toxins Review Fungal Bioactive Anthraquinones and Analogues Marco Masi and Antonio Evidente * Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant’Angelo, Via Cintia 4, 80126 Napoli, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-081-2539178 Received: 20 October 2020; Accepted: 7 November 2020; Published: 12 November 2020 Abstract: This review, covering the literature from 1966 to the present (2020), describes naturally occurring fungal bioactive anthraquinones and analogues biosynthesized by the acetate route and concerning several different functionalized carbon skeletons. Hydrocarbons, lipids, sterols, esters, fatty acids, derivatives of amino acids, and aromatic compounds are metabolites belonging to other different classes of natural compounds and are generated by the same biosynthetic route. All of them are produced by plant, microorganisms, and marine organisms. The biological activities of anthraquinones and analogues comprise phytotoxic, antibacterial, antiviral, anticancer, antitumor, algicide, antifungal, enzyme inhibiting, immunostimulant, antiplatelet aggregation, cytotoxic, and antiplasmodium activities. The review also covers some practical industrial applications of anthraquinones. Keywords: anthraquinones; natural analogues; fungi; biological activity Key Contribution: This review, covering the literature from 1966 to the present (2020), concerns fungal anthraquinones and their biological activity including phytotoxic, antibacterial, antiviral, anticancer, algicide, antifungal, enzyme inhibiting, immunostimulant, antiplatelet aggregation, and antiplasmodium activities. The review also covers some practical industrial applications of anthraquinones. 1. Introduction Anthraquinones are a group of natural compounds with a plethora of biological activities and potential practical applications. Most of them are produced by plant and micro-organisms among the living organisms [1,2]. They are acetate-derivative metabolites biosynthesized starting from a polyketide containing eight C2 units, which generates in turn with three aldol type condensations the carbon skeleton of anthraquinones except for the two carbonyl oxygens of the central ring. The latter are introduced by successive steps with an oxidation process. One example of this kind of biosynthesis is reported in Figure1 for endocrin, a fungal anthraquinone produced by several Penicillium and Aspergillus species [3]. Among secondary metabolites anthraquinones are the most investigated natural products for their mechanism of action [4]. Plants, microorganisms, lichens, and algae are producers of metabolites possessing diverse biological activities such as phytotoxic, antibacterial, antiviral, anticancer, antitumor, algicide, antifungal, enzyme inhibiting, immunostimulant, antiplatelet aggregation, cytotoxic and antiplasmodium activities. Anthraquinones are frequently reported among the plethora of different classes of natural compounds as alkaloids, hydrocarbons, lipids, sterols, esters, fatty acids, derivatives of amino acids, terpenoids, and aromatic compounds [5–7]. The activity of several hydroxyl- and amino-anthraquinones cannot be exploited due to their weak solubility in water. Thus, some of them are converted into water-soluble analogues by biotransformation [8]. Anthraquinones have Toxins 2020, 12, 714; doi:10.3390/toxins12110714 www.mdpi.com/journal/toxins Toxins 2020, 12, 714 2 of 30 Toxins 2020, 12, x FOR PEER REVIEW 2 of 31 biotransformationalso industrial application [8]. Anthraquinon as naturales dyes have substituting also industrial synthetic application chemicals as natural in formulation dyes substituting to avoid syntheticundesired chemicals collateral in eff formulationects [9]. to avoid undesired collateral effects [9]. Some previousprevious reviewsreviews have have described described fungal fungal anthraquinones anthraquinones such such as that as published that published by Gessler by Gesslerat al. (2013) at al. [ 10(2013)], limited [10], tolimited 12 natural to 12 anthraquinones, natural anthraquinones, and those onand anthraquinones those on anthraquinones specifically producedspecifically by produced derived marineby derived fungi marine [11]; also fung amongi [11]; them also theamong treatment them ofthe the treatment anthraquinones of the anthraquinonessynthesized by a synthesized single fungal by species a single such fungal as Phoma specieswas such reported as Phoma [12 was]. reported[12]. Figure 1. Biosynthesis of the anthra anthraquinonequinone carbon skeleton. This reviewreview describes describes an an advanced advanced overview overview on anthraquinones, on anthraquinones, and related and analoguesrelated analogues grouped groupedfor the first for timethe first according