Potential Pharmacological Resources: Natural Bioactive Compounds from Marine-Derived Fungi

In recent years, a considerable number of structurally unique metabolites with biological and pharmacological activities have been isolated from the marine-derived fungi, such as polyketides, alkaloids, peptides, lactones, terpenoids and steroids. Some of these compounds have anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, antioxidant, antibiotic and cytotoxic properties. This review partially summarizes the new bioactive compounds from marine-derived fungi with classification according to the sources of fungi and their biological activities. Those fungi found from 2014 to the present are discussed.     

Bioactive Terpenes from Marine-Derived Fungi

Marine-derived fungi continue to be a prolific source of secondary metabolites showing diverse bioactivities. Terpenoids from marine-derived fungi exhibit wide structural diversity including numerous compounds with pronounced biological activities. In this review, we survey the last five years’ reports on terpenoidal metabolites from marine-derived fungi with particular attention on those showing marked biological activities.     

Diversity and antibacterial activities of fungi derived from the Gorgonian Echinogorgia rebekka from the South China Sea

The diversity of symbiotic fungi associated with the gorgonian coral Echinogorgia rebekka from the Weizhou coral reef in the South China Sea was investigated. Combined with morphologic traits, ITS-rDNA sequences revealed 18 fungal strains from this gorgonian. All of the 18 fungi belonged to the phylum Ascomycota and were distributed among seven genera in five orders: Eurotiales (Aspergillus and Penicillium), Pleosporales (Alternaria), Capnodiales (Cladosporium), Trichosphaeriales (Nigrospora) and Hypocreales (Hypocrea and Nectria). Antibacterial activities of these fungal strains were investigated with five pathogenic bacteria. All of the 18 fungal strains displayed different levels of antibacterial activities, most of which exhibited moderate to high antibacterial activities to the Gram-positive pathogens Staphylococcus aureus and Micrococcus tetragenus, and showed relatively low bioactivities to other three pathogenic bacteria. Several fungal strains in the genera Penicillium and Cladosporium with strong antibacterial activities provide potential for further research on isolation of bioactive secondary metabolites.     

Bioactivity Potential of Marine Natural Products from Scleractinia-Associated Microbes and In Silico Anti-SARS-COV-2 Evaluation

Marine organisms and their associated microbes are rich in diverse chemical leads. With the development of marine biotechnology, a considerable number of research activities are focused on marine bacteria and fungi-derived bioactive compounds. Marine bacteria and fungi are ranked on the top of the hierarchy of all organisms, as they are responsible for producing a wide range of bioactive secondary metabolites with possible pharmaceutical applications. Thus, they have the potential to provide future drugs against challenging diseases, such as cancer, a range of viral diseases, malaria, and inflammation. This review aims at describing the literature on secondary metabolites that have been obtained from Scleractinian-associated organisms including bacteria, fungi, and zooxanthellae, with full coverage of the period from 1982 to 2020, as well as illustrating their biological activities and structure activity relationship (SAR). Moreover, all these compounds were filtered based on ADME analysis to determine their physicochemical properties, and 15 compounds were selected. The selected compounds were virtually investigated for potential inhibition for SARS-CoV-2 targets using molecular docking studies. Promising potential results against SARS-CoV-2 RNA dependent RNA polymerase (RdRp) and methyltransferase (nsp16) are presented.     

Marine-Derived Indole Alkaloids and Their Biological and Pharmacological Activities

Novel secondary metabolites from marine macroorganisms and marine-derived microorganisms have been intensively investigated in the last few decades. Several classes of compounds, especially indole alkaloids, have been a target for evaluating biological and pharmacological activities. As one of the most promising classes of compounds, indole alkaloids possess not only intriguing structural features but also a wide range of biological/pharmacological activities including antimicrobial, anti-inflammatory, anticancer, antidiabetic, and antiparasitic activities. This review reports the indole alkaloids isolated during the period of 2016–2021 and their relevant biological/pharmacological activities. The marine-derived indole alkaloids reported from 2016 to 2021 were collected from various scientific databases. A total of 186 indole alkaloids from various marine organisms including fungi, bacteria, sponges, bryozoans, mangroves, and algae, are described. Despite the described bioactivities, further evaluation including their mechanisms of action and biological targets is needed to determine which of these indole alkaloids are worth studying to obtain lead compounds for the development of new drugs.     

