Anthraquinones and Derivatives from Marine-Derived Fungi

Anthraquinones and Derivatives from Marine-Derived Fungi: History

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Subjects: Biotechnology & Applied Microbiology

Contributor:

Mireille Fouillaud

Mekala Venkatachalam

Emmanuelle Girard-Valenciennes

Yanis Caro

Laurent Dufossé

Anthraquinones and their derivatives constitute a large group of quinoid compounds with about 700 molecules described. They are widespread in fungi and their chemical diversity and biological activities attracted attention of industries in such fields as pharmaceuticals, clothes dyeing, and food colorants. As marine microorganisms appeared as producers of an astonishing variety of structurally unique secondary metabolites, they may represent a promising resource for identifying new candidates for therapeutic drugs or daily additives.

anthraquinone
marine
fungi
pigment
biological activity
antitumor
antibiotic
cytotoxicity

1. Introduction

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 [7]. 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) [10] 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 [13].

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).

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 [20]. 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 [27] 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.

Figure 1. Anthraquinone general structure (R1–R8: lateral substituents).

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

Marine ecosystems host a wide biodiversity of filamentous fungi found in free waters, inert organic or inorganic matter. They can also be included as endophytes or pathogens in marine plants, planktons, vertebrates and invertebrates [31]. Their different roles in these environments are still poorly known, although their implications in lignocellulolytic compounds degradation and mineralization of organic matter has been repeatedly demonstrated [7,32,33]. Yet the notion of “marine fungus” is still under debate in the world of mycologists. Fungi are usually recognized as ubiquitous because they inhabit a plethora of ecosystems, from terrestrial milieus to aquatic environments (Figure 2). Marine and marine-derived fungi therefore form an ecological, not a taxonomic, group [34]. From the widely adopted definition of Kohlmeyer et al. (1979) [8], they are divided into two ecotypes:

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.

Figure 2. Marine habitats hosting fungal anthraquinones producers. (a) Tree and marine plants growing in a submerged area (b) Aplysina aerophoba (mediterranean sponge), usual host of endophytic filamentous fungi; (c) Aspergillus versicolor, exhibiting a pink pigment.

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 [35]. 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 [36].

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) [37]. 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 [39]. 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. [44], 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. [45], Caro et al. [16], and Gessler et al. [17]. They have revealed a large taxonomic distribution, confirming that the biosynthesis of anthraquinones is widespread in the fungal world, from macroscopic fungi to molds, as well as in lichens (symbiosis between algae and fungi). An extended list of the marine-derived fungal species producing anthraquinoid compounds with related differences is presented in Table 1. It indicates that, among the widespread compounds identified in marine-derived isolates, physcion, emodin, and chrysophanol and subsequently catenarin, erythroglaucin, macrosporin, and questin are frequently detected. The stuctural diversity of the compounds identified, along with the colors—(mentioned as a tag accompanying the molecule formula) are described in Table 2.

Table 1. Marine-derived fungi producing anthraquinones and some derivatives.

Genus	Species/Strain No	Name of Compounds Produced	Source of Isolation	Refs.
Alternaria	Al. eichorniae	4-deoxyBostrycin, Bostrycin	Mar. Plant pathogen	[46]
	Al. (SK11)	(+) α S-alterporriol C, 6-methylquinizarin, Alterporriol S, Austrocortinin	Mangrove Plant end.	[47]
	Al. sp. ZJ-2008003	Alterporriol C, K–R, Altersolanol B and C, Macrosporin	Mar. Org end.	[48]
	Al. sp. ZJ9-6B	Alterporriols C–M, Altersolanol A, Dactylariol, Macrosporin, Physcion, TetrahydroAltersolanol B	Mar. Plant end.	[49]
Aspergillus	A. glaucus	10,10′-dimer of Emodin and Physcion, Catenarin, Cynodontin, Emodin, Erythroglaucin, Helminthosporin, Physcion, Questin, Rubrocristin, Tritisporin, Variecolorquinone A	Mangrove sed.	[50,51,52,53]
	A. sp. 05F16	1-deoxytetrahydrobostrycin, Tetrahydrobostrycin	Algal end.	[54]
	A. sp. SCSIOF063	(1′S)-7-chloroaverantin, 1′-O-methylaverantin 1′-O-methyl-7-chloroaverantin, 6-O-methyl-7-chloroaverantin, 6-O-methyl-7-chloroaverythrin, 6-O-methyl-7-bromoaverantin, 6,1′-O,O-dimethyl-7-chloroaverantin, 6,1′-O,O-dimethyl-7-bromoaverantin, 6,1′-O,O-dimethylaverantin, 7-chloroaverantin-1′-butyl ether, 7-chloroaverythrin	Sed.	[55]
	A. variecolor B-17	(2S)-2,3-dihydroxypropyl1,6,8-trihydroxy-3-methyl-9,10-dioxoanthracene-2carboxylate, Catenarin, Emodin, Fallacinol, Physcion, Erythroglaucin, Questin, Questinol, Rubrocristin, Variecolorquinone A,	Sed.	[56]
	A. versicolor	7-hydroxyemodin 6,8-methyl ether, Emodin, Isorhodoptilometrin-methyl ether, Methyl emodin	Algal end.	[57]
	A. versicolor EN-7 (Genbank no EU042148)	6,8-di-O-methylversiconol 6,8-di-O-methylnidurufin 6,8-di-O-methylaverantin 6,8-di-O-methylversicolorin A, Aversin: (−)-isomer	Algal end.	[58]
Curvularia	C. lunata	Cytoskyrin A, Lunatin	Mar. Org end.	[50,51,59,60]
Eurotium	E. cristatum (ECE)	Catenarin, Emodin, Erythroglaucyn, Physcion, Physcion anthrone, Questin, Rubrocristin	Mar. Org end.	[36,61]
	E. repens	Catenarin, Erythroglaucyn, Physcion, Physcion anthrone	Mar. Org end.	[36,62]
	E. rubrum	6,3-O-(α-d-ribofuranosyl)-questin, Questin	Mar. Plant end.	[63]
Unidentified	Fungus Isolate 1850 and 2526	Averufin, Nidurufin, versicolorin C	Mar. Plant end.	[64]
	Fungus ZSUH-36	1′-O-methyl averantin, 6,8-di-O-methyl averufanin, 6,8-di-O-methyl averufin, 6,8,1′-tri-O-methyl averantin, Versicolorin C	Mar. Plant end.	[65]
Fusarium	F. sp. No. B77	5-acetyl-2-methoxy-1,4,6-trihydroxy-anthraquinone	Mangrove Plant end.	[66]
	F. sp. ZZF60	6,8-dimethoxy-1-methyl-2-(3-oxobutyl) anthraquinone	Mangrove Plant end.	[67]
	F. sp. No. ZH-210	Fusaquinon A,B,C	Mangrove sed.	[68]
	F. sp. PSU-F14, F. sp. PSU-F135	Austrocortirubin, Bostrycin	Mar. Org end.	[69]
Halorosellinia	H. sp. (No. 1403)	1,4,5,6,7,9-hexahydroxy-2-methoxy-7-methyl-5β,9β, 8aβ,6α,10aα—hexahydroanthracene10(10aH)-one, Austrocortirubin, Demethoxyaustrocortirubin, Hydroxy-9,10-anthraquinone, SZ-685C	Mar. Plant-derived	[70,71]
Lichens	Arthonia elegans, Biatorella conspersa, B. ochrophora, Pyrenula cerina, Sphaerophorus fragilis, Stereocaulon corticatulum,v. procerum, Trypethelium aeneum, T. aureomaculata, etc.	Physcion	Lichens	[72]
	Caloplaca sp.	Phallacinol (=Teloschistin=Fallacinol))	Lichen	[73,74]
	Caloplaca ehrenbergii, C. schaereri, C. spitsbergensis, etc.	1-O-methyl-7-chloroemodin, 7-chloro-1,6,8-trihydroxy-3-methyl-10-anthrone, 7-chlorocitreorosein, 7-chloroemodic acid, 7-chloroemodin, 7-chloroemodinal, Emodin, Phallacinol, Physcion	Lichens	[75,76,77]
	Gliocladium sp. T 31	Citreorosein, Emodin, Isorhodoptilometrin	Lichen	[78]
	Letrouitia hafellneri, L. leprolytoides	7-chloroemodinal, 7-chloroemodin, Fragilin, Physcion	Lichens	[79,80]
Microsphaeropsis	M. sp.	1,3,6,8-tetrahydroxyanthraquinone, 1,3,6,8-tetrahydroxy-2-(1-hydroxyethyl)anthraquinone 1,3,6,8-tetrahydroxy-2-(1-methoxyethyl)anthraquinone 1,2,3,6,8-pentahydroxy-7-(1-methoxyethyl)anthraquinone	Mar. Org end.	[81]
Monodictys	M. sp.	Chrysophanol, Emodin, Monodictyquinone A, Pachybasin	Mar. Org end.	[14,82]
Nigrospora	N. spp.	1-deoxytetrahydrobostrycin, 4-deoxybostrycin, Bostrycin, 4a-epi-9α-methoxydihydrodeoxybostrycin, 10-deoxybostrycin	Mar. Plant/Org end.	[68,83,84]
	N. sp. MA75	4-deoxybostrycin, Bostrycin	Marine	[85]
	N. sp. 1403	4-deoxybostrycin, Bostrycin	Mangrove	[86]
Paecilomyces	P. sp. (Tree 1-7)	Chrysophanol, Emodin	Mangrove	[87]
Penicillium	P. citrinum PSU-F51 (Accession no JQ66600)	Chrysophanol, Citreorosein, Emodin, Penicillanthranins A and B	Mar. Org end.	[88]
	P. chrysogenum	Skyrin	Salt lake	[89]
	P. flavidorsum SHK1-27	6,8-O-dimethylaverufin, 8-O-methylaverufin, Averufin, Averantin, Versiconol, Versicolorin A&B, Nidurufin	Marine	[90]
	P. oxalicum 2-HL-M-6	Aloe emodin, Chrysophanol, Citreorosein, Citreorosein-3-O-sulfate, Emodin, Emodin-3-O-sulfate, Isorhodoptilometrin	Mangrove sed.	[91]
Phomopsis	P. sp. PSU-MA214	Phomopsanthraquinone, 1-hydroxy-3-methoxy-6-methylanthraquinone, Ampelanol, Macrosporin	Mangrove Plant endo	[92]
Stemphylium	S. sp. 33231	2-O-acetylaltersolanol B, Alterporriol T–W, Altersolanol B&C, Auxarthrol C, Macrosporin	Mangrove Plant end.	[93]
	S. globuliferum	6-O-methylalaternin, Acetylalterporriol D and E, Alterporriol D and E, Altersolanol A,B and C, Dihydroaltersolanol B and C, Macrosporin, Stemphylanthranol A and B	Salt lake Plant end.	[94]
Trichoderma	T. aureoviride PSU-F95	Coniothranthraquinone 1, Trichodermaquinone	Mar. Org end.	[88]
Xylaria	X. sp. 2508	Altersolanol A, Bostrycin, Deoxybostrycin, Xylanthraquinone	Marine	[95]

