Asterosaponins: Structures,Taxonomic Distribution,Biogenesis and Biological Activities

Asterosaponins are a class of steroid oligoglycosides isolated from starfish with characteristic structures and diverse biological activities. In this review, we have attempted to combine the most important data concerning asterosaponins and give a list of these secondary metabolites with their structural peculiarities. The purpose of this review is to provide a brief but as complete as possible principal information about their chemical structures, taxonomic distribution in the marine environment, distribution in different geographical areas and depths, some properties, biological activities, and functions. Some other rare steroid metabolites from starfish, closely related in structures and probably biogenesis to asterosaponins, are also discussed.     

Structures and Biological Activities of Diketopiperazines from Marine Organisms: A Review

Diketopiperazines are potential structures with extensive biological functions, which have attracted much attention of natural product researchers for a long time. These compounds possess a stable six-membered ring, which is an important pharmacophore. The marine organisms have especially been proven to be a wide source for discovering diketopiperazine derivatives. In recent years, more and more interesting bioactive diketopiperazines had been found from various marine habitats. This review article is focused on the new 2,5-diketopiperazines derived from marine organisms (sponges and microorganisms) reported from the secondary half-year of 2014 to the first half of the year of 2021. We will comment their chemical structures, biological activities and sources. The objective is to assess the merit of these compounds for further study in the field of drug discovery.     

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.     

Biological Activities of Ethanolic Extracts from Deep-Sea Antarctic Marine Sponges

We report on the screening of ethanolic extracts from 33 deep-sea Antarctic marine sponges for different biological activities. We monitored hemolysis, inhibition of acetylcholinesterase, cytotoxicity towards normal and transformed cells and growth inhibition of laboratory, commensal and clinically and ecologically relevant bacteria. The most prominent activities were associated with the extracts from sponges belonging to the genus Latrunculia, which show all of these activities. While most of these activities are associated to already known secondary metabolites, the extremely strong acetylcholinesterase inhibitory potential appears to be related to a compound unknown to date. Extracts from Tetilla leptoderma, Bathydorus cf. spinosus, Xestospongia sp., Rossella sp., Rossella cf. racovitzae and Halichondria osculum were hemolytic, with the last two also showing moderate cytotoxic potential. The antibacterial tests showed significantly greater activities of the extracts of these Antarctic sponges towards ecologically relevant bacteria from sea water and from Arctic ice. This indicates their ecological relevance for inhibition of bacterial microfouling.     

Biological Activities of Aqueous and Organic Extracts from Tropical Marine Sponges

We report on screening tests of 66 extracts obtained from 35 marine sponge species from the Caribbean Sea (Curaçao) and from eight species from the Great Barrier Reef (Lizard Island). Extracts were prepared in aqueous and organic solvents and were tested for hemolytic, hemagglutinating, antibacterial and anti-acetylcholinesterase (AChE) activities, as well as their ability to inhibit or activate cell protein phosphatase 1 (PP1). The most interesting activities were obtained from extracts of Ircinia felix, Pandaros acanthifolium, Topsentia ophiraphidites, Verongula rigida and Neofibularia nolitangere. Aqueous and organic extracts of I. felix and V. rigida showed strong antibacterial activity. Topsentia aqueous and some organic extracts were strongly hemolytic, as were all organic extracts from I. felix. The strongest hemolytic activity was observed in aqueous extracts from P. acanthifolium. Organic extracts of N. nolitangere and I. felix inhibited PP1. The aqueous extract from Myrmekioderma styx possessed the strongest hemagglutinating activity, whilst AChE inhibiting activity was found only in a few sponges and was generally weak, except in the methanolic extract of T. ophiraphidites.     