Culturable Microorganisms Associated with Sea Cucumbers and Microbial Natural Products

Sea cucumbers are a class of marine invertebrates and a source of food and drug. Numerous microorganisms are associated with sea cucumbers. Seventy-eight genera of bacteria belonging to 47 families in four phyla, and 29 genera of fungi belonging to 24 families in the phylum Ascomycota have been cultured from sea cucumbers. Sea-cucumber-associated microorganisms produce diverse secondary metabolites with various biological activities, including cytotoxic, antimicrobial, enzyme-inhibiting, and antiangiogenic activities. In this review, we present the current list of the 145 natural products from microorganisms associated with sea cucumbers, which include primarily polyketides, as well as alkaloids and terpenoids. These results indicate the potential of the microorganisms associated with sea cucumbers as sources of bioactive natural products.     

A Brief Review of Bioactive Metabolites Derived from Deep-Sea Fungi

Deep-sea fungi, the fungi that inhabit the sea and the sediment at depths of over 1000 m below the surface, have become an important source of industrial, agricultural, and nutraceutical compounds based on their diversities in both structure and function. Since the first study of deep-sea fungi in the Atlantic Ocean at a depth of 4450 m was conducted approximately 50 years ago, hundreds of isolates of deep-sea fungi have been reported based on culture-dependent methods. To date more than 180 bioactive secondary metabolites derived from deep-sea fungi have been documented in the literature. These include compounds with anticancer, antimicrobial, antifungal, antiprotozoal, and antiviral activities. In this review, we summarize the structures and bioactivities of these metabolites to provide help for novel drug development.     

Aaptamine Derivatives with Antifungal and Anti-HIV-1 Activities from the South China Sea Sponge Aaptos aaptos

Five new alkaloids of aaptamine family, compounds (1–5) and three known derivatives (6–8), have been isolated from the South China Sea sponge Aaptos aaptos. The structures of all compounds were unambiguously elucidated by spectroscopic analyses, as well as by comparison with the literature data. Compounds 1–2 are characterized with triazapyrene lactam skeleton, whereas compounds 4–5 share an imidazole-fused aaptamine moiety. These compounds were evaluated in antifungal and anti-HIV-1 assays. Compounds 3, 7, and 8 showed antifungal activity against six fungi, with MIC values in the range of 4 to 64 μg/mL. Compounds 7–8 exhibited anti-HIV-1 activity, with inhibitory rates of 88.0% and 72.3%, respectively, at a concentration of 10 μM.     

Molecular Architecture and Biomedical Leads of Terpenes from Red Sea Marine Invertebrates

Marine invertebrates including sponges, soft coral, tunicates, mollusks and bryozoan have proved to be a prolific source of bioactive natural products. Among marine-derived metabolites, terpenoids have provided a vast array of molecular architectures. These isoprenoid-derived metabolites also exhibit highly specialized biological activities ranging from nerve regeneration to blood-sugar regulation. As a result, intense research activity has been devoted to characterizing invertebrate terpenes from both a chemical and biological standpoint. This review focuses on the chemistry and biology of terpene metabolites isolated from the Red Sea ecosystem, a unique marine biome with one of the highest levels of biodiversity and specifically rich in invertebrate species.     

Exploring Chemical Diversity of Phorbas Sponges as a Source of Novel Lead Compounds in Drug Discovery

Porifera, commonly referred to as marine sponges, are acknowledged as major producers of marine natural products (MNPs). Sponges of the genus Phorbas have attracted much attention over the years. They are widespread in all continents, and several structurally unique compounds have been identified from this species. Terpenes, mainly sesterterpenoids, are the major secondary metabolites isolated from Phorbas species, even though several alkaloids and steroids have also been reported. Many of these compounds have presented interesting biological activities. Particularly, Phorbas sponges have been demonstrated to be a source of cytotoxic metabolites. In addition, MNPs exhibiting cytostatic, antimicrobial, and anti-inflammatory activities have been isolated and structurally characterized. This review provides an overview of almost 130 secondary metabolites from Phorbas sponges and their biological activities, and it covers the literature since the first study published in 1993 until November 2021, including approximately 60 records. The synthetic routes to the most interesting compounds are briefly outlined.     

