In recent decades, marine organisms focused the attention of researchers for their huge potential in producing bioactive compounds [1,2,3,4]. Among them, the microorganisms gradually took on an important role because they appear to be prolific producers of a wide diversity of secondary metabolites [5,6]. Cultivated in bioreactors, they also represent a sustainable and easily “upscalable” resource, therefore not endangering fragile marine ecosystems. Among these microorganisms, fungi, which had their terrestrial glory days after the discovery of penicillin, are again at the forefront in the search for new marine molecules in view of their rich biodiversity, even in deep-sea niches . Around 70,000 fungal species have already been described worldwide, and among them about 1500 species of marine-derived fungi were mentioned, primarily from coastal ecosystems [8,9]. As 70% of the earth is submerged, Gareth Jones (1998)  estimated the total number of marine and marine-derived fungal species to be a minimum of 72,000, indicating that the inherent discovery of new compounds is still in its infancy. Several fungal metabolites from marine origin have already demonstrated their originality and efficacy in different domains. As an example, in the field of therapeuthics, we can mention the two chemically unusual cyclodepsipeptides patented in 2008—scopularides A and B—from the marine-derived Scopulariopsis brevicaulis, demonstrating anticancer activities [11,12], as well as the halimide (plinabuline) from an endophytic Aspergillus sp. CNC-139 isolated from the green algae Halimeda lacrymosa, already achieving phase II clinical tests .
Biosynthetically, many extrolites produced by filamentous fungi are polyketides, and several papers report that polyketides seem to dominate marine natural products of fungal origin [14,15]. Polyketides represent an array of often structurally complex natural products including such classes as anthraquinones, hydroxyanthraquinones, naphthalenes, naphthoquinones, flavonoids, macrolides, polyenes, tetracyclines, and tropolones. Many of them have already exhibited either positive or negative effects, as wide as those that are antimicrobial, anticancer, antioxidant, immunomodulatory, cytotoxic, or carcinogenic. This closely concerns the class of anthraquinones whose effects, depending on the nature and amount of compound, can either be beneficial or noxious towards living organisms. These compounds, little studied because of their bad reputation, mainly arising from their benzenic patterns, are, however, worthy of the same attention as other families of fungal compounds, whose members have become pillars of the global pharmacopeia (antibiotics) and are widely used in food or staining industries (azaphilone colorants from Monascus spp. in Asia). Within this review, we investigate the present knowledge of the anthraquinonoid compounds listed to date from marine-derived filamentous fungi′s productions. This overview highlights the molecules identified for the first time and comes along with interesting characteristics: the panel of colors, their known roles in the biology of the organisms, and some specific in vitro biological activities. As the natural products constitute the dynamic element of the present global market, we hope this review can help broadening the horizon towards innovative substances.
2. Anthraquinones from Marine-Derived Fungi
About 700 anthraquinone derivatives were identified in plants, lichens, and fungi; 43 have already been described from fungal cultures [16,17]. Due to their structure, they exhibit interesting chromatic properties and decline a wide range of nuances in colors. Thus, they first presented a great interest in the field of dyeing molecules, highly requested in cosmetics, clothes dyeing and foodstuff industries. From their structures, hydroxyanthraquinone pigments have a relative stability. They also possess good light-fastness properties, which often makes metallization unnecessary. Nevertheless, they can easily form complexes with several metal salts (or cations in general) (aluminium, barium, calcium, copper, palladium, iron) [18,19,20,21,22] and exhibit superior brightness compared to azo-pigments [23,24]. This capacity to form metallic complexes is of a great interest in an industrial context: The complex forms often reduce the solublity in water, enhancing the solvent solubility, without loosing the brightness . In the textile industry, hydroxyanthraquinone are, moreover, considered “reactive dyes,” as they form a covalent bond with the fibers, usually cotton, although they are used to a small extent on wool and nylon. Therefore, they have it it possible to achieve extremely high wash fastness properties by relatively simple dyeing methods. Thereby, the literature abundantly reports the interest for marine organisms with respect to the production of new molecules and, among them, new pigments [25,26]. Besides their coloring properties, anthraquinoid compounds exhibit a wide range of diverse biological activities, sparsely mentioned in the literature. Regarding this aspect, their “Dr Jekyll and Mr Hyde” physiognomy  needs to be carefully elucidated in order to examine their potential use in pharmaceutical or alimentary fields, with maximum objectivity.