time according to their to natural their natural sources. so Inurces. particular, In particular, in addition in addition to the to isolation the isolation from fromfungal fungal sources sources and their and chemical their chemical characterization, characterization, their potential their potential applications applications in different in fields different such fieldsas agriculture, such as medicineagriculture, and medicine the dyes industryand the aredyes considered industry on are the considered basis of their onbiological the basisactivities. of their biologicalThe firstactivities. section chronologically describes the fungal anthraquinones starting from 1966 to the presentThe first day section focusing chronologically on their sources, describes structures, the andfung biologicalal anthraquinones activities. starting The second from section 1966 to treats the presentthe industrial day focusing application on their of anthraquinones sources, structures, in a di anfferentd biological field essentially activities. as The natural second dyes. section This parttreats is thefocused industrial on the application comparison of between anthraquinones natural andin a syntheticdifferent field anthraquinone essentially based as natural dyes, dyes. their This chemical part isderivatization focused on andthe classification,comparison between and the natural advanced and methods synthetic used anthraquinone in the treatment based of thedyes, relative their chemicalindustrial derivatization wastewater to and avoid classification, severe negative and the environmental advanced methods pollution. used Finally, in the treatment the main pointsof the relativedescribed industrial are summarized wastewater in the to conclusion.avoid severe negative environmental pollution. Finally, the main points described are summarized in the conclusion. 2. Fungal Anthraquinones and Analogues 2. FungalDothistromin Anthraquinones (1, Figure and2, Table Analogues1) was isolated as the main phytotoxin produced by Dothistroma pini (Hulbary), a pathogen inducing necrotic disease characterized by the formation of red bands Dothistromin (1, Figure 2, Table 1) was isolated as the main phytotoxin produced by on the infected needles of Pinus radiata and other pines [13]. The same fungus also produced six Dothistroma pini (Hulbary), a pathogen inducing necrotic disease characterized by the formation of other anthraquinones: bisdeoxydothistromin; bisdeoxydehydrodothistromin; 6-deoxyversicolorin C; red bands on the infected needles of Pinus radiata and other pines [13]. The same fungus also produced six other anthraquinones: bisdeoxydothistromin; bisdeoxydehydrodothistromin; Toxins 20202020,, 1212,, 714x FOR PEER REVIEW 3 of 31 30 6-deoxyversicolorin C; averufin; nidurufin; averythrin (6–11, Figure 2, Table 1). No biological averufin; nidurufin; averythrin (6–11, Figure2, Table1). No biological activity was reported for 2–7 [14]. activity was reported for 2–7 [14]. More recently, averythrin was also isolated from the marine More recently, averythrin was also isolated from the marine derived fungus Aspergillus versivolor [15]. derived fungus Aspergillus versivolor [15]. OH O OH O O O O O R 2 R OH O R1 3 OH O R 1, R =R =R =OH 1 2 3 3, R=OH 2, R =OH, R =R =H 1 2 3 4, R=H O O H3CO O HO OH O OH O 5, R=H OH O 6, R=OH R 7 O O O H3CO H3CO OH R OH OH O OH O OH 8, R=OH 10 9, R=H O R1 O O H3CO H OH OH O H3CO OH OH OH OH O R2 H OH O OH 12, R =H, R =OH H H 1 2 13, R =R =H 11 HO 1 2 O OH 14 Figure 2. BioactiveBioactive anthraquinones anthraquinones an andd analogues analogues produced produced by Dothistroma pini, Aspergillus versicolor, AlternariaAlternaria porri, porri, Alternaria Alternaria solani, solani, Alternaria Alternaria cucumerina, cucumerina, Alternaria Alternaria bataticola, bataticola, Diaporthe Diaporthe angelicae angelicaeand Stemphyfium and Stemphyfium botryosum botryosum. Macrosporin and and 6-methylxanthopurpurin 3-methyl 3-methyl ether ether ( (88 andand 99,, Figure Figure 22,, TableTable1 1)) are are two two anthraquinones producedproduced bybyAlternaria Alternaria bataticola bataticola, the, the causal causal agent agent of of a black a black spot spot of sweet of sweet potato potato [16]. [16].Compound Compound8 was 8 also was isolated also isolated from other from fungi other of thefungi same of genusthe same as A. genus porri, A.as solani A. porriand, A. cucumerinasolani and A.while cucumerina9 was isolated while also 9 was from isolatedA. solani also[16 from]. Then A. solani macrosporin [16]. Then was macrosporin isolated together was withisolated another together two withanthraquinones, another two namedanthraquinones, altersolanols named A and altersolanols J (10 and 11 A, Figureand J (210, Table and 111),, asFigure