Abreviations: Mar. Plant end.: marine plant endophyte; Mar. Org. end.: marine organism endophyte other than plant; Sed.: sediment.

Table 2. Structural diversity of anthraquinoid compounds identified in marine-derived fungi (increasing mol. mass.).

Mol. Formula/Mol. mass	Trivial name	Structure	IUPAC NAME	Source	Refs
C₁₄H₈O₃/224	Hydroxy-9,10-anthraquinone		1-hydroxy-3-methylanthraquinone	Halorosellinia sp. No. 1403	[70]
C₁₅H₁₀O₃/238	Pachybasin		1-hydroxy-3-methylanthraquinone	Monodictys sp.	[14,82]
C₁₅H₁₀O₄/254	Chrysophanol		1,8-dihydroxy-3-methylanthraquinone	Monodictys sp. Paecilomyces sp. P. citrinum PSU-F51 P. oxalicum 2-HL-M-6	[14,82] [87] [88] [91]
C₁₅H₁₀O₄/254	6-Methylquinizarin		1,4-dihydroxy-methylanthraquinone	Al. sp. (SK11)	[47]
C₁₆H₁₂O₄/268	1-Hydroxy-3-methoxy-6-methylanthraquinone		----	Phomopsis sp. PSU-MA214	[92]
C₁₅H₁₀O₅/270	Aloe emodin		1,8-dihydroxy-3-(hydroxymethyl)anthraquinone	P. oxalicum 2-HL-M-6	[91]
C₁₅H₁₀O₅/270	Emodin		1,3,8-trihydroxy-6-methylanthraquinone	A. glaucus A. variecolor B-17 A. versicolor Caloplaca spp. (e.g., C. ehrenbergii, C. schaereri, C. spitsbergensis, etc.) Eurotium Cristatum Gliocladium sp. T31 Monodictys sp. Paecilomyces sp. P. citrinum PSU-F51 P. oxalicum 2-HL-M-6	[91] [56] [61] [75,76,77,79,96] [36] [78] [14,82] [87] [88] [57]
C₁₅H₁₀O₅/270	Helminthosporin		1,5,8-trihydroxy-3-methylanthraquinone	A. glaucus	[50,51,52,53]
C₁₄H₈O₆/272	1,3,6,8-Tetrahydroxyanthraquinone		----	A.versicolor Microsphaeropsis	[97] [81]
C₁₅H₁₄O₅/274	Coniothranthraquinone 1		(2S,3R)-2,3,5-trihydroxy-7-methyl-1,2,3,4-tetrahydroanthraquinone	Trichoderma aureoviride (PSU-F95)	[88,98]
C₁₆H₁₂O₅/284	1-Methylemodin		1,3-dihydroxy-8-methoxy-6-methylanthraquinone	A. versicolor	[57]
C₁₆H₁₂O₅/284	Austrocortinin		1,4-dihydroxy-2-methoxy-7-methylanthraquinone	Al. sp. (SK11)	[47]
C₁₆H₁₂O₅/284	Macrosporin		1,7-dihydroxy-3-methoxy-6-methylanthraquinone	Al. sp. ZJ9-6B Al. sp. ZJ-2008003 Phomopsis sp. PSU-MA214 Stemphylium globuliferum Stemphylium sp. 33231	[49] [48] [92] [94] [93]
C₁₆H₁₂O₅/284	Marcrospin		1,6-dihydroxy-3-methoxy-7-methylanthraquinone	Al. sp. ZJ9-6B	[49]
C₁₆H₁₂O₅/284	Monodictyquinone A		1,8-dihydroxy-2-methoxy-6-methylanthraquinone	Monodictys sp.	[14,82]
C₁₆H₁₂O₅/284	Phallacinol/Fallacinol		1,8-dihydroxy-3-(hydroxy-methyl)-6-methoxyanthraquinone	A. variecolor B-17 Caloplaca spp. (e.g., C. ehrenbergii, C. schaereri, C. spitsbergensis, etc.)	[99] [73,74,76,77,79,96]
C₁₆H₁₂O₅/284	Physcion		1,8-dihydroxy-3-methoxy-6-methylanthraquinone	Al. sp. ZJ9-6B A. glaucus A. variecolor B-17 Eurotium repens Eurotium cristatum Caloplaca spp. (e.g., C. ehrenbergii, C. schaereri, C. spitsbergensis, etc.) Letrouitia hafellneri, L. leprolytoides, Arthonia elegans, Biatorella conspersa, B. ochrophora, Pyrenula cerina, Sphaerophorus fragilis, Stereocaulon corticatulum, v. procerum, Trypethelium aeneum, T. aureomaculata	[49] [50,51,52,53] [56] [62] [36,61] [75,76,77,79,96] [72,80]
C₁₆H₁₂O₅/284	Questin		1,6-dihydroxy-8-methoxy-3-methylanthraquinone	A. glaucus A. variecolor B-17 Eurotium cristatum (ECE) Eurotium rubrum	[50],[51] [56] [52,53] [36,61,63]
C₁₅H₁₀O₆/286	Catenarin		1,4,5,7-tetrahydroxy-2-methylanthraquinone	A. glaucus A. variecolor B-17 Eurotium cristatum (ECE) Eurotium repens	[50,51] [56] [52,53] [36,62]
C₁₅H₁₀O₆/286	Citreorosein		ω-hydroxyemodin (OHM) or 1,3,8-trihydroxy-6-(hydroxymethyl) anthraquinone	Gliocladium. sp. T31 P. citrinum PSU-F51 P. oxalicum 2-HL-M-6	[78] [88] [91]
C₁₅H₁₀O₆/286	Cynodontin		1,4,5,8-tetrahydroxy-2-methylanthraquinone	A. glaucus	[50,51,52,53]
C₁₅H₁₀O₆/286	Lunatin		1,3,8-trihydroxy-6-methoxyanthraquinone	Curvularia lunata	[50,51,59,60]
C₁₅H₁₀O₇/286	Tritisporin		1,4,5,7-tetrahydroxy-2-(hydroxylmethyl) anthraquinone	A. glaucus	[50,51,52,53]
C₁₅H₁₄O₆/290	Trichodermaquinone		(2S,3R)-2,3,5-trihydroxy-7-(hydroxylmethyl)-1,2,3,4-tetrahydroanthraquinone	Trichoderma aureoviride (PSU-F95)	[88,98]
C₁₅H₁₄O₆/290	Demethoxyaustrocortirubin		1,4-dihydroxy-6-methylanthraquinone	Halorosellinia sp. No. 1403	[70,71]
C₁₅H₁₄O₆/290	7-Hydroxyemodin 6,8-methyl ether		2,8-dihydroxy-1,3-dimethoxy-6-methyl anthraquinone	A. versicolor	[57]
C₁₆H₁₀O₄/300	Erythroglaucin		1, 4, 5-trihydroxy-7-methoxy-2-methylanthraquinone	A. glaucus A. variecolor B-17 Eurotium cristatum (ECE) Eurotium repens	[50,51,52,53] [56] [36,61] [36]
C₁₆H₁₂O₆/300	Carviolin		1,3-dihydroxy-6-(hydroxymethyl)-8-methoxyanthraquinone	P. dravuni	[100]
C₁₆H₁₂O₆/300	Questinol		1,6-dihydroxy-3-(hydroxymethyl)-8-methoxyanthraquinone	A. variecolor B-17	[56]
C₁₆H₁₂O₆/300	Rubrocristin		1,4,7-trihydroxy-5-methoxy-2-methylanthraquinone	A. glaucus A. variecolor B-17 Eurotium cristatum (ECE)	[50,51,52,53] [56] [36,61]
C₁₆H₁₂O₆/300	6-O-methylalaternin		1,2,8-trihydroxy-6-methoxy-3-methylanthraquinone	Stemphylium globuliferum	[94]
C₁₆H₁₂O₆/300	1,4,6-Trihydroxy-2-methoxy-7-methyl-anthraquinone		3,5,8-trihydroxy-7-methoxy-2-methylanthraquinone	Halorosellinia sp. No. 1403	[70]
C₁₅H₉O₅Cl/304	7-Chloroemodin		----	Caloplaca spp. (e.g., C. ehrenbergii, C. schaereri, C. spitsbergensis, etc.)	[75,76,77,79,96]
C₁₆H₁₆O₆/304	Altersolanol B		(2S,3R)-2,3,5-trihydroxy-7-methoxy-2-methyl-1,2,3,4-tetrahydroanthraquinone	Al. sp. ZJ-2008003 Stemphylium sp. 33231	[48] [93]
C₁₆H₁₈O₆/306	Fusaquinon A		(2R,3S,4aR,9S,9aS)-3,5,8-trihydroxy-7-methoxy-2-methyl-2,3,4,4a,9,9a-hexahydro-2,9-epoxyanthracen-10(1H)-one	Fusarium sp. No. ZH-210	[68]
