV-2.

Novel Antiretroviral Structures from Marine Organisms.

In spite of significant advancements and success in antiretroviral therapies directed against HIV infection, there is no cure for HIV, which scan persist in a human body in its latent form and become reactivated under favorable conditions. Therefore, novel antiretroviral drugs with different modes of actions are still a major focus for researchers. In particular, novel lead structures are being sought from natural sources. So far, a number of compounds from marine organisms have been identified as promising therapeutics for HIV infection. Therefore, in this paper, we provide an overview of marine natural products that were first identified in the period between 2013 and 2018 that could be potentially used, or further optimized, as novel antiretroviral agents. This pipeline includes the systematization of antiretroviral activities for several categories of marine structures including chitosan and its derivatives, sulfated polysaccharides, lectins, bromotyrosine derivatives, peptides, alkaloids, diterpenes, phlorotannins, and xanthones as well as adjuvants to the HAART therapy such as fish oil. We critically discuss the structures and activities of the most promising new marine anti-HIV compounds.

Looking at Marine-Derived Bioactive Molecules as Upcoming Anti-Diabetic Agents: A Special Emphasis on PTP1B Inhibitors.

Diabetes mellitus (DM) is a chronic metabolic disease with high morbimortality rates. DM has two types: type 1, which is often associated with a total destruction of pancreatic beta cells, and non-insulin-dependent or type 2 diabetes mellitus (T2DM), more closely associated with obesity and old age. The main causes of T2DM are insulin resistance and/or inadequate insulin secretion. Protein-tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling pathways and plays an important role in T2DM, as its overexpression may induce insulin resistance. Thus, since PTP1B may be a therapeutic target for both T2DM and obesity, the search for novel and promising natural inhibitors has gained much attention. Hence, several marine organisms, including macro and microalgae, sponges, marine invertebrates, sea urchins, seaweeds, soft corals, lichens, and sea grasses, have been recently evaluated as potential drug sources. This review provides an overview of the role of PTP1B in T2DM insulin signaling and treatment, and highlights the recent findings of several compounds and extracts derived from marine organisms and their relevance as upcoming PTP1B inhibitors. In this systematic literature review, more than 60 marine-derived metabolites exhibiting PTP1B inhibitory activity are listed. Their chemical classes, structural features, relative PTP1B inhibitory potency (assessed by IC50 values), and structure⁻activity relationships (SARs) that could be drawn from the available data are discussed. The upcoming challenge in the field of marine research-metabolomics-is also addressed.

Recent advancement of novel marine fungi derived secondary metabolite fibrinolytic compound FGFC in biomedical applications: a review.

For several decades, products derived from marine natural sources (PMN) have been widely identified for several therapeutic applications due to their rich sources of bioactive sub-stances, unique chemical diversity, biocompatibility and excellent biological activity. For the past 15 years, our research team explored several PMNs, especially fungi fibrinolytic compounds (FGFCs). FGFC is an isoindolone alkaloid derived from marine fungi, also known as staplabin analogs or Stachybotrys microspora triprenyl phenol (SMTP). For instance, our previous studies explored different types of FGFCs such as FGFC 1, 2, 3 and 4 from the marine fungi Stachybotrys longispora FG216 derived metabolites. The derivatives of FGFC are potentially employed in several disease treatments, mainly for stroke, cancer, ischemia, acute kidney injury, inflammation, cerebral infarction, thrombolysis and hemorrhagic activities, etc. Due to the increasing use of FGFCs in pharmaceutical and biomedical applications, it is important to understand the fundamental signaling concept of FGFCs. Hence, for the first time, this review collectively summarizes the background, types, mode of action and biological applications of FGFCs and their current endeavors for future therapies.

Marine-Derived Bioactive Metabolites as a Potential Therapeutic Intervention in Managing Viral Diseases: Insights from the SARS-CoV-2 In Silico and Pre-Clinical Studies.