2.1. Anthraquinone′s Basic Structure
Anthraquinones represent a class of molecules of the quinone family, based on a structure composed of three benzene rings. The basic structure 9,10-anthracenedione, also called 9,10-dioxoanthracene (formula C14H8O2), includes two ketone groups on the central ring (Figure 1). The diversity of the anthraquinoid compounds relies on the nature and the position of the substituents, replacing the H atoms on the basic structure (R1 to R8), as diverse as: –OH, –CH3, –OCH3, –CH2OH, –CHO, –COOH, or more complex groups. When n hydrogen atoms are replaced by hydroxyl groups, the molecule is called hydroxyanthraquinone (HAQN). From their structure, HAQN derivatives absorb visible light and are colored.
An important characteristic of the anthraquinone compound is their electronic absorption spectra. The strong absorption in the ultraviolet region is due to the presence of chromophore formed by the system of conjugated double bonds. The spectra of anthraquinone are highly complex because of the presence of absorption bands due to the benzenoid transitions, in addition to quinonoid absorptions. The benzenoid bands appear fairly regularly within the range 240–260, with intense absorption at 250 nm and in 320–330 nm, and with medium absorption at 322 nm, whereas the quinonoid bands absorb at 260–290 nm. These areas of selective absorption are characteristic, and the pattern in the ultraviolet region is not seriously affected by substitution. In addition, hydroxyl anthraquinones show an absorption band(s) at 220–240 nm, not shown by the parent compound. In the visible area, an unsubstituted anthraquinone has a weak yellow color, and its electronic absorption spectrum contains a small peak at 405 nm. The presence of substituents in position 1 and 4 induces a significant bathochromic shift, intensifying the color more significantly than the substituents in the 1,5 and 1,8 positions. Thus, with an alcoholic solution of magnesium acetate, 1,2-dioxyderivative is colored in violet; 1,4-dioxyderivative in purple; and 1,8-dioxyderivative in red-orange [28,29,30]. Therefore, fungal anthraquinones range from pale yellow to dark red or brown colors, through to violet.
2.2. Ecology of Marine-Derived Fungal Anthraquinones Producers
obligate marine fungi (true ones) that grow and sporulate only in seawater. Their spores are able to germinate and form new thalli in salted environment.
transitional marine fungi (marine-derived fungi) that come from terrestrial or freshwater media and have undergone physiological adaptation to survive, grow, or reproduce in the marine environment.
In fungi, anthraquinones are produced from different steps or branches of the polyketides pathway. Today, it is clear that, as far as secondary metabolites and a priori anthraquinoid productions are concerned, a great variability appears among species of the same genus, even among strains in the same species. This could undoubtly be related to the capacities a fungus has to develop, in order to face some specific conditions in specific ecosystems. As an illustration, the composition of the quinoid pigment complexes of P. funiculosum strains isolated from various types of soils are quite different when cultivated in the same artificial culture media . That is why, even if the polyketides pathway is mentioned in a strain, not all strains inside the species are anthraquinones producers. In the same way, if the fungal metabolism is able to express anthtraquinones and (simultaneously) to excrete toxins, the presence of these secondary products are highly dependent on external physico-chemical conditions .
Thus, a high diversity of molecules is now expected from unexplored marine-derived fungi, which are considered promising novel sources of chemical diversity. The potential of marine-derived microorganisms to produce unique and original molecules could therefore come from specific metabolic or genetic adaptations appearing to meet very specific combinations of physico-chemical parameters (high osmotic pressure, low O2 penetration, low temperature, limited light access, high pressure, or regular tidal ebbs and flows) . Indeed, the two marine ecotypes lead to particular behaviors and consecutively to specific products, compared to the terrestrial congeners: either the challenge of facing unusual living conditions (exogenous fungi) or the use of specific procedures naturally adapted to the marine niches (i.e., indigenous micromycetes, naturally selected for aquatic environments). This skill is, for instance, exemplified by marine macroorganisms′ fungal endophytes as corals or sponges. For now, the highest diversity of marine-derived fungi seems to be found in tropical regions, mainly in tropical mangroves, which are extensively studied because of their high richness in organic matters. Obviously, these biotopes seem favorable to the development of a high diversity of heterotrophic microorganisms based on the diversity of organic and inorganic substrates [8,38].