Overview on Biological Activities and Molecular Characteristics of Sulfated Polysaccharides from Marine Green Algae in Recent Years

Among the three main divisions of marine macroalgae (Chlorophyta, Phaeophyta and Rhodophyta), marine green algae are valuable sources of structurally diverse bioactive compounds and remain largely unexploited in nutraceutical and pharmaceutical areas. Recently, a great deal of interest has been developed to isolate novel sulfated polysaccharides (SPs) from marine green algae because of their numerous health beneficial effects. Green seaweeds are known to synthesize large quantities of SPs and are well established sources of these particularly interesting molecules such as ulvans from Ulva and Enteromorpha, sulfated rhamnans from Monostroma, sulfated arabinogalactans from Codium, sulfated galacotans from Caulerpa, and some special sulfated mannans from different species. These SPs exhibit many beneficial biological activities such as anticoagulant, antiviral, antioxidative, antitumor, immunomodulating, antihyperlipidemic and antihepatotoxic activities. Therefore, marine algae derived SPs have great potential for further development as healthy food and medical products. The present review focuses on SPs derived from marine green algae and presents an overview of the recent progress of determinations of their structural types and biological activities, especially their potential health benefits.     

Bacterial Exopolysaccharides from Extreme Marine Habitats: Production,Characterization and Biological Activities

Many marine bacteria produce exopolysaccharides (EPS) as a strategy for growth, adhering to solid surfaces, and to survive adverse conditions. There is growing interest in isolating new EPS producing bacteria from marine environments, particularly from extreme marine environments such as deep-sea hydrothermal vents characterized by high pressure and temperature and heavy metal presence. Marine EPS-producing microorganisms have been also isolated from several extreme niches such as the cold marine environments typically of Arctic and Antarctic sea ice, characterized by low temperature and low nutrient concentration, and the hypersaline marine environment found in a wide variety of aquatic and terrestrial ecosystems such as salt lakes and salterns. Most of their EPSs are heteropolysaccharides containing three or four different monosaccharides arranged in groups of 10 or less to form the repeating units. These polymers are often linear with an average molecular weight ranging from 1 × 10⁵ to 3 × 10⁵ Da. Some EPS are neutral macromolecules, but the majority of them are polyanionic for the presence of uronic acids or ketal-linked pyruvate or inorganic residues such as phosphate or sulfate. EPSs, forming a layer surrounding the cell, provide an effective protection against high or low temperature and salinity, or against possible predators. By examining their structure and chemical-physical characteristics it is possible to gain insight into their commercial application, and they are employed in several industries. Indeed EPSs produced by microorganisms from extreme habitats show biotechnological promise ranging from pharmaceutical industries, for their immunomodulatory and antiviral effects, bone regeneration and cicatrizing capacity, to food-processing industries for their peculiar gelling and thickening properties. Moreover, some EPSs are employed as biosurfactants and in detoxification mechanisms of petrochemical oil-polluted areas. The aim of this paper is to give an overview of current knowledge on EPSs produced by marine bacteria including symbiotic marine EPS-producing bacteria isolated from some marine annelid worms that live in extreme niches.     

Meroterpenes from Marine Invertebrates: Structures,Occurrence, and Ecological Implications

Meroterpenes are widely distributed among marine organisms; they are particularly abundant within brown algae, but other important sources include microorganisms and invertebrates. In the present review the structures and bioactivities of meroterpenes from marine invertebrates, mainly sponges and tunicates, are summarized. More than 300 molecules, often complex and with unique skeletons originating from intra- and inter-molecular cyclizations, and/or rearrangements, are illustrated. The reported syntheses are mentioned. The issue of a potential microbial link to their biosynthesis is also shortly outlined.     