C₁₆H₁₈O₆/307	Dihydroaltersolanol B		(2S,3R)-2,3,5-trihydroxy-7-methoxy-2-methyl-1,2,3,4,4a,9a-hexahydroanthraquinone	Stemphylium globuliferum	[94]
C₁₅H₁₉O₇/311	Xylanthraquinone		----	Xylaria sp. 2508	[95]
C₁₇H₁₄ O₆/314	Isorhodoptilometrin		(R)-1,3,8-trihydroxy-6-(2-hydroxypropyl)anthraquinone	Gliocladium sp. T31 P. oxalicum 2-HL-M-6	[78] [91]
C₁₆H₁₂O₇/317	1,3,6,8-Tetrahydroxy-2-(1-hydroxyethyl) anthraquinone		1,3,6,8-tetrahydroxy-2-(1-hydroxyethyl) anthracene-9,10-dione	Microsphaeropsis	[81]
C₁₆H₁₁O₅Cl/318	1-O-Methyl-7-chloroemodin		2-chloro-1,6-dihydroxy-8-methoxy-3-methylanthraquinone	Caloplaca spp. (e.g., C. ehrenbergii, C. schaereri, C. spitsbergensis, etc.)	[75,76,77,79,96]
C₁₅H₉O₆Cl/320	7-Chlorocitreorosein		----	Caloplaca spp. (e.g., C. ehrenbergii, C. schaereri, C. spitsbergensis, etc.)	[75,76,77,79,96]
C₁₆H₁₆O₇/320	Austrocortirubin		1,4-dihydroxy-2-methoxy-7-methylanthraquinone	Fusarium spp. PSU-F14 and PSU-F135 Halorosellinia sp. No. 1403 Nigrospora sp. ZJ-2010006	[69] [70,71] [84]
C₁₆H₁₆O₇/320	Altersolanol C		(1R,2R,3R)-1,2,3,5-tetra-hydroxy-7-methoxy-2-methyl-1,2,3,4-tetra-hydroanthraquinone	Al. sp. ZJ9-6B Al. sp. ZJ-2008003 Stemphylium sp. 33231	[49] [48] [93]
C₁₆H₁₆O₇/320	4-Deoxybostrycin		(2R,3S,4aS,9aS,10R)-2,3,5,8,10-pentahydroxy-6-methoxy-3-methyl-1,3,4,4a,9a,10-hexahydroanthracen-9(2H)-one	Nigrospora sp. 1403 Nigrospora sp. MA75	[68,83,84,86,101] [85]
C₁₆H₁₆O₇/320	2,3,5,8-Tetrahydroxy-7-methoxy-2-methyl-1,2,3,4-tetrahydroanthraquinone	----	2,3,5,8-tetrahydroxy-7-methoxy-2-methyl-1,2,3,4-tetrahydroanthracene-9,10-dione	Al. eichorniae	[46]
C₁₆H₁₆O₇/321	10-Deoxybostrycin		---	Nigrospora sp.	[84]
C₁₆H₁₈O₇/323	Dihydroaltersolanol C		(1R,2R,3R)-1,2,3,5-tetra-hydroxy-7-methoxy-2-methyl-1,2,3,4,4a,9a-hexahydroanthraquinone	Stemphylium globuliferum	[94]
C₁₆H₂₀O₇/324	Fusaquinon C		(2S,3R,4aR,9aR,10S)-2,3,5,8,10-pentahydroxy-6-methoxy-3-methyl-1,3,4,4a,9a,10-hexahydroanthracen-9(2H)-one	Fusarium sp. No. ZH-210	[68]
C₁₆H₂₁O₇/325	1-Deoxytetrahydrobostrycin		(2R,3S)-2,3,5,8,10-pentahydroxy-6-methoxy-3-methyl-1,3,4,4a,9a,10-hexahydroanthracen-9(2H)-one	A. sp. 05F16 Nigrospora sp.	[54] [83]
C₁₅H₂₀O₈/328	Fragilin		2-chloro-1,8-dihydroxy-3-methoxy-6-methylanthraquinone	Letrouitia hafellneri L. leprolytoides	[79,80]
C₁₇H₁₂O₇/328	5-Acetyl-2-methoxy-1,4,6-trihydroxyanthraquinone		----	Fuarium sp. B77	[66]
C₁₈H₁₆O₆/328	Isorhodoptilometrin-1-methylether		1,3-dihydroxy-6-2-hydroxypropyl-8-methoxyanthraquinone	A. versicolor	[57]
C₁₇H₁₄O₇/329	1,3,6,8-Tetrahydroxy-2-(1-methoxyethyl)anthraquinone		---	Microsphaeropsis	[81]
C₁₈H₂₀O₆/332	Phomopsanthraquinone		(2R,3S)-7-ethyl-1,2,3,4-tetrahydro-2,3,8-trihydroxy-6-methoxy-3-methylanthraquinone	Phomopsis sp. PSU-MA214	[92]
C₁₆H₁₆O₈/336	Altersolanol A		(1R,2S,3R,4S)-1,2,3,4,5-pentahydroxy-7-methoxy-2-methyl-1,2,3,4-tetrahydroanthraquinone	Stemphylium globuliferum Xylaria sp. 2508	[94] [95]
C₁₆H₁₆O₈/336	Bostrycin		(5S,6R,7S)-5,6,7,9,10-pentahydroxy-2-methoxy-7-methyl-5,6,7,8-tetrahydroanthracene-1,4-dione	A. sp. strain 05F16 Al. eichorniae Fusarium spp. PSU-F14/PSU-F135 Halorosellinia sp. No. 1403 Nigrospora sp. Xylaria sp. 2508	[46,102] [69] [68,86,101,103] [84] [54] [95]
C₁₆H₁₈O₈/338	SZ-685C		1,2,3,5,8-pentahydroxy-6-methoxy-3-methyl-1,2,3,4-tetrahydroanthraquinone	Halorosellinia sp. No. 1403	[70,101,104,105,106,107]
C₁₆H₂₀O₈/340	Fusaquinon B		(1R,2S,3R,4aR,9aS,10S)-1,2,3,5,8,10-hexahydroxy-6-methoxy-3-methyl-1,3,4,4a,9a,10-hexahydroanthracen-9(2H)-one	Fusarium sp. No. ZH-210	[68]
C₁₆H₂₁O₈/340	Tetrahydroxybostrycin		1,2,3,5,8,10-hexahydroxy-6-methoxy-3-methyl-1,3,4,4a,9a,10-hexahydroanthracen-9(2H)-one	A. sp. 05F16 Nigrospora sp. MA75	[54] [85]
C₁₈H₁₂O₇/340	Versicolorin C		4,6,8-trihydroxy-3,3a-dihydroanthra[2,3-b]furo[3,2-d]furan-5,10(2H,12aH)-dione	Fungus ZSUH-36 Fungus Isolate 1850 and isolate 2526	[65] [64]
C₁₈H₁₈O₇/346	2-O-Acetylaltersolanol B		(2R,3S)-3,8-dihydroxy-6-methoxy-3-methyl-9,10-dioxo-1,2,3,4,9,10-hexahydroanthracen-2-yl acetate	Stemphylium sp. 33231	[93]
C₁₇H₁₄O₈/347	1,2,3,6,8-Pentahydroxy-7-(1-methoxyethyl)anthraquinone		1,2,3,6,8-pentahydroxy-7-(1-methoxyethyl)anthracene-9,10-dione	Microsphaeropsis	[81]
C₁₅H₁₀O₈S/350	Emodin-3-O Sulfate		4,5-dihydroxy-7-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yl hydrogen sulfate	P. oxalicum 2-HL-M-6	[91]
C₁₆H₁₅O₉/351	Auxarthrol C		(1S,2R,3R,4R,4aR,9aS)-1,2,3,4,5-pentahydroxy-7-methoxy-2-methyl-1,2,3,4-tetrahydro-4a,9a-epoxyanthraquinone	Stemphylium sp. 33231	[93]
C₁₉H₁₁O₇/351	8-O-MethylversicolorinB		4,8-dihydroxy-6-methoxy-3,3a-dihydroanthra[2,3-b]furo[3,2-d]furan-5,10(2H,12aH)-dione	A. versicolor endolichenic	[108]
C₂₁H₂₀O₅/352	6,8-Dimethoxy-1-methyl-2-(3-oxobutyl)anthraquinone		----	Fusarium sp. ZZF60	[67]
C₁₉H₁₃O₇/353	8-O-Methylversicolorin A		4,8-dihydroxy-6-methoxyanthra[2,3-b]furo[3,2-d]furan-5,10(3aH,12aH)-dione	A. versicolor endolichenic	[108]
C₂₀H₁₈O₆/354	Averythrin		(E)-2-(hex-1-en-1-yl)-1,3,6,8-tetrahydroxyanthraquinone	A. sp. SCSIO F063 A. versicolor endolichenic	[55] [108]
C₃₀H₁₈O₁₀/358	Skyrin		2,2′,4,4′,5,5′-hexahydroxy-7,7′-dimethyl-[1,1′-bianthracene]-9,9′,10,10′-tetraone	P. chrysogenum	[89]
C₁₆H₁₂O₈S/364	Macrosporin-7-O-sulfate		Sodium 8-hydroxy-6-methoxy-3-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yl sulfate	Stemphylium sp. 33231	[93]
