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Review

The Genus Cladosporium: A Rich Source of Diverse and Bioactive Natural Compounds

by
Maria Michela Salvatore
1,
Anna Andolfi
1,2,* and
Rosario Nicoletti
3,4
1
Department of Chemical Sciences, University of Naples ‘Federico II’, 80126 Naples, Italy
2
BAT Center—Interuniversity Center for Studies on Bioinspired Agro-Environmental Technology, University of Naples ‘Federico II’, Portici, 80055 Naples, Italy
3
Council for Agricultural Research and Economics, Research Centre for Olive, Fruit and Citrus Crops, 81100 Caserta, Italy
4
Department of Agricultural Sciences, University of Naples ‘Federico II’, 80055 Portici, Italy
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(13), 3959; https://doi.org/10.3390/molecules26133959
Submission received: 11 June 2021 / Revised: 22 June 2021 / Accepted: 24 June 2021 / Published: 28 June 2021
(This article belongs to the Special Issue Natural Secondary Metabolites II)
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Abstract

:
Fungi are renowned as one of the most fruitful sources of chemodiversity and for their ubiquitous occurrence. Among the many taxonomic groupings considered for the implications deriving from their biosynthetic aptitudes, the genus Cladosporium stands out as one of the most common in indoor environments. A better understanding of the impact of these fungi on human health and activities is clearly based on the improvement of our knowledge of the structural aspects and biological properties of their secondary metabolites, which are reviewed in the present paper.

1. Introduction

Results of recent research in the mycological field have further disclosed the pervasive diffusion of fungi in the genus Cladosporium (Dothideomycetes, Cladosporiaceae). Basically saprophytic, these Ascomycetes are spread in every kind of terrestrial and marine environment, where they establish various symbiotic relationships with plants and animals [1]; moreover, they are among the most frequent fungi detected in indoor spaces [2,3]. This latter connotation implies obvious opportunities for interactions with people, which can sometimes evolve into undesirable effects in terms of allergic or even pathogenic reactions [4,5,6,7,8].
Over the past two decades, investigations into the occurrence of Cladosporium spp. have been boosted by their tremendous ecological adaptability, as well as their frequent implication in human activities and medical aspects. Fundamental support from the molecular tools for species identification has enabled mycologists to disclose an exceptional taxonomic variation, with as many as 218 accepted species considered in the most recent update [3] and more new species added to the list in the last three years [9,10,11]. Considering the importance of secondary metabolites as mediators of biological interactions, this versatility has also generated notable research activity concerning the metabolome of these fungi and its biological properties, which are revised in the present paper.

2. Fifty Years of Metabolomic Studies in Cladosporium

A set of 68 Cladosporium strains have been examined so far, about 2/3 of which have been formally classified at the species level and ascribed to 12 taxa (Table 1). In this respect, the most frequent species are represented by the progenitors of the three main species complexes of the genus [1,3]. This may imply that in some cases the taxonomic identification has been approximate, as it only relied on morphological characters or ITS sequences. Concerning the origin, the examined strains are almost equally distributed between terrestrial and marine sources, with a prevalence of those recovered as endophytes or from sediments (Figure 1).
Despite the low number of strains, a long list of products has been reported from Cladosporium, starting with the finding of cladosporin in 1971 [12]. In fact, from analysis of the available literature, a total of 244 chemically defined compounds can be extracted, belonging to different classes of secondary metabolites, such as azaphilones, benzofluoranthenones, coumarins and isocumarins, lactones, naphthalenones, macrolides, perylenequinones, sterols and others (Table 2). Of course, this list includes both known metabolites and compounds, which have been first characterized from these fungi, with the latter representing a remarkable share (147, corresponding to about 60%). In our survey, we avoided considering some products that are known intermediates in biosynthetic processes, clearly represent possible contaminants of the fungal cultures, or were just tentatively identified [13,14,15,16,17,18,19,20,21].
Some errors and overlapping in the compound names attribution have arisen during the accurate examination of the available literature on this topic. In particular, we can consider two recurring issues, which are “more names, one chemical structure” and “one name, more chemical structures”. For instance, cladosporin certainly belongs to the first case because its chemical structure is also known by the name asperentin [97]. For this reason, in Table 2, we added in brackets eventual additional names for compounds that fall under this case.
On the other hand, due to the intense research activity concerning this fungal genus, it has happened that some authors conducted their research parallel to the finding of closely related compounds. The temporal proximity in publishing has sometimes caused the attribution of the same name to different chemical structures (e.g., cladosporiumin I). In the case of cladosporol G, this issue was rather a consequence of author inaccuracy, since the elapsed time of about one year between the consecutive reports would have afforded an accurate preliminary check. In all cases of homonymy in Table 2, we have added the Latin suffix “bis” to the compounds that have been characterized later, as inferred from the date of submission to the journal.
Additional nomenclatural issues are represented by the absence of a proposed name, or authors’ choice to follow IUPAC rules instead of introducing trivial names derived from closely related compounds. Indeed, the use of trivial names represents a very common and useful guideline in natural product research because systematic names can be so convoluted and difficult to parse.