The questions on the effect of interactions between organisms on microbes extrolites is amply fueled in the case of a very producive lichen′s symbioses. A lichen is a composite organism that emerges from algae or cyanobacteria (or both) living with filaments of a fungus in a mutually beneficial (symbiotic) relationship. About 20,000 lichen species are known in the world, and there are approximately 700 species known from coastal rocks and urbanized shores . Most work on aquatic lichens was done in temperate areas, as, in the tropics, lichens are less developed on costal rocks. One interesting skill is that lichen associations are primarily terrestrial but require alternate wetting and drying regimes for their survival. In marine environments, these circumstances occur principally in tidal zones on coastal rocks, subject to varying water levels and different degrees of inundation. Another feature is that the whole combined life form has properties that are very different from properties of its component organisms alone. Thus, tropical stream margins are promising biota for species and therefore compounds that are new to science.
2.3. Structural Diversity and Colors of Anthraquinoid Extrolites from Marine-Derived Fungi
2.3.1. Present Knowledge about Anthraquinonoid Compounds from Fungi
Today′s knowledge indicates that a large part of compounds identified in terrestrial fungi can often be isolated from the same species living in marine environments. For instance, catenarin, emodin, erythroglaucin, physcion, questin, and rubrocristin or physcion anthrone are produced by marine-derived Aspergillus and/or Eurotium species, as well as by their terrestrial counterparts. According to Bick et al. and Fain et al. [40,41], the most widespread anthraquinones in fungi are 1,8-dihydroxy and 1,5,8 or 1,6,8-trihydroxy anthraquinone derivatives. They appear either as simple forms, as glycosides, or other complexes attached through an O- or C-bond in the side chain, which can enhance the water solubility. Some dimeric structures (formed through C–C bonds) are also produced from fungi, (e.g., alterporriols, skyrin, rubroskyrin, luteoskyrin, icterinoidin, rubellin, rufoolivacin, etc.). Some dimers may contain not only monomeric anthraquinones but also naphthoquinones and other products of polyketide synthesis. According to Fujitake et al. [42,43] and Suzuki et al. , the dimeric anthraquinone 5,5′-biphyscion (named hinakurin), chrysotalunin, (−)-7,7′-biphyscion, microcarpin, chrysophanol, and physcion are predominant in soil, but they seem rare in organisms. If hinakurin, chrysotalunin, and (−)-7,7′-biphyscion have not been found in fungi yet, it is now clear that chrysophanol and physcion are frequent fungal productions, and that fungi are able to synthesize dimers. These organisms, widely represented in soil, may have a transient appearance of monomeric and dimeric anthraquinones in telluric biotopes, certainly evolving to complex (humic) polymers. However, these statements rely on decades of terrestrial studies. The increase in knowledge on marine and marine-derived anthraquinones from fungi will certainly elucidate this aspect.
2.3.2. Nature and Colors of Compounds from Marine-Derived Fungi
Most anthraquinoid compounds of natural origin have complex structures with several functional substituent groups. In nature and/or cultures, a wide range of hues appears, from pale yellow to dark brown, through to orange, red, or violet pigmentations. Anthraquinoid compounds generaly color sexual stages or resistance forms (ascomata, spores, conidia, etc.) but sometimes also impregnate mycelium or are excreted in the growth environment. Thus, the structural localization and the colors of these secondary metabolites seem to highly depend on the fungal species and may vary with the amount of compound produced in relation with the environmental conditions.
Genera and Species
Many genera producing anthraquinones have been isolated from marine environments, either from water, sediments, or decaying plants or from living organisms such as invertebrates, plants (endophytes), and algae. To date, strains in the genera—Alternaria, Aspergillus, Eurotium, Fusarium, Halorosellinia, Microsphaeropsis, Monodictys, Nigrospora, Paecilomyces, Penicillium, Phomopsis, and Stemphylium—have been clearly mentioned as marine-derived anthraquinones producers.