HPLC-ESI-IT-MS/MS Analysis and Biological Activity of Triterpene Glycosides from the Colombian Marine Sponge Ectyoplasia ferox

The marine sponge Ectyoplasia ferox produces antipredatory and allelopathic triterpenoid glycosides as part of its chemical defense repertoire against predators, competitors, and fouling organisms. These molecules are responsible for the pharmacological potential found in the glycosides present in this species. In order to observe the glycochemical diversity present in E. ferox, a liquid chromatography coupled to a tandem mass spectrometry approach to analyse a complex polar fraction of this marine sponge was performed. This gave valuable information for about twenty-five compounds three of which have been previously reported and another three which were found to be composed of known aglycones. Furthermore, a group of four urabosides, sharing two uncommon substitutions with carboxyl groups at C-4 on the terpenoid core, were identified by a characteristic fragmentation pattern. The oxidized aglycones present in this group of saponins can promote instability, making the purification process difficult. Cytotoxicity, cell cycle modulation, a cell cloning efficiency assay, as well as its hemolytic activity were evaluated. The cytotoxic activity was about IC₅₀ 40 µg/mL on Jurkat and CHO-k₁ cell lines without exhibiting hemolysis. Discussion on this bioactivity suggests the scanning of other biological models would be worthwhile.     

Malabaricane and Isomalabaricane Triterpenoids,Including Their Glycoconjugated Forms

In this review, we discuss structural diversity, taxonomic distribution, biological activities, biogenesis, and synthesis of a rare group of terpenoids, the so-called malabaricane and isomalabaricane triterpenoids, as well as some compounds derived from them. Representatives of these groups were found in some higher and lower terrestrial plants, as well as in some fungi, and in a relatively small group of marine sponges. The skeletal systems of malabaricanes and isomalabaricanes are similar to each other, but differ principally in the stereochemistry of their tricyclic core fragments, consisting of two six-membered and one five-membered rings. Evolution of these triterpenoids provides variety of rearranged, oxidized, and glycoconjugated products. These natural compounds have attracted a lot of attention for their biosynthetic origin and biological activity, especially for their extremely high cytotoxicity against tumor cells as well as promising neuroprotective properties in nanomolar concentrations.     

Sphingolipids of Asteroidea and Holothuroidea: Structures and Biological Activities

Sphingolipids are complex lipids widespread in nature as structural components of biomembranes. Commonly, the sphingolipids of marine organisms differ from those of terrestrial animals and plants. The gangliosides are the most complex sphingolipids characteristic of vertebrates that have been found in only the Echinodermata (echinoderms) phylum of invertebrates. Sphingolipids of the representatives of the Asteroidea and Holothuroidea classes are the most studied among all echinoderms. In this review, we have summarized the data on sphingolipids of these two classes of marine invertebrates over the past two decades. Recently established structures, properties, and peculiarities of biogenesis of ceramides, cerebrosides, and gangliosides from starfishes and holothurians are discussed. The purpose of this review is to provide the most complete information on the chemical structures, structural features, and biological activities of sphingolipids of the Asteroidea and Holothuroidea classes.     

Sulfur-Containing Metabolites from Marine and Terrestrial Fungal Sources: Origin,Structures, and Bioactivities

Organosulfur natural products (NPs) refer to the different kinds of small molecular-containing sulfur (S) elements. Sulfur-containing NPs tightly link to the biochemical processes and play an important role in the pharmaceutical industry. The majority of S-containing NPs are generally isolated from Alliaceae plants or bacteria, and those from fungi are still relatively rare. In recent years, an increasing number of S-containing metabolites have been discovered in marine and terrestrial fungi, but there is no comprehensive and targeted review to summarize the studies. In order to make it more straightforward to better grasp the fungal-derived S-containing NPs and understand the particularity of marine S-containing NPs compared to those from terrestrial fungi, we summarized the chemical structures and biological activities of 89 new fungal-derived S-containing metabolites from 1929 when the penicillin was discovered to the present in this current review. The structural and bioactive diversity of these S-containing metabolites were concluded in detail, and the preliminary mechanism for C-S bond formation in fungi was also discussed briefly.     