Scopararanes C-G: new oxygenated pimarane diterpenes from the marine sediment-derived fungus Eutypella scoparia FS26

Five new oxygenated pimarane diterpenes, named scopararanes C-G (1-5) were isolated from the culture of a marine sediment-derived fungus Eutypella scoparia FS26 obtained from the South China Sea. The structures of these compounds were established on the basis of extensive spectroscopic analysis. The absolute configurations of compounds 1-5, were determined by CD spectroscopic analysis and comparison with literature data. All isolated compounds (1-5) were evaluated for their cytotoxic activities against MCF-7, NCI-H460, and SF-268 tumor cell lines by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) method.     

New Hippolide Derivatives with Protein Tyrosine Phosphatase 1B Inhibitory Activity from the Marine Sponge Hippospongia lachne

Five new sesterterpenoids, compounds 1–5, have been isolated from the sponge Hippospongia lachne off Yongxing Island in the South China Sea. The structures of compounds 1–5 were elucidated through extensive spectroscopic analysis, including HRMS, 1D, and 2D NMR experiments. The stereochemistry, including absolute configurations of these compounds, was determined by spectroscopic, chemical, and computational methods. Compounds 1 and 5 showed moderate protein tyrosine phosphatase 1B (PTP1B) inhibitory activities with IC₅₀ values of 5.2 μM and 8.7 μM, respectively, more potent than previously reported hippolides.     

Natural Products from Marine Fungi—Still an Underrepresented Resource

Marine fungi represent a huge potential for new natural products and an increased number of new metabolites have become known over the past years, while much of the hidden potential still needs to be uncovered. Representative examples of biodiversity studies of marine fungi and of natural products from a diverse selection of marine fungi from the author’s lab are highlighting important aspects of this research. If one considers the huge phylogenetic diversity of marine fungi and their almost ubiquitous distribution, and realizes that most of the published work on secondary metabolites of marine fungi has focused on just a few genera, strictly speaking Penicillium, Aspergillus and maybe also Fusarium and Cladosporium, the diversity of marine fungi is not adequately represented in investigations on their secondary metabolites and the less studied species deserve special attention. In addition to results on recently discovered new secondary metabolites of Penicillium species, the diversity of fungi in selected marine habitats is highlighted and examples of groups of secondary metabolites produced by representatives of a variety of different genera and their bioactivities are presented. Special focus is given to the production of groups of derivatives of metabolites by the fungi and to significant differences in biological activities due to small structural changes.     

Neuronal Modulators from the Coral-Associated Fungi Aspergillus candidus

Three new p-terphenyl derivatives, named 4″-O-methyl-prenylterphenyllin B (1) and phenylcandilide A and B (17 and 18), and three new indole-diterpene alkaloids, asperindoles E–G (22-24), were isolated together with eighteen known analogues from the fungi Aspergillus candidus associated with the South China Sea gorgonian Junceela fragillis. The structures and absolute configurations of the new compounds were elucidated on the basis of spectroscopic analysis, and DFT/NMR and TDDFT/ECD calculations. In a primary cultured cortical neuronal network, the compounds 6, 9, 14, 17, 18 and 24 modulated spontaneous Ca²⁺ oscillations and 4-aminopyridine hyperexcited neuronal activity. A preliminary structure–activity relationship was discussed.     

Progress in Research on Bioactive Secondary Metabolites from Deep-Sea Derived Microorganisms

Deep sea has an extreme environment which leads to biodiversity of microorganisms and their unique physical and biochemical mechanisms. Deep-sea derived microorganisms are more likely to produce novel bioactive substances with special mechanism of action for drug discovery. This article reviews secondary metabolites with biological activities such as anti-tumor, anti-bacterial, anti-viral, and anti-inflammatory isolated from deep-sea fungi and bacteria during 2018–2020. Effective methods for screening and obtaining natural active compounds from deep-sea microorganisms are also summarized, including optimizing the culture conditions, using genome mining technology, biosynthesis and so on. The comprehensive application of these methods makes broader prospects for the development and application of deep sea microbial bioactive substances.     