Some of the common terrestrial genera—Aspergillus, Eurotium, Alternaria, Penicillium and Fusarium—have been extensively investigated concerning their secondary metabolite′s productions, and the anthraquinoid molecules produced were reviewed by Velmurugan et al. , Caro et al. , and Gessler et al. [17
2.1. Marine Animals
Two new 4-hydroxy-2-pyridone alkaloids, arthpyrones (1–2), were isolated from the fungus Arthrinium arundinis ZSDS1-F3, which obtained from sponge (Xisha Islands, China). Compounds 1 and 2 had significant in vitro cytotoxicities against the K562, A549, Huh-7, H1975, MCF-7, U937, BGC823, HL60, Hela and MOLT-4 cell lines, with IC50 values ranging from 0.24 to 45 μM. Furthermore, compound 2 displayed significant AchE inhibitory activity (IC50 = 0.81 μM), whereas compound 1 showed modest activity (IC50 = 47 μM) (Figure 1) .
Chemical examination of the solid culture of the endophytic fungus Stachybotrys chartarum isolated from the sponge Niphates recondita (Weizhou Island in Beibuwan Bay, Guangxi Province of China) resulted in the isolation of seven new phenylspirodrimanes, named chartarlactams (3–9). Compounds 3–9 exhibited potent lipid-lowering effects in HepG2 cells in a dose of 10 μM (Figure 2) .
The extract of a strain of Aspergillus versicolor MF359 (from the sponge of Hymeniacidon perleve, Bohai Sea, China) yielded one new secondary metabolites, named 5-methoxydihydrosterigmatocystin (10). Compound 10 showed potent activity against Staphylococcus aureus (S. aureus) and Bacillus subtilis (B. subtillis) with MIC values of 12.5 and 3.125 μg/mL, respectively (Figure 3) .
The fungus Diaporthaceae sp. PSU-SP2/4 from marine sponge (Trang city, Thailand) generated a new pentacyclic cytochalasin (diaporthalasin, 11). Compound 11 displayed potent antibacterial activity against both S. aureus and methicillin-resistant S. aureus (MRSA) with equal MIC values of 2 μg/mL (Figure 3) .
A new chevalone derivative, named chevalone E (12), was isolated from the ethyl acetate extract of the undescribed marine sponge-associated fungus Aspergillus similanensis KUFA 0013, which was collected from the Similan Islands, Phang Nga Province, Southern Thailand. Compound 12 was found to show synergism with the antibiotic oxacillin against methicillin-resistant S. aureus (Figure 3) .
Xylarianaphthol-1 (13), a new dinaphthofuran derivative, was isolated from an Indonesian marine sponge-derived fungus of order Xylariales on the guidance of a bioassay using the transfected human osteosarcoma MG63 cells (MG63luc+). Compound 13 activated p21 promoter stably transfected in MG63 cells with dose-dependent pattern. Expression of p21 protein in the wild-type MG63 cells was also promoted by xylarianaphthol-1 treatment, indicating compound 13 was expected to contribute to cancer prevention or treatment (Figure 3) .
A new polyketide with a new carbon skeleton, lindgomycin (14), was extracted from mycelia and culture broth of different Lindgomycetaceae strains, which were isolated from a sponge of the Kiel Fjord in the Baltic Sea (Germany) and from the Antarctic. Compound 14 showed antibiotic activities with IC50 value of 5.1 (±0.2) μM against MRSA (Figure 3) .
The fungus Aspergillus terreus SCSGAF0162 was isolated from gorgonian corals Echinogorgia aurantiaca (the South China Sea). Three lactones including three territrem derivatives (15–17) and a butyrolactone derivative (18) were isolated from the fungus under solid-state fermentation of rice. Among them, compounds 15 and 16 showed strong inhibitory activity against acetylcholinesterase with IC50 values of 4.2 ± 0.6 and 4.5 ± 0.6 μM, respectively. This was the first report that compounds 17 and 18 had evident antiviral activity towards HSV-1, with IC50 values of 16.4 ± 0.6 and 21.8 ± 0.8 μg·mL–1, respectively. Moreover, compound 15 had obvious antifouling activity with EC50 values of 12.9 ± 0.5 μg·mL–1 toward barnacle Balanus amphitrite larvae (Figure 4) .
Two new dihydrothiophene-condensed chromones, oxalicumones (19–20) were isolated from a culture broth of the marine gorgonian-associated fungus Penicillium oxalicum SCSGAF 0023. Compounds 19 and 20 showed significant cytotoxicity against several carcinoma cell lines with IC50 less than 10 μM (Figure 5) .