2.1. Alkaloids

Aspernigrin A (1) was originally characterized from the culture of a sponge-derived Aspergillus niger strain with its structure assigned mainly from its NMR and MS data [100], but it was structurally revised after reisolating from an endophytic strain of Cladosporium herbarum [47].
Cladosporine A (4) is the first indole diterpenoid alkaloid reported as a product of a Cladosporium strain [84]. In the class of alkaloids (Figure 2), cladosin E (3) and 2-methylacetate-3,5,6-trimethylpyrazine (6) are other new natural products from strains of Cladosporium sphaerospermum [60] and an endophytic Cladosporium sp. [85].

2.2. Azaphilones

Azaphilones are a structurally variable family of fungal polyketide metabolites possessing a highly oxygentated pyranoquinone bicyclic core and a quaternary carbon center. Well-known from genera such as Aspergillus, Penicillium and Talaromyces [101,102], these compounds have also been reported from the Cladosporium species (Figure 3) [49,52]. In particular, two new azaphilones, named perangustols A and B (11,12), were isolated from a marine-derived isolate of Cladosporium perangustum together with the new natural product, bicyclic diol (9) [52].

2.3. Benzofluorantheneones

During a screening of microbial extracts, a series of novel reduced benzofluorantheneones (13–16) was identified in the fermentation broth of a strain of Cladosporium cladosporioides recovered from a dead insect (Figure 4) [27,28].

2.4. Benzopyrones

A member of the benzopyrenes family named coniochaetone K (19) was isolated for the first time as a product of a coral symbiotic strain of Cladosporium halotolerans (Figure 5) [43]. This compound is particularly interesting because it has an uncommon carboxylic group in the backbone at position C-8’. It was identified together with the already known coniochaetones A-B (17,18) and several compounds belonging to the xanthones group. However, it must be underlined that a compound with the same name was previously characterized from a strain of Penicillium oxalicum, which differs in the absence of a carboxylic group and the presence of an additional hydroxyl group in the cyclopentane ring [103].

2.5. Binaphtopyrones

So far, members of the family of binaphthopyrones (Figure 6) were isolated only from an extremophilic strain of C. cladosporioides collected from a hypersaline lake in Egypt. In particular, cladosporinone (20), together with some viriditoxin derivatives (21–23), was isolated for the first time from this strain grown in a fermentation broth fortified with 3.5% sea salt [22]. The finding of compounds with original structures from fungi in extreme habitats is not unusual, considering that these microorganisms require special survival strategies for growing and reproducing, and adaptation to such conditions requires the modification of gene regulation and metabolic pathways [104].

2.6. Butanolides and Butenolides

Some metabolites from the cladospolide series are members of the family of butanolides and butenolides (Figure 7), a subgroup of lactones with a four-carbon ring structure. Many of them were isolated from several species of Cladosporium along with other cladospolides that are members of the series of macrolides [32,44,67,71,94].

2.7. Cinnamic acid Derivatives

Phenylalanine and tyrosine are precursors for a wide range of natural products. Commonly in plants and fungi, a frequent step is the elimination of ammonia from the side chain to generate cinnamic acids and related compounds. Caffeic and coumaric acids are among the most common naturally occurring cinnamic acids, which can also be found in a range of esterified forms, such as quinic acid forming chlorogenic acid [105]. Caffeic, chlorogenic and coumaric acids (30–32, Figure 8) were detected in the culture extract of an endophytic strain of Cladosporium velox isolated from stem of Tinospora cordifolia. Comparative analysis of the metabolite profiles of this strain showed similar composition with stem and leaf extracts of the host plant [70].