C₁₅H₉O₉S/365	Citreorosein-3-O-sulfate		4,5-dihydroxy-7-(hydroxymethyl)-9,10-dioxo-9,10-dihydroanthracen-2-yl hydrogen sulfate	P. oxalicum 2-HL-M-6	[91]
C₂₀H₁₄O₇/365	6,8-di-O-methylversico-lorinA		4-hydroxy-6,8-dimethoxyanthra[2,3-b]furo[3,2-d]furan-5,10(3aH,12aH)-dione	A. versicolor endolichenic A. versicolor EN-7 (Genbank no EU042148)	[108] [58]
C₂₁H₁₉O₆/367	8-O-Methylaverythrin		(E)-2-(hex-1-en-1-yl)-1,3,6-trihydroxy-8-methoxyanthraquinone	A. versicolor endolichenic	[108]
C₂₀H₁₆O₇/368	Aversin		4-hydroxy-6,8-dimethoxy-3,3a-dihydroanthra[2,3-b]furo[3,2-d]furan-5,10(2H,12aH)-dione	A. versicolor endolichenic	[108]
C₂₀H₁₆O₇/368	Aversin : (−)-isomer		4-hydroxy-6,8-dimethoxy-3,3a-dihydroanthra[2,3-b]furo[3,2-d]furan-5,10(2H,12aH)-dione	A. versicolor EN-7 (Genbank no EU042148)	[58]
C₂₀H₂₀O₇/372	Averantin		(S)-1,3,6,8-tetrahydroxy-2-(1-hydroxyhexyl)anthraquinone	A. sp. SCSIO F063	[55]
C₂₀H₂₀O₇/372	Averantin = (S)-(−)-averantin		(S)-1,3,6,8-tetrahydroxy-2-(1-hydroxyhexyl)anthraquinone	A. sp. SCSIO F063	[55]
C₂₁H₁₈O₇/382	6-O-Methylaverufin		7,9-dihydroxy-11-methoxy-2-methyl-3,4,5,6-tetrahydro-2H-2,6-epoxyanthra[2,3-b]oxocine-8,13-dione	Fungus ZSUH-36 A. versicolor EN-7	[65] [58]
C₂₀H₁₆O₈/384	Nidurufin		5,7,9,11-tetrahydroxy-2-methyl-3,4,5,6-tetrahydro-2H-2,6-epoxyanthra[2,3-b]oxocine-8,13-dione	Fungus Isolate 1850 and isolate 2526	[64]
C₂₀H₁₅O₈/386	Averufin		7,9,11-trihydroxy-2-methyl-3,4,5,6-tetrahydro-2H-2,6-epoxyanthra[2,3-b]oxocine-8,13-dione	A. versicolor Fungus ZSUH-36 Fungus Isolate 1850 and isolate 2526	[109] [65] [64]
C₂₁H₂₂O₇/386	1′-O-Methylaverantin		1,3,6,8-tetrahydroxy-2-(1-methoxyhexyl)anthraquinone	A. sp. SCSIO F063 Fungus ZSUH-36	[55] [65]
C₁₉H₁₅O₉/388	(2S)-2,3-Dihydroxy-propyl-1,6,8-trihydroxy-3-methyl-9,10-dioxoanthracene-2-carboxylate		(1S,5′S,6′R,7′S,8′R)-1′,2,5′,6′,7′,8,8′-heptahydroxy-3′,6-dimethoxy-3,6′-dimethyl-5′,6′,7′,8′,8′a,10′a-hexahydro-[1,2′-bianthracene]-9,9′,10,10′-tetraone	A. variecolor B-17	[56]
C₂₀H₁₇ClO₆/388	7-Chloroaverythrin		(E)-2-chloro-7-(hex-1-en-1-yl)-1,3,6,8-tetrahydroxyanthraquinone	A. sp. SCSIO F063	[55]
C₂₀H₂₀O₈/388	6,8-Di-O-methylversiconol		2-(1,4-dihydroxybutan-2-yl)-1,3-dihydroxy-6,8-dimethoxyanthraquinone	A. versicolor EN-7 (Genbank no EU042148)	[58]
C₂₂H₂₀O₇/396	6,8-Di-O-methylaverufin		7-hydroxy-9,11-dimetho-xy-2-methyl-3,4,5,6-tetra-hydro-2H-2,6-epoxyanthra[2,3-b]oxocine-8,13-dione	A. versicolor endolichenic	[108]
C₂₂H₂₀O₇/396	6,8-Di-O-methylnidurufin		5,7-dihydroxy-9,11-dime-thoxy-2-methyl-3,4,5,6-tetrahydro-2H-2,6-epoxyanthra[2,3-b]oxocine-8,13-dione	A. versicolor endolichenic A. versicolor EN-7 (Genbank no EU042148)	[108] [58]
C₂₂H₂₂O₇/398	6,8-Di-O-methylaverufanin		1,3-dihydroxy-6,8-dimethoxy-2-(6-methyltetra-hydro-2H-pyran-2-yl)anthracene-9,10-dione	Fungus ZSUH-36	[65]
C₂₂H₂₄O₇/400	6,1′-O,O-Dimethylaverantin		(S)-1,3,8-trihydroxy-6-methoxy-2-(1-methoxyhexyl)anthraquinone	A. sp. SCSIO F063	[55]
C₂₀H₁₇O₉/401	Variecolorquinone A		(S)-2,3-dihydroxypropyl 1,6-dihydroxy-8-methoxy-3-methyl-9,10-dioxo-9,10-dihydroanthracene-2-carboxylate	A.glaucus A. variecolor B-17	[50,51,52,53] [56]
C₂₂H₂₄O₇/401	6,8-Di-O-methylaveran-tin		(S)-1,3-dihydroxy-2-(1-hydroxyhexyl)-6,8-dimetho-xyanthraquinone	A. versicolor EN-7 (Genbank no EU042148) A. sp. SCSIO F063	[58] [55]
C₂₁H₁₉ClO₆/402	6-O-Methyl-7-chloroaverythrin		(E)-2-chloro-7-(hex-1-en-1-yl)-1,6,8-trihydroxy-3-methoxyanthraquinone	A. sp. SCSIO F063	[55]
C₂₀H₁₉ClO₇/407	(1′S)-7-Chloroaverantin		(S)-2-chloro-1,3,6,8-tetrahydroxy-7-(1-hydroxyhexyl)anthraquinone	A. sp. SCSIO F063	[55]
C₂₂H₂₃ClO₇/407	6,1′-O,O-Dimethyl-7-chloroaverantin		(S)-2-chloro-1,6,8-trihydroxy-3-methoxy-7-(1-methoxyhexyl)anthraquinone	A. sp. SCSIO F063	[55]
C₂₃H₂₆O₇/414	6,8,1′-Tri-O-methyl-averantin		1,3-dihydroxy-6,8-dimethoxy-2-(1-methoxyhexyl)anthraquinone	A.versicolor endolichenic Fungus ZSUH-36	[108] [65]
C₂₁H₁₉O₉/415	6-3-O-(Ribofuranosyl)questin		1,6-dihydroxy-6-O-(ribofuranosyl)-8-methoxy-3-methylanthraquinone	Eurotium rubrum	[63]
C₂₁H₂₁ClO₇/420	1′-O-methyl-7-chloro averantin		(S)-2-chloro-1,3,6,8-tetrahydroxy-7-(1-methoxy-hexyl)anthraquinone	A. sp. SCSIO F063	[55]
C₂₁H₂₁ClO₇/421	6-O-methyl-7-chloro-averantin		(S)-2-chloro-1,6,8-trihydroxy-7-(1-hydroxyhexyl)-3-methoxyanthraquinone	A. sp. SCSIO F063	[55]
C₂₄H₂₈O₈/444	Averantin-1′-butyl ether		(S)-2-(1-butoxyhexyl)-1,3,6,8-tetrahydroxy-anthraquinone	A. sp. SCSIO F063	[55]
C₂₄H₂₇ClO₇/463	7-Chloroaverantin-1′-butyl ether		(S)-2-(1-butoxyhexyl)-7-chloro-1,3,6,8-tetrahy-droxyanthraquinone	A. sp. SCSIO F063	[55]
C₂₁H₂₁BrO₇/465	6-O-Methyl-7-bromoaverantin		(S)-2-bromo-1,6,8-trihydroxy-7-(1-hydroxyhexyl)-3-methoxyanthraquinone	A. sp. SCSIO F063	[55]
C₂₂H₂₃BrO₇/479	6,1′-O,O-Dimethyl-7-bromoaverantin		(S)-2-bromo-1,6,8-trihydroxy-3-methoxy-7-(1-methoxyhexyl)anthraquinone	A. sp. SCSIO F063	[55]
C₂₄H₂₃O₁₁/487	Macrosporin2-O-(6′-acetyl)-a-d-glucopyranoside		((2R,3S,4S,5R,6R)-3,4,5-trihydroxy-6-((8-hydroxy-6-methoxy-3-methyl-9,10-dioxo-9,10-dihydroanthracen-2-yl)oxy)tetrahydro-2H-pyran-2-yl)methyl acetate	Stemphylium sp. 33231	[93]
C₂₈H₂₄O₁₀/520	Penicillanthranin A		(1S,3R,4S)-1-(6-ethyl-1,3,8-trihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl)-6,8-dihy-droxy-3,4,5-trimethyliso-chroman-7-carboxylic acid	P. citrinum PSU-F51	[88]
C₂₈H₂₄O₁₁/536	Penicillanthranin B		(1S,3R,4S)-6,8-dihydroxy-3,4,5-trimethyl-1-(1,3,8-trihydroxy-6-(hydroxy-methyl)-9,10-dioxo-9,10-dihydroanthracen-2-yl)isochroman-7-carboxylic acid	P. citrinum PSU-F51	[88]