Worldwide urbanization and subsequent migration have accelerated the emergence and spread of diverse novel human diseases. Among them, diseases caused by viruses could result in epidemics, typified by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which hit the globe towards the end of December 2019. The global battle against SARS-CoV-2 has reignited interest in finding alternative treatments for viral infections. The marine world offers a large repository of diverse and unique bioactive compounds. Over the years, many antiviral compounds from marine organisms have been isolated and tested in vitro and in vivo. However, given the increasing need for alternative treatment, in silico analysis appears to provide a time- and cost-effective approach to identifying the potential antiviral compounds from the vast pool of natural metabolites isolated from marine organisms. In this perspective review, we discuss marine-derived bioactive metabolites as potential therapeutics for all known disease-causing viruses including the SARS-CoV-2. We demonstrate the efficacy of marine-derived bioactive metabolites in the context of various antiviral activities and their in silico, in vitro, and in vivo capacities.

New tridecapeptides of the theonellapeptolide family from the Indonesian sponge Theonella swinhoei.

Chemical analysis of the organic extract of Theonella swinhoei yielded two new tridecadepsipeptides of the theonellapeptolide family, namely sulfinyltheonellapeptolide, characterized by a methylsulfinylacetyl group at the N-terminus, and theonellapeptolide If, the first member of this class of compounds to show four valine residues. The structures of the compounds, isolated along with the known theonellapeptolide Id, were determined by extensive 2D NMR and MS/MS analyses followed by application of Marfey's method. The isolated peptides exhibited moderate antiproliferative activity against HepG2 cells, a hepatic carcinoma cell line.

Reconciling the Gap between Medications and their Potential Leads: The Role of Marine Metabolites in the Discovery of New Anticancer Drugs: A Comprehensive Review.

One-third of people will be diagnosed with cancer at some point in their lives, making it the second leading cause of death globally each year after cardiovascular disease. The complex anticancer molecular mechanisms have been understood clearly with the advent of improved genomic, proteomic, and bioinformatics. Our understanding of the complex interplay between numerous genes and regulatory genetic components within cells explaining how this might lead to malignant phenotypes has greatly expanded. It was discovered that epigenetic resistance and a lack of multitargeting drugs were highlighted as major barriers to cancer treatment, spurring the search for innovative anticancer treatments. It was discovered that epigenetic resistance and a lack of multitargeting drugs were highlighted as major barriers to cancer treatment, spurring the search for innovative anticancer treatments. Many popular anticancer drugs, including irinotecan, vincristine, etoposide, and paclitaxel, have botanical origins. Actinomycin D and mitomycin C come from bacteria, while bleomycin and curacin come from marine creatures. However, there is a lack of research evaluating the potential of algae-based anticancer treatments, especially in terms of their molecular mechanisms. Despite increasing interest in the former, and the promise of the compounds to treat tumours that have been resistant to existing treatment, pharmaceutical development of these compounds has lagged. Thus, the current review focuses on the key algal sources that have been exploited as anticancer therapeutic leads, including their biological origins, phytochemistry, and the challenges involved in converting such leads into effective anticancer drugs.

Comprehensive screening of marine metabolites against class B1 metallo-ß-lactamases of Klebsiella pneumoniae using two-pronged in silico approach.

The emergence of antibiotic resistance is one of the major global threats in healthcare. Metallo-ß-Lactamases (MBL) are a class of enzymes in bacteria that cleave ß-lactam antibiotics and confer resistance. MBLs are further divided into subclasses B1, B2 and B3. Of these, subclasses B1-MBLs (including NDM-1, VIM-2 and IMP-1) constitute the clinically prevalent lactamases conferring resistance. To date, no effective drugs are available clinically against MBLs. In this work, we aim to identify potent inhibitors for the B1 subclass of MBL from available marine metabolites in Comprehensive Marine Natural Product database through integrated in silico approaches. We have used two methods, namely, the high-throughput strategy and the pharmacophore-based strategy to identify potential inhibitors from marine metabolites. High-throughput virtual screening identified N-methyl mycosporine-Ser, which had the highest binding affinity to NDM-1. The pharmacophore-based approach based on co-crystallized ligands identified makaluvic acid and didymellamide with higher binding affinity across B1-MBLs. Taking into account of the advantage of a pharmacophore model-based approach with higher binding affinity, we conclude that both makaluvic acid and didymellamide show potential broad-spectrum effects by binding to all three B1-MBL receptors. The study also indicates the need to take multiple in silico approaches to screen and identify novel inhibitors. Together, our study reveals promising inhibitors that can be identified from marine systems.Communicated by Ramaswamy H. Sarma.