具有活性的红树林真菌的多样性研究进展——优势菌为子囊菌和半知菌

红树林作为一种特殊的植物群落具有丰富的真菌资源,红树林真菌是具有特殊结构的生物活性物质的重要来源,相关研究近来倍受关注。本文列举出近年来产生次级代谢产物的具有活性的红树林真菌,分析后发现,具有活性的红树林真菌主要以子囊菌和半知菌为优势菌,这与绝大多数具有活性的海洋真菌主要以子囊菌亚门和半知菌亚门为多数的分布情况是一致的。     

Advances in Marine Microbial Symbionts in the China Sea and Related Pharmaceutical Metabolites

Marine animals and plants such as sponges, sea squirts, corals, worms and algae host diverse and abundant symbiotic microorganisms. Marine microbial symbionts are possible the true producers or take part in the biosynthesis of some bioactive marine natural products isolated from the marine organism hosts. Investigation of the pharmaceutical metabolites may reveal the biosynthesis mechanisms of related natural products and solve the current problem of supply limitation in marine drug development. This paper reviews the advances in diversity revelation, biological activity and related pharmaceutical metabolites, and functional genes of marine microbial symbionts from the China Sea.     

Secondary Metabolites from Marine Sponges of the Genus Oceanapia: Chemistry and Biological Activities

In this review, we summarized the distribution of the chemically investigated Oceanapia sponges, including the isolation and biological activities of their secondary metabolites, covering the literature from the first report in 1989 to July 2019. There have been 110 compounds reported during this period, including 59 alkaloids, 33 lipids, 14 sterols and 4 miscellaneous compounds. Besides their unique structures, they exhibited promising bioactivities ranging from insecticidal to antibacterial. Their complex structural characteristics and diverse biological properties have attracted a great deal of attention from chemists and pharmaceuticals seeking to perform their applications in the treatment of disease.     

Eurothiocin A and B,Sulfur-Containing Benzofurans from a Soft Coral-Derived Fungus Eurotium rubrum SH-823

Two new sulfur-containing benzofuran derivatives, eurothiocin A and B (1 and 2), along with five known compounds, zinniol (3), butyrolactone I (4), aspernolide D (5), vermistatin (6), and methoxyvermistatin (7), were isolated from the cultures of Eurotium rubrum SH-823, a fungus obtained from a Sarcophyton sp. soft coral collected from the South China Sea. The new compounds (1 and 2) share a methyl thiolester moiety, which is quite rare among natural secondary metabolites. The structures of these metabolites were assigned on the basis of detailed spectroscopic analysis. The absolute configurations of 1 and 2 were determined by comparison of the experimental and calculated electronic circular dichroism (ECD) data. Compounds 1 and 2 exhibited more potent inhibitory effects against α-glucosidase activity than the clinical α-glucosidase inhibitor acarbose. Further mechanistic analysis showed that both of them exhibited competitive inhibition characteristics.     

Lobophorin C and D, new kijanimicin derivatives from a marine sponge-associated actinomycetal strain AZS17

Marine sponge Hymeniacidon sp. was collected from coastal waters of the East China Sea to isolate symbiotic microorganisms. The resulting sponge-associated actinomycete, Streptomyces carnosus strain AZS17, was cultivated in a 20 L volume of medium for production of bioactive secondary metabolites. Bioassay-guided isolation and purification by varied chromatographic methods yielded two new compounds of kijanimicin derivatives, AS7-2 and AS9-12. Their structures were elucidated by spectroscopy and comparison with literatures. Results showed these two compounds were structurally similar to the previously reported compounds lobophorin A and B, yet differed in specific bond forms, stereochemistry and optical activities. The two novel compounds were named lobophorin C and D. In vitro cytotoxicity investigation by MTT assay indicated their selective activities. Lobophorin C displayed potent cytotoxic activity against the human liver cancer cell line 7402, while lobophorin D showed significant inhibitory effect on human breast cancer cells MDA-MB 435.