C₃₂H₂₄O₈/536	(trans)-R (cis)-Emodin-Physcion bianthrone		2,4,4′,5,5′-pentahydroxy-2′-methoxy-7,7′-dimethyl-[9,9′-bianthracene]-10,10′(9H,9′H)-dione	A. glaucus	[50,51,52,53]
C₃₂H₂₁O₁₀/565	Alterporriol Q		1′,2,7′,8-tetrahydroxy-3′,6-dimethoxy-3,6′-dimethyl-[1,2′-bianthracene]-9,9′,10,10′-tetraone	Al. sp. ZJ-2008003	[48]
C₃₂H₂₁O₁₀/565	Alterporriol R		2,4′,6′,8-tetrahydroxy-2′,6-dimethoxy-3,7′-dimethyl-[1,1′-bianthracene]-9,9′,10,10′-tetraone	Al. sp. ZJ-2008003	[48]
C₃₂H₂₂O₁₀/566	Alterporriol V		2,2′,8,8′-tetrahydroxy-6,6′-dimethoxy-3,3′-dimethyl-[1,1′-bianthracene]-9,9′,10,10′-tetraone	Stemphylium sp. 33231	[93]
C₃₀H₂₂O₁₂/574	Cytoskyrin A		(6R,14R,17S,18R,19R,20S)-1,7,9,15,17,20-hexahydroxy-3,11-dimethoxy-6,13a,5a,14-(epibutane[1,2,3,4]tetrayl)cycloocta[1,2-b:5,6-b′]dinaphtha-lene-5,8,13,16(6H,14H)-tetraone	Curvularia lunata	[50,51,59,60]
C₃₂H₂₆O₁₀/586	Alterporriol K		(5S,8R)-4,4′,5,7′,8-penta-hydroxy-1,1′-dimethoxy-6′,8-dimethyl-5,6,7,8-tetrahydro-[2,2′-bianthracene]-9,9′,10,10′-tetraone	Al. sp. ZJ9-6B Al. sp. ZJ-2008003	[49] [48]
C₃₂H₃₀O₁₃/590	Alterporriol T		(6R,6′S,7R,7′R,8R)-1′,4,6,6′,7,7′,8-heptahydroxy-2,3′-dimethoxy-6′,7-dime-thyl-5,5′,6,6′,7,7′,8,8′-octahydro-[1,2′-bianthracene]-9,9′,10,10′-tetraone	Stemphylium sp. 33231	[93]
C₃₂H₂₅O₁₂/601	Alterporriol L		(6S,7R,8R)-4,4′,6,7,7′,8-hexahydroxy-1,1′-dimethoxy-6′,7-dimethyl-5,6,7,8-tetrahydro-[2,2′-bianthracene]-9,9′,10,10′-tetraone	Al. sp. ZJ9-6B Al. sp. ZJ-2008003	[49] [48]
C₃₂H₂₅O₁₂/601	Alterporriol M		(6S,7S,8R)-4,4′,6,7,7′,8-hexahydroxy-1,1′-dimethoxy-6′,7-dimethyl-5,6,7,8-tetrahydro-[2,2′-bianthracene]-9,9′,10,10′-tetraone	Al. sp. ZJ9-6B Al. sp. ZJ-2008003	[49] [48]
C₃₂H₂₅O₁₂/601	Alterporriol P		(5′R,6′R,7′R)-1′,2,5′,6′,7′,8-hexahydroxy-3′,6-dimethoxy-3,6′-dimethyl-5′,6′,7′,8′,8′a,10′a-hexahydro-[1,2′-bianthracene]-9,9′,10,10′-tetraone	Al. sp. ZJ-2008003	[48]
C₃₂H₂₆O₁₂/602	Alterporriol W		(1′R,6R,7R,8R)-2′,4,6,7,8,8′-hexahydroxy-2,6′-dimethoxy-3′,7-dimethyl-5,6,7,8-tetrahydro-[1,1′-bianthracene]-9,9′,10,10′-tetraone	Stemphylium sp. 33231	[93]
C₃₂H₃₀O₁₂/606	Alterporriol U		(6R,6′S,7S,7′R)-1′,4,6,6′,7,7′-hexahydroxy-2,3′-di-methoxy-6′,7-dimethyl-5,5′,6,6′,7,7′,8,8′-octahy-dro-[1,2′-bianthracene]-9,9′,10,10′-tetraone	Stemphylium sp. 33231	[93]
C₃₁H₃₂O₁₃/612	Alterporriol S		(2′S,3′R,4′S,6R,7S,9′R)-1,2′,3′,4,5′,6,7,8′-octahy-droxy-7′-methoxy-2′,4′,7-trimethyl-2′,3′,4′,4′a,5,6,7,8,9′,9′a-decahydro-[2,9′-bianthracene]-9,10,10′(1′H)-trione	Al. sp. (SK11)	[47]
C₃₂H₂₅O₁₃/617	(+)-aS-alterporriol C		(1S,5′S,6′R,7′S,8′R)-1′,2,5′,6′,7′,8,8′-heptahydroxy-3′,6-dimethoxy-3,6′-dime-thyl-5′,6′,7′,8′,8′a,10′a-hexahydro-[1,2′-bianthracene]-9,9′,10,10′-tetraone	Al. sp. (SK11)	[47]
C₃₂H₂₅O₁₃/617	Alterporriol C		(1S,5′R,6′S,7′R,8′S)-1′,2,5′,6′,7′,8,8′-heptahydroxy-3′,6-dimethoxy-3,6′-dime-thyl-5′,6′,7′,8′,8′a,10′a-hexahydro-[1,2′-bianthracene]-9,9′,10,10′-tetraone	Al. sp. (SK11) Al. sp. ZJ-2008003	[47] [48]
C₃₂H2₉O₁₄/637	Alterporriol N		(6R,6′R,7R,7′R,8R,8′R)-4,4′,6,6′,7,7′,8,8′-octahy-droxy-2,2′-dimethoxy-7,7′-dimethyl-5,5′,6,6′,7,7′,8,8′-octahydro-[1,1′-bianthracene]-9,9′,10,10′-tetraone	Al. sp. ZJ-2008003	[48]
C₃₂H2₉O₁₄/637	Alterporriol O		(2R,2′R,3S,3′S)-2,2′,3,3′,8,8′-hexahydroxy-6,6′-dimethoxy-3,3′-dimethyl-1,1′,2,2′,3,3′,4,4′-octahy-dro-[1,1′-bianthracene]-9,9′,10,10′-tetraone	Al. sp. ZJ-2008003	[48]
C₃₄H₃₃O₁₇/713	Acetylalterporriol D		(1′S,5S,5′S,6R,6′R,7S,7′S,8R,8′R)-4,4′,5,5′,6′,7,7′,8,8′-nonahydroxy-2,2′-dimethoxy-7,7′-dimethyl-9,9′,10,10′-tetraoxo-5,5′,6,6′,7,7′,8,8′,9,9′,10,10′-dodecahydro-[1,1′-bianthracen]-6-yl acetate	Stemphylium globuliferum	[94]
C₃₄H₃₃O₁₇/713	Acetylalterporriol E		(1′R,5S,5′S,6R,6′R,7S,7′S,8R,8′R)-4,4′,5,5′,6′,7,7′,8,8′-nonahydroxy-2,2′-dimethoxy-7,7′-dimethyl-9,9′,10,10′-tetraoxo-5,5′,6,6′,7,7′,8,8′,9,9′,10,10′-dodecahydro-[1,1′-bianthracen]-6-yl acetate	Stemphylium globuliferum	[94]
C₃₄H₃₃O₁₇/713	Alterporriol D		(1S,5S,5′S,6R,6′R,7S,7′S,8R,8′R)-4,4′,5,5′,6,6′,7,7′,8,8′-decahydroxy-2,2′-dimethoxy-7,7′-dimethyl-5,5′,6,6′,7,7′,8,8′-octahy-dro-[1,1′-bianthracene]-9,9′,10,10′-tetraone	Stemphylium globuliferum	[94]
C₃₄H₃₃O₁₇/713	Alterporriol E		(1R,5S,5′S,6R,6′R,7S,7′S,8R,8′R)-4,4′,5,5′,6,6′,7,7′,8,8′-decahydroxy-2,2′-dimethoxy-7,7′-dimethyl-5,5′,6,6′,7,7′,8,8′-octahy-dro-[1,1′-bianthracene]-9,9′,10,10′-tetraone	Stemphylium globuliferum	[94]
C₄₈H₄₀O₂₁/952	Stemphylanthranol A		(5S,5′′S,6R,6′′R,7S,7′′S,8R,8′′R)-2′,4,4′′,5,5′′,6,6′′,7,7′′,8,8′,8′′-dodecahydroxy-2,2′′,6′-trimethoxy-3′,7,7′′-trimethyl-5,5′′,6,6′′,7,7′′,8,8′′-octahydro-[1,1′:5′,1′′-teranthracene]-9,9′,9′′,10,10′,10′′-hexaone	Stemphylium globuliferum	[94]
C₄₈H₄₀O₂₁/952	Stemphylanthranol B		(5S,5′′R,6R,6′′R,7S,7′′R,8R,8′′R)-2′,4,4′′,5,5′′,6,7,7′′,8,8′,8′′-undecahydroxy-2,2′′,6′-trimethoxy-3′,6′′,7,7′′-tetramethyl-5,5′′,6,6′′,7,7′′,8,8′′-octahydro-[1,1′:7′,1′′-tetranthracene]-9,9′,9′′,10,10′,10′′-hexaone	Stemphylium globuliferum	[94]
----	7-Chloroemodic acid	----	----	Caloplaca spp. (e.g., C. ehrenbergii, C. schaereri, C. spitsbergensis, etc.)	[75,76,77,79,96]
----	7-Chloroemodinal	----	----	Caloplaca spp. (e.g., C. ehrenbergii, C. schaereri, C. spitsbergensis, etc.)L. hafellneri L. leprolytoides	[75,76,77,79,96] [80]
----	7-Chloro-1,6,8-trihydroxy-3-methyl-10-anthrone	----	----	Caloplaca spp. (e.g., C. ehrenbergii, C. schaereri, C. spitsbergensis, etc.)	[75,76,77,79,96]