Volatile Organic Compounds,Indole, and Biogenic Amines Assessment in Two Mediterranean Irciniidae (Porifera,Demospongiae)

Solid phase microextraction (SPME) coupled to gas chromatography-mass spectrometry (GC-MS) was employed for the headspace determination of the volatile organic fraction emitted by two of the most common Mediterranean demosponges, Ircinia variabilis and Sarcotragus spinosulus, and of indole and some biogenic amines released by sponges in an aqueous medium. A total of 50/30 µm divinylbenzene/carboxen/polydimethylsiloxane and 75 µm carboxen/polydimethylsiloxane fibers were used for the headspace extraction of low molecular weight sulfur compounds from a hermetically sealed vial containing sponge fragments, while the direct immersion determination of indole and biogenic amines was performed. The biogenic amines were extracted after in-solution derivatization with isobutyl chloroformate. All analytical parameters (linearity, limits of detection, and quantification, precision, and recovery) were evaluated for indole and biogenic amines. SPME-GC-MS proved to be a reliable means of highlighting the differences between molecules released by different sponges, principally responsible for their smell. The combined approaches allowed the identification of several volatile compounds in the headspace and other molecules released by the sponges in an aqueous medium, including indole and the BAs cadaverine, histamine, isobutylamine, isopentylamine, propylamine, 2-phenylethylamine, putrescine and tryptamine. The results obtained represent a further contribution to the picture of odoriferous molecules secreted by sponges.     

Kurilosides A1, A2, C1, D,E and F—Triterpene Glycosides from the Far Eastern Sea Cucumber Thyonidium (= Duasmodactyla) kurilensis (Levin): Structures with Unusual Non-Holostane Aglycones and Cytotoxicities

Six new monosulfated triterpene tetra-, penta- and hexaosides, namely, the kurilosides A₁ (1), A₂ (2), C₁ (3), D (4), E (5) and F (6), as well as the known earlier kuriloside A (7), having unusual non-holostane aglycones without lactone, have been isolated from the sea cucumber Thyonidium (= Duasmodactyla) kurilensis (Levin) (Cucumariidae, Dendrochirotida), collected in the Sea of Okhotsk near Onekotan Island from a depth of 100 m. Structures of the glycosides were established by 2D NMR spectroscopy and HR-ESI mass spectrometry. Kurilosides of the groups A and E contain carbohydrate moieties with a rare architecture (a pentasaccharide branched by C(4) Xyl1), differing from each other in the second monosaccharide residue (quinovose or glucose, correspondingly); kurilosides of the group C are characterized by a unique tetrasaccharide branched by a C(4) Xyl1 sugar chain; and kurilosides of the groups D and F are hexaosides differing from each other in the presence of an O-methyl group in the fourth (terminal) sugar unit. All these glycosides contain a sulfate group at C-6 of the glucose residue attached to C-4 Xyl1 and the non-holostane aglycones have a 9(11) double bond and lack γ-lactone. The cytotoxic activities of compounds 1–7 against mouse neuroblastoma Neuro 2a, normal epithelial JB-6 cells and erythrocytes were studied. Kuriloside A₁ (1) was the most active compound in the series, demonstrating strong cytotoxicity against the erythrocytes and JB-6 cells and a moderate effect against Neuro 2a cells.     

Triterpene Glycosides from the Far Eastern Sea Cucumber Psolus chitonoides: Chemical Structures and Cytotoxicities of Chitonoidosides E1, F,G, and H