2.8. Citrinin Derivatives

Four new compounds from a marine-derived strain of Cladosporium sp. were reported as citrinin derivatives (34–37, Figure 9) [92]. Citrinin is a polyketide mycotoxin first isolated from Penicillium citrinum [106]. Considering the existence of the name cladosporin for the product (39) since 1971 [12] and cladosporine A (4) [84], the use of the same name for this new series is questionable. Furthermore, a known citrinin dimeric derivative named citrinin H1 (33) was isolated from a strain of Cladosporium sp. [85].

2.9. Coumarins and Isocoumarins

Cladosporin (39) is a member of 3,4-dihydroisocoumarins, a subgroup of isocoumarins that are commonly produced by fungi, along with coumarins [107]. Coumarins and isocoumarins are structural isomers, and their general moieties are respectively characterized by a chromen-2-one and 1H-isochromen-1-one [108]. Cladosporin was reported for the first time from mycelium of C. cladosporioides [12], but its absolute stereochemistry was elucidated only 17 years later using 2H decoupled 2H, 13C NMR shift correlation [36]. Cladosporin has also been isolated from the culture filtrate of another strain of C. cladosporioides together with its epimer in C-6′ named isocladosporin (42, Figure 10) [24,37]. It must be noted that 39 was later found from Aspergillus flavus [97] and an unidentified Aspergillus strain [109], but it was wrongly reported as a new compound with the name asperentin. As a consequence, some of its analogues were characterized as asperentin-8-methyl ether (38) and 5′-hydroxyasperentin (40) [25].
Kotanin (43) and orlandin (44) are two closely related dimeric coumarins produced by an endophytic strain of C. herbarum isolated from the leaves of Cynodon dactylon [47], which were previously reported as products of plant-associated Aspergillus strains [110,111].

2.10. Cyclohexene Derivatives

Four new cyclohexene derivatives named cladoscyclitols A–D (47–50) were obtained from the culture broth of a mangrove endophytic fungus Cladosporium sp. (Figure 11) [82].

2.11. Depsides

Four new despsides (51–54) were isolated from an endophytic strain of Cladosporium uredinicola (Figure 12) [69]. The authors later revised the structures of 3-hydroxy-2,4,5-trimethylphenyl 4-[(2,4-dihydroxy-3,6-dimethylbenzoyl)oxy]-2-hydroxy-3,6-dimethylbenzoate (52) and 3-hydroxy-2,5-dimethylphenyl 4-[(2,4-dihydroxy-3,6-dimethylbenzoyl)oxy]-2-hydroxy-3,6-dimethylbenzoate (54) [98].

2.12. Diketopiperazines

The diketopiperazines (55–58) reported in Figure 13 were identified via GC-MS in the crude extract of the culture filtrate of a strain of C. cladosporioides along with several volatile metabolites [17]. The structure of compounds in this class is based on a cyclic scaffold deriving from the condensation of two α-amino acids.

2.13. Flavonoids

The investigation of compounds produced by a previously mentioned endophytic strain of C. velox isolated from Tinospora cordifolia led to the identification, via RP-HPLC, of the known flavonenes called catechin (60) and epicatechin (61) by comparison of their retention times with those of commercially available standard compounds (Figure 14) [70].
The known (2S)-7,4′-dihydroxy-5-methoxy-8-(γ,γ-dimethylallyl)-flavanone (59) is a prenylated flavanone in which prenylation is represented by 3,3-dimethylallyl substituent at position 8’ [93].

2.14. Gibberellins

A strain of C. sphaerospermum from salt-stressed soybean plants was able to induce maximum plant growth in both soybean and Waito-C rice. Interestingly, high amounts of gibberellins (62–68) were detected in its culture filtrate (Figure 15) [57]. Gibberellins are diterpenoid hormones involved in many aspects of plant growth and development, hence playing a role in the mutualistic plant-endophyte interactions [112].

2.15. Fusicoccane Diterpene Glycosides

Cotylenin A (69) is the major and most structurally complex metabolite of fusicoccane diterpene glycosides isolated from the Cladosporium species (Figure 16). Cotylenins A–D (69–72) are characterized by the presence of a common aglycone named cotylenol and an unusual sugar moiety consisting in a 6-O-methyl-α-d-glucosyl derivative with an oxygenated C5-isoprene unit [72,73,74].

2.16. Lactones

This class includes structurally diverse compounds with a 1-oxacycloalkan-2-one structure in common. Cladosporactone A (74), cladosporimide A (75) and herbaric acid (76) are lactones isolated for the first time from a marine-derived strain of Cladosporium sp. (Figure 17) [35,45,93].