Abbreviations: A.: Aspergillus; Al.: Alternaria; P.: Penicillium. Orange brown: Marinedrugs 14 00064 i001 ; Orange: Marinedrugs 14 00064 i002 ; Yellow: Marinedrugs 14 00064 i003 ; Red: Marinedrugs 14 00064 i004 ; Bronze: Marinedrugs 14 00064 i005 .

Ubiquitous Fungi

The Aspergillus glaucus group, A. variecolor, A. versicolor as well as Eurotium cristatum, E. repens and E. rubrum, very rife on earth, were also identified in marine niches.

To date, Aspergillus glaucus is the best anthraquinones producer from this Aspergillus/Eurotium cluster, according to the diversity of anthraquinoids molecules listed (11 different molecules from personal data [110]). Nine (9) isolates originate from marine or salted environments (sea, saltern, mangrove), suggesting a developed capacity to face high NaCl concentrations. These marine-derived isolates produce the main part of the new compounds identified in this genus up to now, besides endolichenic Aspergilli.

Catenarin, emodin, erythroglaucin, physcion, questin, and rubrocristin or physcion anthrone are commonly produced by marinederived Aspergillus and/or Eurotium species, as well as by their terrestrial counterparts. Moreover, Variecolorquinone A, which seems specific to the Aspergillus family, is synthesized by Aspergillus glaucus and A. variecolor B-17 from salted environments.

10,10′-dimer of emodin and physcion along with cynodontin, helminthosporin, tritisporin, unusual in this genus are excreted by the mangrove strain A. glaucus HB1-19. Two new hexahydroanthrones—tetrahydrobostrycin and 1-deoxytetrahydrobostrycin—are produced by Aspergillus sp. 05F16, a strain isolated from an unidentified alga collected in a coral reef (Indonesia).

The new methyl-emodin and 7-hydroxyemodin 6,8-methyl ether, along with emodin, were identified in the A. versicolor anendophytic strain isolated from the Red Sea green alga Halimeda opuntia. The new 6,8-di-O-methyl averantin, along with six known congeners are also synthesized by A. versicolor EN-7 (Genbank noEU042148), an endophytic fungus of Sargassum thumbergii (brown algae).

The common genus Eurotium consists in teleomorphic, often xerophilic, species, usually related to Aspergillus anamorphs, especially from the A. glaucus group. Anke et al. [36] reported that, inside the Eurotium genus, E. rubrum, and E. cristatum produce the highest diversity of compounds; regarding anthraquinones, physcion, physcion anthrone, erythroglaucyn, catenarin, rubrocristin and emodin have been identified in their cultures. They also demonstrated that, inside a species, there was a great variability towards anthraquinones production, as some strains of Eurotium (among them E. rubrum and E. herbariorum) behaved differently in the same culture conditions. Moreover, some of the strains studied did not produce any anthraquinone, in the conditions of the experiment. Butinar et al. [111], noticed that, in Slovenian solar salterns, E. amstellodami, E. herbariorum and E. repens contributed to indigenous fungal community in hypersaline water environments, while E. rubrum and E. chevaliery were only temporal inhabitants of brine at lower salinities. In contrast, they stated that, for the six Eurotium strains isolated from these salterns, the qualitative secondary metabolites profiles were not different from those of strains isolated from foods or other habitats. However, the new 6,3-O-(α-d-ribofuranosyl) questin (anthraquinone gylycoside) is a new questin derivative from the marine-derived E. rubrum QEN-0407-G2, isolated from the marine mangrove plant Hibiscus tiliaceus. This compound, produced along with questin, seems unusual in the genus [63].

The unidentified fungus ZSUH-36 (isolated from the Shenzhen mangrove plant Acanthus ilicifolius Linn.), the isolate 1850 (from a leaf of Kandelia candel from an estuarine mangrove in Hong Kong), and the mangrove endophytic strain 2526 produce versicolorin C, although the A enantiomer seems more common from the terrestrial producers Aspergillus versicolor and A. parasiticus. The two marine-derived strains, isolate 1850 and isolate 2526, also excrete the new nidurufin, along with the known averufin, also found in emerged Aspergillus parasiticus and A. versicolor. Fungus strain ZSUH-36 produces several new compounds, namely, 6,8-di-O-methyl averufin, 6,8-di-O-methyl averufanin, 1′-O-methyl averantin, and 6,8,1′-tri-O-methyl averantin.

Penicillium is a very widespread genus on earth and in marine biotopes. It seems to adjust easily to multiples conditions and to be a source of original compounds. The most commonly represented molecules in the terrestrial strains are emodin (and derivatives), rugulosin, and skyrin (or luteoskyrin), and then carviolin and chrysophanol (personal data, [110]). Penicillium citrinum PSU-F51 isolated from the gorgonian sea fan Annella sp. and P. oxalicum 2-HL-M-6 (from the sea mud sample) synthesize the common chrysophanol and emodin, but also citreorosein (ω-hydroxyemodin), a compound that, to date, is only isolated from the coprophilous ascomycete Zopfiella longicaudata IFM4630 [88,91]. Penicillanthranins A and B (two new anthraquinone-citrinin derivatives) are also excreted by Penicillium citrinum PSU-F51. Two new molecules—citreorosein-3-O-sulfate and emodin-3-O-sulfate as well as 1,8-dihydroxy-3-(hydroxymethyl) anthracene-9,10-dione (aloe emodin)—are engendered by P. oxalicum 2-HL-M-6. This strain also produces isorhodoptilometrin, which is uncommon, as it is only known from one plant-endophytic Aspergillus sp. (strain YL-6) [91,112]. Penicillium chrysogenum (from a saline lake in Antarctica) is the only aquatic fungus known for the production of skyrin, similarly to its terrestrial counterpart and four other terrestrial strains (P. islandicum, Talaromyces wortmanii, and Dermocybe spp.) [89]. In a related genera, Paecilomyces sp. (Tree 1-7), a mangrove-derived fungus from a Taiwan strait, also produces chrysophanol and emodin [87].

Endophytes and/or Pathogens

Trichoderma is a frequent genus among vegetal root-associated fungi (endophytes and symbionts). Few marine-derived strains have been identified, to date, as anthraquinoid producers. However, the frequent emodin, ω-hydroxyemodin, pachybasin, ω-hydroxypachybasin, 1-hydroxy-3-methoxyanthraquinone, 2-methylquinizarin, and chrysophanol were detected in Trichoderma aureoviride PSU-F95, cultured from a gorgonian sea fan Annella sp. [88]. This strain also produces the new trichodermaquinone (tetrahydroanthraquinone), the rare coniothranthraquinone, or isorhodoptilometrin. Trichoderma strains from terrestrial origin rather produce chrysophanol and pachybasin (personal data, [110]).

Several species of Alternaria are terrestrial plants pathogens. Terrestrial Alternaria anthraquinones′ producers are found in many species, including A. eichorniae, also isolated from marine environments. The main represented compounds in this genus are macrosporin, altersolanol A, and 6-methylxanthopurpurin-3-O-methyl ether. However, original compounds were mainly isolated from marine-derived isolates. Indeed, alterporriols (A, B, C), altersolanol A, austrocortinin, bostrycin, physcion, and macrosporin are excreted by Alternaria species, originating from marine niches. Alterporriols C is commonly found in terrestrial and aquatic strains, but, until now, alterporriol A and B are only ones known from Alternaria′s marine-derived strains or from the terrestrial brother-group Stemphylium (S. globuliferum). This similarity in extrolite production with this genus also concerns altersolanol A, produced by several Stemphylium strains, from terrestrial or salted environments (S. botryosum v. lactucum, S. globuliferum).

Concerning original compounds, Alternaria eichorniae, a pathogen of the water hyacinth Eichhornia crassipes, produces 4-deoxybostrycin, a rare compound only identified in a marine-derived Nigrospora sp. [46]. Alternaria sp. ZJ9-6B, a mangrove strain from the South China Sea, synthesizes seven new compounds: alterporriol K, L and M, dactylariol, alternariol (AOH), alternariol methyl ether (AME), and tetrahydroaltersolanol B [49]. The mangrove endophytic strain Alternaria sp. SK11, from the root of Excoecaria agallocha collected in the South China Sea, produces alterporriol S, (+)-aS-alterporriol C, 6-methylquinizarin along with the known austrocortinin [47]. Alternaria sp. ZJ-2008003, a fungus obtained from a Sarcophyton sp. soft coral from the South China Sea, is the only known strain to produce alterporriols N–R (five new alterporriol-type anthranoid dimers) [48].