The fungal strain Nigrospora oryzae SCSGAF 0111 (from marine gorgonian Verrucella umbraculum, South China Sea) yielded two new citrinins, nigrospins B and C (21–22). Compounds 21–22 showed weak antifungal activity against Aspergillus versicolor with inhibition zone of 8 cm at 50 μg/paper disc, with a positive control thiram of 8 cm at 5 μg/paper disc (Figure 6) .
Two nucleoside derivatives (23–24) were isolated from the fungus Aspergillusversicolor which was derived from the gorgonian Dichotella gemmacea in the South China Sea. Compounds 23/24 (a mixture of compound 23:compound 24 at a ratio of 7:10) exhibited selective antibacterial activity against Staphylococcus epidermidis with an MIC value of 12.5 μM (Figure 6) .
Two new sulfur-containing benzofuran derivatives, eurothiocin A and B (25 and 26) were isolated from the fungus Eurotium rubrum SH-823 which was obtained from a Sarcophyton sp. soft coral in the South China Sea. The compounds (25 and 26) shared a methyl thiolester moiety, which was quite rare in natural secondary metabolites. Both of them exhibited more potent inhibitory effects against α-glucosidase activity than acarbose, which was the clinical α-glucosidase inhibitor. Further mechanistic analysis demonstrated that both of them exhibited competitive inhibition characteristics (Figure 7) .
Chondrostereum sp. was isolated from the inner tissue of a soft coral Sarcophyton tortuosum, which was collected from the Hainan Sanya National Coral Reef Reserve, China. When this fungus was cultured in a liquid medium containing glycerol as the carbon source, a new metabolite, chondrosterin 27 was obtained. Compound 27 exhibited potent cytotoxic activities against the cancer cell lines CNE-1 and CNE-2 with the IC50 values of 1.32 and 0.56 μM (Figure 7) .
A steroid derivative, compound 28 was isolated from the fermentation broth of a gorgonian-derived Aspergillus sp. fungus. The fungus was isolated from the inner part of the fresh gorgonian M. abnormalis, which was collected from the Xisha Islands coral reef of the South China Sea. Compound 28 inhibited the larval settlement of barnacle Balanus amphitrite with EC50 18.40 ± 2.0 μg/mL (Figure 7) .
A new diphenyl ether derivative, talaromycin A (29) was isolated from a gorgonian-derived fungus, Talaromyces sp. The fungal strain was isolated from a piece of fresh tissue from the inner part of the gorgonian Subergorgia suberosa, collected from the Weizhou coral reef in the South China Sea. Compound 29 showed potent antifouling activities against the larval settlement of the barnacle Balanus amphitrite with the EC50 value 2.8 ± 0.2 μg/mL (Figure 7) .
Liang et al.  investigated the influence on secondary metabolites with variety of cultivation parameters of marine fungus, Neosartorya pseudofischeri, which was isolated from the inner tissue of starfish Acanthaster planci. Glycerol-peptone-yeast extract (GlyPY) and glucose-peptone-yeast extract (GluPY) media were applied to culture this fungus. A novel gliotoxin (30) was produced with GluPY medium. Compound 30 displayed significant inhibitory activities against three multidrug-resistant bacteria, S. aureus (ATCC29213), MRSA (R3708) and Escherichia coli (E. coli) (ATCC25922), as well as cytotoxicities against some cell lines including human embryonic kidney (HEK) 293 cell line and human colon cancer cell lines, HCT-116 and RKO (a poorly differentiated colon carcinoma cell line) (Figure 8).
A novel isobenzofuranone derivative, pseudaboydins A (31) was isolated from the marine fungus, Pseudallescheria boydii, associated with the starfish, Acanthaster planci. Compound 31 showed moderate cytotoxic activity against HONE1, SUNE1 and GLC82 with IC50 values of 37.1, 46.5 and 87.2 μM, respectively (Figure 8) .
Three new cyclohexadepsipeptides of the isaridin class including isaridin G (32), desmethylisaridin G (33), and desmethylisaridin C1 (34) were isolated and identified from the marine bryozoan-derived fungus Beauveria felina EN-135. Compounds 32–34 showed inhibitory activity against E.coli with MIC values of 64, 64, and 8 μg/mL, repectively. This is the first report on antibacterial activities of the isaridins (Figure 9) .