Mass Spectrometry Metabolomics Approach Reveals Anti-Trichomonas vaginalis Scaffolds from Marine Fungi.

Trichomoniasis is the most common non-viral sexually transmitted infection (STI) in the world caused by Trichomonas vaginalis. Failures in the treatment with the 5-nitroimidazole class including parasite resistance to metronidazole elicit new alternatives. Marine natural products are sources of several relevant molecules, presenting a variety of metabolites with numerous biological activities. In this work, we evaluated the anti-T. vaginalis activity of fungi associated with marine invertebrates by mass spectrometry-based metabolomics approaches. After screening of six marine fungi, extract from Penicillium citrinum FMPV 15 has shown to be 100% active against T. vaginalis, and the gel permeation column on Sephadex LH-20® yielded twelve organic fractions which five showed to be active. Metabolomics and statistical analyses were performed with all the samples (extract and fractions), and several compounds were suggested to be related to the activity. These components include citrinin, dicitrinin C, citreoisocoumarin, dihydrocitrinone, decarboxycitrinin, penicitrinone C, and others. The minimum inhibitory concentration (MIC) value of anti-T. vaginalis activity of citrinin was 200 µM. The marine fungi metabolites show potential as new alternatives to overcome drug resistance in T. vaginalis infections.

Structure- and Ligand-Based in silico Studies towards the Repurposing of Marine Bioactive Compounds to Target SARS-CoV-2.

This work was a structured virtual screening for marine bioactive compounds with reported antiviral activities which were subjected to structure-based studies against SARS-CoV-2 co-crystallized proteins. The molecular docking of marine bioactive compounds against the main protease (Mpro, PDB ID: 6lu7 and 6y2f), the spike glycoprotein (PDB ID: 6vsb), and the RNA polymerase (PDB ID: 6m71) of SARS-CoV-2 was performed. Ligand-based approach with the inclusion of rapid overlay chemical structures (ROCS) was also addressed in order to examine the probability of these marine compounds sharing relevance and druggability with the reported drugs. Among the examined marine library, the highest scores in different virtual screening aspects were displayed by compounds with flavonoids core, acyl indole, and pyrrole carboxamide alkaloids. Moreover, a complete overlay with the co-crystallized ligands of Mpro was revealed by sceptrin and debromo-sceptrin. Thalassoilin (A-B) which was found in the Red Sea exhibited the highest binding and similarity outcomes among all target proteins. These data highlight the importance of marine natural metabolites in regard to further studies for discovering new drugs to combat the COVID-19 pandemic.

Metabolites with Antioxidant Activity from Marine Macroalgae.

Reactive oxygen species (ROS) attack biological molecules, such as lipids, proteins, enzymes, DNA, and RNA, causing cellular and tissue damage. Hence, the disturbance of cellular antioxidant homeostasis can lead to oxidative stress and the onset of a plethora of diseases. Macroalgae, growing in stressful conditions under intense exposure to UV radiation, have developed protective mechanisms and have been recognized as an important source of secondary metabolites and macromolecules with antioxidant activity. In parallel, the fact that many algae can be cultivated in coastal areas ensures the provision of sufficient quantities of fine chemicals and biopolymers for commercial utilization, rendering them a viable source of antioxidants. This review focuses on the progress made concerning the discovery of antioxidant compounds derived from marine macroalgae, covering the literature up to December 2020. The present report presents the antioxidant potential and biogenetic origin of 301 macroalgal metabolites, categorized according to their chemical classes, highlighting the mechanisms of antioxidative action when known.

Bioactive marine metabolites derived from the Persian Gulf compared to the Red Sea: similar environments and wide gap in drug discovery.