Stemphylium globuliferum (from Juncus acutus collected from an hypersaline lake in Egypt) generates the common compounds alterporriol D and E, altersolanol A and B, and macrosporin, as well as the genus specific 6-O-methylalaternin [94]. Seven new compounds can also be found in this strain: altersolanol C, dihydroaltersolanol B and C, acetylalterporriols D and E (atropisomers), and stemphylanthranols A and B (the first naturally occurring trimeric anthraquinone derivatives). This endophytic/pathogenic fungus seems very productive in new compounds in marine environments. Indeed, the strain Stemphylium sp. 33231, obtained from the mangrove plant Bruguiera sexangula var. rhynchopetala, excreted four new alterporriol-type anthranoid dimers, along with 17 analogues [93]. In terrestrial habitats, the genus Stemphylium (anamorph of Pleospora) consists of plants pathogens/endophytes. The number of original molecules found in its productions is feeding the idea of originality in compounds coming from plant/microbe associations (alterporriol G and H (atropisomers), altersolanols K and L, as well as the new stemphypyrone) [113].

Fusarium is a widespread plant pathogen. The marine-derived Fusarium strains, mainly associated with marine organisms, produce four completely new anthraquinoid compounds. Fusarium sp. No. B77 (a mangrove endophytic strain from the south China sea) produces the new 5-acetyl-2-methoxy-1,4,6-trihydroxy-anthraquinone, and F. sp. ZZF60, another mangrove endophytic fungus from the same area, synthesizes the new 6,8-dimethoxy-1-methyl-2-(3-oxobutyl)-anthraquinone. The strain F. sp. No. ZH-210 coming from mangrove sediments of Zhuhai (China) produces the new fusaquinon B and C (red anthraquinone derivatives) along with the new fusaquinon A (colorless) [68]. Fusarium spp. PSU-F14 and PSU-F135 (endophytes from the gorgonian sea fan Annella sp., collected in Thailand) excrete the known bostrycin but also austrocortirubin, mainly known from the terrestrial macromycete Cortinarius spp.

Microsphaeropsis sp. (associated with the mediterranean sponge Aplysina aerophoba) produces 1,3,6,8-tetrahydroxyanthraquinone, also extracted from terrestrial Geosmithia, Trichoderma, and Verticicladiella. Three new C2-derivatives of 1,3,6,8-tetrahydroxyanthraquinone were also isolated from this marine derive fungi for the first time.

Monodictys (from a Japanese sea urchin Anthocidaris crassipina) is producing the common pachybasin, which was found for the first time from this species, along with emodin and chrysophanol, and also the new monodictyquinone A.

Halorosellinia sp. No. 1403 isolated from Kandelia sp. decayed woody tissue in Mai Po (Hong Kong, South China Sea) from a salt lake in the Bahamas excretes austrocortirubin, demethoxyaustrocortirubin, hydroxy-9,10-anthraquinone and two new compounds: 1,4,6-trihydroxy-2-methoxy-7-methylanthracene-9,10-dione and the patented 2,3,4,5,8,10-hexahydroxy-7-methoxy-3-methyl-1,3,4,10-tetrahydro-9(2H)-anthracenone (patented compound SZ-685C, [104]).

The endophytic Nigrospora sp. isolated from the mangrove plant Bruguiera sexangula is able to synthesize the new 1-deoxytetrahydrobostrycin (synonym: 8-hydroxytetrahydroaltersolanol B) along with bostrycin and 4-deoxybostrycin, depending on the culture media [83,114]. Nigrospora sp. 1403, endophytic from Kandelia candel in a marine mangrove (South China Sea), also produces bostrycin as two terrestrial strains [114,115] along with deoxybostrycin [86]. Nigrospora sp. isolated from an unidentified sea anemone excretes the new compounds 4a-epi-9α-methoxydihydrodeoxybostrycin and 10-deoxybostrycin along with seven known anthraquinone derivatives [84].

The new (2R,3S)-7-ethyl-1,2,3,4-tetrahydro-2,3,8-trihydroxy-6-methoxy-3-methyl-9,10-anthracenedione (new tetrahydroanthraquinone derivative) and the compound 1-hydroxy-3-methoxy-6-methylanthraquinone (first time isolation from fungi), along with macrosporin and tetrahydroaltersolanol B&C, were extracted from a culture of Phomopsis sp. strain (PSU-MA214) isolated from a leaf of a mangrove plant Rhizophora apiculata. This is different from a terrestrial strain of P. juniperovora (PM0409092) producing the common altersolanol A.

Curvularia lunata (anamorphic stage of Cochliobolus lunatus), isolated from the marine sponge Niphates olemda in Indonesia, excretes the new lunatin and cytoskyrin A, a molecule only known from one another species Cytospora sp. CR 200 (endophyte from the buttonwood tree Conocarpus erecta in Costa Rica) [60].

Reviewed by Crous et al. [116], many species of Arthinium are associated with plants as endophytes or parasites, even in marine conditions. Somes strains of Athrinium phaeospermum cause cutaneous infections of humans. Others are involved in endophytic plant relationships, producing growth promoting substances, e.g., in Carex kobomugi. The endophytic Arthrinium phaeospermum CBS 142.55 (type strain of Botryoconis sanguinea) produced bostrycin with some minor unidentified red and yellow pigments when cultured on malt extract agar [117]. Bostrycin is produced by Bostrychonema alpestre, the causal agent of water hyacinth blight disease, as well as by other plant pathogenic fungi such as Alternaria eichorniae, Nigrospora oryzae, Arthrinium phaeospermum and Fusarium spp. Bostrychonema alpestre (terrestrial strains) also excretes austrocortilutein and torosachrysone mainly found in macrofungi as Dermocybe splendida [118].

As far as bostrycin is concerned, the originally proposed structure [119,120,121] was revised by Kelly and his co-workers in 1985 [122] on the basis of the total synthesis of (+/−)-bostrycin and an X-ray crystal structure of the O-isopropylidene derivative. This revision also concerns its derivative 4-deoxybostrycin found in serveral marine isolates [68,84,86,101,123].

A marine-derived strain of Xylaria sp. 2508 produces a new compound, xylanthraquinone, along with three known anthraquinones, altersolanol A, deoxybostrycin, and bostrycin [95]. The Xylariaceae is one of the largest families of endophytic filamentous fungi isolated from plants material in terrestrial biotopes. There, they essentially grow under the form of mycelial structure, and their fruiting bodies (stromata) seem to form only when their host is stressed or diseased. However, the pigments seem to be mainly extracted from their fruiting stages [124]. Under marine conditions the morphological structures of fungi are not yet precisely described, and researchers suppose that fungi are mainly growing under mycelial structures. Nevertheless, this does not prohibit the synthesis of these anthraquinoid molecules.

To date, over 100 different anthraquinoid metabolites have been identified in around 27 marine-derived fungal isolates, belonging to at least 22 identified species.

Lichens

Caloplaca, Collema, Collemopsidium, Lichina, Ochrolechia, Ramalina, Tephromela, Verrucaria, and Xanthoria species are frequent among lichenic maritime populations [125]. They are known, in marine as in terrestrial biota, to be frequent producers of the common physcion (parietin). This anthraquinoid compound is excreted by Xanthoria aureola and X. parietina collected from exposed maritime rocks (South Norway) [126,127]. A high diversity of specific compounds can, however, be obtained from lichens, particularly in species producing chlorinated anthraquinones [76,96,128]. The production of special anthraquinones is a major characteristic of most species in the family Teloschistaceae (Caloplaca, Xanthoria, etc.) [72,77]. In the genus Xanthoria, and in closely related species of Caloplaca, antraquinoid molecules seem to be the only lichenic secondary compounds present [129,130]). The majority of species produce the widespread parietin and its chemical relatives, but also fragilin, emodin, and chloroemodin, accompanied by varying amounts of their oxydation products [128,129,131]. Caloplaca spp. isolated from calciferous rocks in Central Asia (C. schaereri; C. spitsbergensis, C. ehrenbergii, and other species) effectively produce 7-chlorocitreorosein and 7-chloro-1,6,8-trihydroxy-3-methyl-10-anthrone, as well as 7-chloroemodic acid, 7-chloroemodinal, and 1-O-methyl-7-chloroemodin, but also fallacinol (teloschistin) and fallacinal. Many of these compounds, widespread among lichens, are not found outside from the lichen′s group.

Some fungal mycobiontes involved in lichen associations also proved their capacity to produce several original anthraquinoid molecules in separate cultures. For instance, Aspergillus versicolor, a mycobionte in Lobaria retigera excretes averythin, 8-O-methylaverythin, 8-O-methylversicolorin A and B, 6,8-di-O-methylversicolorin A, 6,8-di-O-methylaverufin, and 6,8,1′-tri-O-methylaverantin [108].

3. Biosynthesis and Known Roles for Anthraquinones in Fungi

The metabolism is the sum of all the biochemical reactions carried out by an organism. Opposite to the primary metabolism, converging to few products common to many organisms, the secondary metabolic pathways diverge to a great diversity of molecules produced from a few key intermediates of primary metabolism. While endometabolites can be found in almost all species of fungi, exometabolites seem taxonomically shared by species–specific profiles [132,133]. Some authors then assert that the nature of the extrolites can act as signatures, specific to the organisms, coming from biogenetics patterns. Thereby, in Dermocybe spp., it was possible to group some subsections with regards to biosynthetis of particular anthraquinoid compounds (skyrin, icterinoidin or hypericin) [134]. Considering the significant shortcomings in these research fields, future studies will gain knowledge about the truth of these claims. Undoubtedly subservient to the genetic skills, the biosynthesis of metabolites such as anthraquinone derivatives is clearly influenced and regulated by a complex set of factors including biotic and abiotic dimensions. Such parameters as temperature, pH, [O₂] availability, light exposure, nature, and abundance of nutritive sources, as well as age and specialization of the fungal structures, have already been proven to have a strong influence on pigments production [135,136,137,138,139].