Bioassay-guided fractionation of a culture extract of Beauveria felina EN-135, an entomopathogenic fungus isolated from an unidentified marine bryozoan, led to the isolation of a new cyclodepsipeptide, iso-isariin D (35); two new O-containing heterocyclic compounds felinones A and B (36 and 37). Compound 35 exhibited potent lethality against brine shrimp (Artemia salina), with LD50 values of 26.58 μΜ, notably stronger than that of the positive control colchicine, while compounds 36 and 37 possessed weak activity. Only compound 37 showed inhibitory activity (MIC value of 32 μg/mL) higher than that of the chloramphenicol control (MIC value of 4 μg/mL) against Pseudomonas aeruginosa (Figure 9) .
2.1.5. Sea Urchin
The Penicillium sp. SF-6013 was isolated from the sea urchin Brisaster latifrons, which was collected from the Sea of Okhotsk. Chemical investigation of strain SF-6013 resulted in the discovery of a new tanzawaic acid derivative, 2E,4Z-tanzawaic acid D (38). Screening for anti-inflammatory effects in lipopolysaccharide (LPS)-activated microglial BV-2 cells indicated that compound 38 inhibited the production of nitric oxide (NO) with IC50 values of 37.8 μM (Figure 10) .
Two new rubrolides, rubrolides R (39) and S (40), were isolated from the fermentation broth of the marine-derived fungus Aspergillus terreus OUCMDZ-1925, which was isolated from the viscera of C. haematocheilus grown in the waters of the Yellow River Delta. Compound 39 showed comparable or superior antioxidation against ABTS radicals to those of trolox and ascorbic acid with an IC50 value of 1.33 μM. Compound 40 showed comparable or superior anti-influenza A (H1N1) virus activity to that of ribavirin with an IC50 value of 87.1 μM. Compounds 39 and 40 showed weak cytotoxicity against the K562 cell line with IC50 values of 12.8 and 10.9 μM, respectively, while were inactive against the A549, HL-60, Hela and HCT-116 cell lines (Figure 10) .
The fungal strain, Aspergillus flavus OUCMDZ-2205, was obtained from the prawn, Penaeus vannamei, from the Lianyungang sea area, Jiangsu Province of China. Two new indole-diterpenoids (41 and 42) were isolated from the fermentation broth of the fungus. Compound 41 exhibited antibacterial activity against S. aureus with a MIC value of 20.5 μM and showed PKC-beta inhibition with an IC50 value of 15.6 μM. Both 41 and 42 could arrest the A549 cell cycle in the S phase at a concentration of 10 μM (Figure 11) .
The marine-derived fungus Eurotium amstelodami was isolated from an unidentified marine animal collected from the Sungsan coast in Jeju Island, Korea. An anthraquinone derivative, questinol (43) was successfully isolated from the broth extract of the fungus for the first time. Questinol (43) did not exhibit cytotoxicity in LPS-stimulated RAW 264.7 cells up to 200 μM while could significantly inhibit NO and PGE2 production at indicated concentrations. Furthermore, it could inhibit the production of pro-inflammatory cytokines, including IL-1β, TNF-α, and IL-6 and suppress the expression level of iNOS in a dose-dependent manner through the western blot analysis. All these results suggest that questinol might be selected as a promising agent for the prevention and therapy of inflammatory disease (Figure 11) .
A novel aspochalasin, 20-β-methylthio-aspochalsin Q (named as aspochalasin V, 44) was isolated from culture broth of Aspergillus sp., which was obtained in the gut of a marine isopod Ligia oceanica (Dinghai in Zhoushan, Zhejiang Province of China). This is the first report about methylthio-substituted aspochalasin derivative. Apochalasin V showed moderate cytotoxic activity against the prostate cancer PC3 cell line and HCT116 cell line with IC50 values of 30.4 and 39.2 μM, respectively (Figure 11) .
Two new cerebrosides, penicillosides A (45) and B (46) were isolated from the marine-derived fungus Penicillium species, which were gained from the Red Sea tunicate, Didemnum species in the Mangrove. Penicilloside A displayed antifungal activity against Candida albicans while penicilloside B illustrated antibacterial activities against S. aureus and E. coli. Additionally, both compounds showed weak activity against HeLa cells (Figure 11) .