Marine life has provided mankind with unique and extraordinary chemical structures and scaffolds with potent biological activities. Many organisms and secondary metabolites derived from fungi and symbionts are found to be more environmentally friendly to study than the marine corals per se. Marine symbionts such as Aspergillus sp., a fungus, which can be isolated and grown in the lab would be a potential and continuous source of bioactive natural compounds without affecting the marine environment. The Red Sea is known for its biodiversity and is well-studied in terms of its marine-derived bioactive metabolites. The harsh environmental conditions lead to the development of unique metabolic pathways. This, in turn, results in enhanced synthesis and release of toxic and bioactive chemicals. Interestingly, the Persian Gulf and the Gulf of Oman carry a variety of environmental stresses, some of which are similar to the Red Sea. When compared to the Red Sea, the Persian Gulf has been shown to be rich in marine fungi as well, and is, therefore, expected to contain elaborate and interesting bioactive compounds. Such compounds may or may not be similar to the ones isolated from the Red Sea environment. Astoundingly, there are a very limited number of studies on the bioactive portfolio of marine-derived metabolites from the Persian Gulf and the Gulf of Oman. In this perspective, we are looking at the Red Sea as a comparator marine environment and bioactive materials repertoire to provide a futuristic perspective on the potential of the understudied and possibly overlooked bioactive metabolites derived from the marine life of the Persian Gulf and the Gulf of Oman despite its proven biodiversity and harsher environmental stress.

Antiangiogenic Effect of Isomalyngamide A Riboside CY01 in Breast Cancer Cells via Inhibition of Migration, Tube Formation and pVEGFR2/pAKT Signals.

BACKGROUND: To block the metastatic and angiogenic pathways during the tumor progression arouses considerable pharmacological interests in the development of anticancer drugs. OBJECTIVE: To develop alternative antiangiogenic and antimetastic agents, we designed and prepared a series of nature inspired isomalyngamide A analogs containing ribose conjugate with 1,2-diaminoethane or 1,3- diaminopropane linkers (1-8). METHODS: The target glycosylated isomalyngamide A analogs 1-8 were constructed through condensation of the malonic acids 16-19 and the corresponding aminoethoxyl ribosides 20 and 21, using HBTU/DIPEA as the coupling agent. The cell growth inhibition assay, cell migration assay, transwell invasion assay, adhesion assay, tube formation assay and western blot analysis were used to validate the biological actions of compounds. RESULTS: The most effective compound, isomalyngamide A riboside 1 (CY01), possessing a D-ribose core structure and a 1,3-diaminopropane linker, showed significant suppression of MDA-MB-231 cell migration and inhibited tube formation of Human Umbilical Vascular Endothelial Cells (HUVECs) in a dose-dependent manner. Effect of the latter is comparable to that of sorafenib, an orally active multikinase inhibitor and an inhibitor of angiogenesis. CY01 also showed slight inhibition on collagen type IV- and laminin-mediated cell adhesion. These actions may be regulated through the blockade of the VEGF/VEGFR2 signaling pathway by inhibiting the VEGF induced phosphorylation of p-VEGFR2 and p-AKT. CONCLUSION: In this effort, we have discovered synthetic and glycosylated marine metabolites which may serve as an alternative antiangiogenic and antimetastic agent during multitherapy.

Marine antimalarials.

Malaria is an infectious disease causing at least 1 million deaths per year, and, unfortunately, the chemical entities available to treat malaria are still too limited. In this review we highlight the contribution of marine chemistry in the field of antimalarial research by reporting the most important results obtained until the beginning of 2009, with particular emphasis on recent discoveries. About 60 secondary metabolites produced by marine organisms have been grouped into three structural types and discussed in terms of their reported antimalarial activities. The major groups of metabolites include isonitrile derivatives, alkaloids and endoperoxide derivatives. The following discussion evidences that antimalarial marine molecules can efficiently integrate the panel of lead compounds isolated from terrestrial sources with new chemical backbones and, sometimes, with unique functional groups.