Four new triterpene disulfated glycosides, chitonoidosides E₁ (1), F (2), G (3), and H (4), were isolated from the Far-Eastern sea cucumber Psolus chitonoides and collected near Bering Island (Commander Islands) at depths of 100–150 m. Among them there are two hexaosides (1 and 3), differing from each other by the terminal (sixth) sugar residue, one pentaoside (4) and one tetraoside (2), characterized by a glycoside architecture of oligosaccharide chains with shortened bottom semi-chains, which is uncommon for sea cucumbers. Some additional distinctive structural features inherent in 1–4 were also found: the aglycone of a recently discovered new type, with 18(20)-ether bond and lacking a lactone in chitonoidoside G (3), glycoside 3-O-methylxylose residue in chitonoidoside E₁ (1), which is rarely detected in sea cucumbers, and sulfated by uncommon position 4 terminal 3-O-methylglucose in chitonoidosides F (2) and H (4). The hemolytic activities of compounds 1–4 and chitonoidoside E against human erythrocytes and their cytotoxic action against the human cancer cell lines, adenocarcinoma HeLa, colorectal adenocarcinoma DLD-1, and monocytes THP-1, were studied. The glycoside with hexasaccharide chains (1, 3 and chitonoidoside E) were the most active against erythrocytes. A similar tendency was observed for the cytotoxicity against adenocarcinoma HeLa cells, but the demonstrated effects were moderate. The monocyte THP-1 cell line and erythrocytes were comparably sensitive to the action of the glycosides, but the activity of chitonoidosides E and E₁ (1) significantly differed from that of 3 in relation to THP-1 cells. A tetraoside with a shortened bottom semi-chain, chitonoidoside F (2), displayed the weakest membranolytic effect in the series.     

Triterpene Glycosides from the Far Eastern Sea Cucumber Thyonidium (=Duasmodactyla) kurilensis (Levin): The Structures,Cytotoxicities, and Biogenesis of Kurilosides A3, D1, G,H, I,I1, J,K, and K1

Nine new mono-, di-, and trisulfated triterpene penta- and hexaosides, kurilosides A₃ (1), D₁ (2), G (3), H (4), I (5), I₁ (6), J (7), K (8), and K₁ (9) and two desulfated derivatives, DS-kuriloside L (10), having a trisaccharide branched chain, and DS-kuriloside M (11), having hexa-nor-lanostane aglycone with a 7(8)-double bond, have been isolated from the Far-Eastern deep-water sea cucumber Thyonidium (=Duasmodactyla) kurilensis (Levin) and their structures were elucidated based on 2D NMR spectroscopy and HR-ESI mass-spectrometry. Five earlier unknown carbohydrate chains and two aglycones (having a 16β,(20S)-dihydroxy-fragment and a 16β-acetoxy,(20S)-hydroxy fragment) were found in these glycosides. All the glycosides 1–9 have a sulfate group at C-6 Glc, attached to C-4 Xyl1, while the positions of the other sulfate groups vary in different groups of kurilosides. The analysis of the structural features of the aglycones and the carbohydrate chains of all the glycosides of T. kurilensis showed their biogenetic relationships. Cytotoxic activities of the compounds 1–9 against mouse neuroblastoma Neuro 2a, normal epithelial JB-6 cells, and erythrocytes were studied. The highest cytotoxicity in the series was demonstrated by trisulfated hexaoside kuriloside H (4), having acetoxy-groups at C(16) and C(20), the latter one obviously compensated the absence of a side chain, essential for the membranolytic action of the glycosides. Kuriloside I₁ (6), differing from 4 in the lacking of a terminal glucose residue in the bottom semi-chain, was slightly less active. The compounds 1–3, 5, and 8 did not demonstrate cytotoxic activity due to the presence of hydroxyl groups in their aglycones.     

High-value components and bioactives from sea cucumbers for functional foods--a review