3.1. Biosynthetic Route and Genes Involved

As polyketides seem to be the most abundant extrolites in fungi, the pathways for their biosynthesis have been widely explored [140]. However, the formation of anthraquinones in fungi is not the most developed area in the literature.

In fungi polyketide compounds are primarily synthesized by the acetate-malonate pathway, which is different from plants using shikimate pathways as well as acetate-malonate metabolism. Depending on the presence of acetate, malonate, or both components, according to the growth conditions, and to the strains involved, the numbers of each residue incorporated differ, and the final secondary metabolites as well. The involvement of each type of molecule can be studied through experiments using [¹³⁻¹⁴C-acetate] and [¹³⁻¹⁴C-malonate], ([141] and other authors such as Gessler et al. [17]. In relation to this acetate-malonate pathway, the biosynthetic relationships seem to form yellow hydroxyanthraquinones (e.g., emodin, physcion, and dermolutein) at the beginning of the pathway (simple structures), whereas the red ones, such as dermorubin or dermocybin, with more complex structures, certainly occur in the latter part of the biosynthesis pathway [16].

Hanson et al. [15] and Gessler et al. [17] summarized that anthraquinones synthesis are regulated by non-reducing polyketide synthases (NR-PKS′s). These multidomains enzymes mediate the regioselective cyclization of polyketides, clearly dominating the final structures. NR-PKS′s form polyketides in which carbonyl groups are not reduced, whereas reducing polyketide synthases partially or fully reduces the carbonyl groups [142,143]. These multifunction complexes, including acyl carrier protein (ACP), transacylase (STA), ketosynthase (KS), malonyl-CoA transacylase (MTA), thioesterase (TE), product template (PT) domain, methyltransferases, and reductases, first ensure the condensation of acetyl-CoA (starter unit) and malonyl-CoA (extender unit). This produces an instable β-polyketide chain (containing a free carboxylate group) precursor of different aromatic structures. There are several types of PKSs found in different organisms (groups I-VIII), but the principles of constructing the poly-β-keto chain are the same with all PKSs.

From these, the fungal PKS are of considerable interest due to their interesting enzymology and the final polyketide structural diversity [144]. One of the earlier major advances in identification of fungal polyketide secondary metabolite gene clusters is the development of a degenerate-primed polymerase chain reaction (PCR), based on the conserved ketosynthase domain of PKS [145]. Javidpour et al. [146] asserted that the specific enzyme product template (PT) domain, determined the regioselectivity of the cyclization of the polyketide chain, and then the final structure of the products. Thus, they appeared as key factors in the biodiversity of these secondary metabolites. In fungi PT, domains are found in all 8 groups, but anthraquinoid compounds seem to be mainly produced from PT IV and V groups, indicating C4-C9 or C6-C11 cyclizations.

Based on a bioinformatical analysis, Liu et al. [147] interestingly clarified the relationships between enzyme sequences, structures, and functions in fungal PKS PT domains. Besides the basic PKS domain, additional functional domains, including the SAT (starter unit-ACP transacylase) domain, the PT (product template) domain, and the TE (thioesterase) releasing domain, are unique to the NR-PKSs. The PT domains have been demonstrated to be involved in controlling specific aldol cyclization and aromatization of the polyketide precursors. For the first cyclization, three commonly cyclizing patterns appear (C2-C7, C4-C9, and C6-C11). The comparison of 661 NR-PKS sequences belonging to ascomycota and basidimycota revealed that the PT domains can be classified into prominent eight groups (I–VIII) corresponding with the representative compounds and the cyclization regioselectivity. Most of the cavity lining residue (CLR) sites were common in all groups, while the regional CLR site mutations resulted in the appearance of finger-like regions with different orientation. The conservative residues in PT sequences were responsible for the cyclization functions and the evolution of the key residues resulted in the differentiations of cyclization functions. Thus, the cavity volumes and shapes, even the catalytic dyad positions of PT domains in different groups, corresponded to characteristic cyclization regioselectivity and compound sizes.

These authors also noticed that the cyclization route of the polyketide chains even differ between actinomycetes and fungi, certainly due to the involvment of different groups of PT enzymes [148]). Moreover, the late steps of the biosynthesis are responsible for the additions and deletions of lateral substituent groups, generating a great diversity of compounds. For instance, they assert that methyl groups of anthraquinones come from methionine residues via S-adenosylmethionine [149,150,151,152,153].

Miethbauer et al. [141] tried to elucidate the biosynthetic pathway of a complex anthraquinone via the synthesis of rubellins. Nineteen species of Ramullaria coming from different regions were tested for the production of rubellins A, B, C, D, E, and F. Seventeen biosynthesized the entire panel of rubellins, more or less intensively, except two of them: R. pratensis and R. inaequalis. They stated that, using [¹³C-acetate], rubellins are naturally synthesized through the polyketide pathway. They demonstrated that the methyl group of acetate must be converted in part to a carboxyl one via protein turnover, or more specifically by biosynthesis, and the subsequent degradation of lysine in fungi [154]. They suggested that rubellin A and B are certainly originating from a dimeric anthraquinone and that helminthosporin (1,5,8-trihydroxy-3-methylanthraquinone) can be considered the primordial monomer. The conversion of the keto group into a lactone is supposed to be carried out by a Baeyer-Villiger monooxygenase [155]. Thus, they proved that, if the majority of the strains can use these rubellins as nonspecific toxins against plants, some of the species are, surprisingly, completely unable to produce such molecules.

The recent whole-genome sequencing of various fungi revealed that these microorganisms have immense biosynthetic potential, surpassing, by far, the chemical diversity observed in laboratory cultures. For example, the genome of many Aspergilli encodes a combined 30 to 80 PKS—non-ribosomal peptide synthetases and polyketide non-ribosomal peptide synthetases hybrids—which far exceed the total number of known polyketides and non-ribosomal peptides [156].

Recently, Bringmann et al. [157] revealed that the pigment chrysophanol can come from an organism-specific route, through a third folding mode involving a remarkable cyclization of a bicyclic diketo precursor. This establishes the first example of multiple convergences in polyketide biosynthesis. The programming of the fungal PKS seems quite complex and suitable to form sophisticated products. An additional level of complexity can be imagined combinatorializing PKS-based pathways with other metabolic routes.

Kakule et al. [158] realized a gene fusions with the idea of testing the connection and compatibility of the PKS and NRPS (nonribosomal peptide synthetase) modules, mediated by the ACP, condensation (C) and ketoreductase (KR) domains. The resulting recombinant gene fusions availed six new compounds. They obtained the first successful fusion between a PKS and NRPS that make highly divergent products as well as previously reported molecules. Thus, they demonstrated that, within the highly reducing (hr) PKS class, noncognate ACPs of closely related members can complement PKS function.

Today, it is rather clear that many of the genes involved in the polyketide pathway are organized in gene clusters, which are often silent or barely expressed under laboratory conditions. This makes their study more difficult. Fortunately, the genome sequences of several filamentous fungi are now publicly available, greatly facilitating the establishment of links between genes and metabolites. To date, complete knowledge about the biosynthetic pathway of hydroxyanthraquinonoid compounds is not yet available, but this knowledge is increasing daily.

3.2. Roles in the Biology of Fungi

Anthraquinones belong to secondary metabolites. The secondary metabolic pathways are today considered as diversions from the primary metabolism, leading to a great diversity of compounds, arising from a few key intermediates. Secondary metabolites, also known as exometabolites, are produced during morphological and chemical differentiation, either accumulated or excreted. In contrast, endometabolites (primary metabolites) fluctuate in concentrations and either transform into other endometabolites or feed into exometabolites. Secondary metabolites are bound to appear when the environmental conditions become unfavorable, in particular when a substrate other than carbon becomes limited [159]. This process of derivation is important in itself. Indeed it is supposed to provide a route for the removal of intermediates, which would otherwise accumulate. This accumulation could probably enable the primary processes leading to these intermediates to remain operational during the time of stress [160]. For researchers, this formerly implied two main features: (1) Cells that are no longer undergoing balanced growth synthesize them for a finite period; and (2) no obvious functions were clearly demonstrated in cell growth for these compounds. Thus, they appeared to researchers to be not vital to the cell life itself. Nowadays, the trend is, through their direct or indirect actions, secondary metabolites are important for the entire organism′s survival [161,162,163]. Due to their chemical and biological properties they are today considered as first-plan actors to help in protection, competition, symbiosis, metal transport, differentiation, etc. The biological significance of anthraquinoids pigments, as others such as carotenoids, involves resistance to a variety of adverse environmental factors (dessication, exposure at extreme temperatures, irradiations), to antimicrobial activity (antibacterial, antiviral). Many observations have now been published with regard to the antioxidant activity of carotenoids pigments, protective action against lethal photooxydation, inhibition of mutagenesis, enhancement of the immune response, and inhibition of tumor development [164]. Melanin was also suggested to act as a shield against immunologically active cells [165].

Besides the intensively investigated fungal azaphilone pigments, anthraquinone compounds have been considered among the most abundant fungal natural products, giving color to spores, sclerotia, sexual bodies, and other developmental structures [139]. Present research suggests that, in specific cases, it is doubtful that pigments are really secondary metabolites [164]. It is now clear that anthraquinones should play a role in the cell life.

This entry is adapted from the peer-reviewed paper 10.3390/md14040064

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