Sea cucumbers, belonging to the class Holothuroidea, are marine invertebrates, habitually found in the benthic areas and deep seas across the world. They have high commercial value coupled with increasing global production and trade. Sea cucumbers, informally named as bêche-de-mer, or gamat, have long been used for food and folk medicine in the communities of Asia and Middle East. Nutritionally, sea cucumbers have an impressive profile of valuable nutrients such as Vitamin A, Vitamin B1 (thiamine), Vitamin B2 (riboflavin), Vitamin B3 (niacin), and minerals, especially calcium, magnesium, iron and zinc. A number of unique biological and pharmacological activities including anti-angiogenic, anticancer, anticoagulant, anti-hypertension, anti-inflammatory, antimicrobial, antioxidant, antithrombotic, antitumor and wound healing have been ascribed to various species of sea cucumbers. Therapeutic properties and medicinal benefits of sea cucumbers can be linked to the presence of a wide array of bioactives especially triterpene glycosides (saponins), chondroitin sulfates, glycosaminoglycan (GAGs), sulfated polysaccharides, sterols (glycosides and sulfates), phenolics, cerberosides, lectins, peptides, glycoprotein, glycosphingolipids and essential fatty acids. This review is mainly designed to cover the high-value components and bioactives as well as the multiple biological and therapeutic properties of sea cucumbers with regard to exploring their potential uses for functional foods and nutraceuticals.     

Unusual Structures and Cytotoxicities of Chitonoidosides A,A1, B,C, D,and E,Six Triterpene Glycosides from the Far Eastern Sea Cucumber Psolus chitonoides

Six new triterpene tetra-, penta- and hexaosides, chitonoidosides A (1), A₁ (2), B (3), C (4), D (5), and E (6), containing one or two sulfate groups, have been isolated from the Far-Eastern sea cucumber Psolus chitonoides, collected near Bering Island (Commander Islands) from the depth of 100–150 m. Three of the isolated compounds (1, 3 and 6) are characterized by the unusual aglycone of new type having 18(20)-ether bond and lacking a lactone in contrast with wide spread holostane derivatives. Another unexpected finding is 3-O-methylxylose residue as a terminal unit in the carbohydrate chains of chitonoidosides B (3), C (4), and E (6), which has never been found before in the glycosides from holothurians belonging to the Psolidae family. Moreover, this monosaccharide is sulfated in the compound 4 into unprecedented 3-O-methylxylose 4-O-sulfate residue. Chitonoidoside C (4) is characterized by tetrasaccharide moiety lacking a part of the bottom semi-chain, but having disaccharide fragment attached to C-4 of Xyl1. Such architecture is not common in sea cucumber glycosides. Cytotoxic activities of the compounds 1–5 against mouse and human erythrocytes and human cancer cell lines: adenocarcinoma HeLa, colorectal adenocarcinoma DLD-1, and leukemia promyeloblast HL-60 cells were studied. The cytotoxic effect of chitonoidoside d (5) was the most significant in this series due to the presence of pentasaccharide disulfated sugar chain in combination with holostane aglycone. Surprisingly, the glycosides 1 and 3, comprising the new aglycone without γ-lactone, demonstrated similar activity to the known compounds with holostane aglycones. Chitonoidoside C (4) was less cytotoxic due to the different architecture of the carbohydrate chain compared to the other glycosides and probably due to the presence of a sulfate group at C-4 in 3-O-MeXyl4.     

Four New Sulfated Polar Steroids from the Far Eastern Starfish Leptasterias ochotensis: Structures and Activities

Three new sulfated steroid monoglycosides, leptaochotensosides A–C (1–3), and a new sulfated polyhydroxylated steroid (4) were isolated from the alcoholic extract of the Far Eastern starfish Leptasterias ochotensis. The structures of compounds 1–4 were established by extensive nuclear magnetic resonance (NMR) and electrospray ionization mass spectrometry (ESIMS) analyses and chemical transformations. Although the isolated compounds did not show any apparent cytotoxicity against melanoma RPMI-7951 and breast cancer T-47D cell lines, leptaochotensoside A (1) demonstrated inhibition of T-47D cell colony formation in a soft agar clonogenic assay at nontoxic doses. In addition, this compound decreased the epidermal growth factor (EGF)-induced colony formation of mouse epidermal JB6 Cl41 cells. The cancer preventive action of 1 is realized through regulation of mitogen-activated protein kinase (MAPK) signaling pathway.