2.17. Macrolides

Macrolides are a large family of compounds characterized by a macrocyclic lactone ring. Rings are commonly 12, 14, or 16 membered [105].
Macrolides with a different number of members were also isolated from cultures of Cladosporium spp. (Figure 18 and Figure 19), many of them reported for the first time. In fact, several 12-membered macrolides were reported from marine-derived strains of the Cladosporium species, such as recifeiolide analogues, namely 5R and 5S-hydroxyrecifeiolides (90–91) [32] and sporiolides A and B (101–102) [88].
The list of macrolides from the Cladosporium species includes pandangolide 1a and pandangolides 1–4 (95–99). Pandangolide 1 and 2 were already known as products of an unidentified fungal species obtained from a marine sponge [113], while pandangolides 3 and 4 were identified for the first time from C. herbarum [44]. Pandangolide 1a was isolated, together with its known diastereomer 95, from a sponge-associated Cladosporium sp. [71].
The investigation of metabolites produced by the mangrove endophytic Cladosporium sp. led to the isolation of new compounds called thiocladospolides A–E (103–107, Figure 19) and the macrodiolide lactam derived from ornithine, called cladospamide A (81), together with the known cladospolide B (83) [33,91]. This latter compound was previously isolated and identified during a screening for new plant growth regulators produced by C. cladosporioides, along with its isomer cladospolide A (82) [114,115,116]. The cladospolide series also includes the diastereomer of 82, named cladospolide C (84), which was isolated from Cladosporium tenuissimum [64].
Two new macrolides (i.e., 4-hydroxy-12-methyloxacyclododecane-2,5,6-trione (88) and 12-methyloxacyclododecane-2,5,6-trione (92)), were isolated from an endophytic strain of C. colocasiae, together with known compounds identified as cladospolide A (82), (6R,12S)-6-hydroxy-12-methyl-1-oxacyclododecane-2,5-dione (86), pandangolide 1 (95), patulolide B (100) and seco-patulolide C (162) [41].
An unusual macrolide with a bicyclo 5–9 ring system, named cladocladosin A (80), was isolated from the mangrove-derived endophytic fungus C. cladosporioides, along with two new sulfur-containing macrodiolides, namely thiocladospolides F and G (108,110) [34]. Moreover, five new thiocladospolides were identified together with some known compounds from a strain of Cladosporium oxysporum (Figure 19) [50]. These new compounds were named thiocladospolides F-J, even if thiocladospolides F and G (109,111) had been previously reported with different structures, representing another example of the issue “one name, more structures”. For this reason, these compounds are reported in Table 2 as thiocladospolides F bis and G bis.

2.18. Naphthalene Derivatives

Two new dimeric naphthalene derivatives, named cladonaphchroms A and B (116, 117), were obtained from a mangrove-derived strain of Cladosporium sp. (Figure 20). These compounds were detected in the fungal culture extract along with some known metabolites, such as 5-hydroxy-2-methyl-4H-chromen-4-one (236), (R)-5-hydroxy-2-methyl-chroman-4-one (237), 1,8-dimethoxynaphthalene (118) and 8-methoxynaphthalen-1-ol (119) [83]. Additionally, 118 was also obtained as product of a mangrove-derived strain of Cladosporium sp. [81].

2.19. Naphthalenones

(−)-trans-(3R,4R)-3,4,8-Trihydroxy-6,7-dimethyl-3,4-dihydronaphthalen-1(2H)-one (141) is a new compound isolated from a mangrove-derived Cladosporium sp. (Figure 21), produced along with six known compounds (i.e., 118,135,137,140) [81]. Scytalone (139) is another compound from this class, isolated from an endophytic strain of C. tenuissimum from Pinus wallichiana [68]. It is a polyketide known as an intermediate in melanin biosynthesis produced by many fungi associated with plants [117,118].
Dimeric tetralones are a subclass of naphthalenones made from two monomers of bicyclic aromatic hydrocarbon and a ketone. A marine-derived strain of Cladosporium sp. also produces new dimeric tetralones: the newly isolated altertoxin XII (120) and the known cladosporol I (130) [87].
Among the compounds in this family, cladosporol A (121) was isolated for the first time from C. cladosporioides [26] and later on from C. tenuissimum together with some analogues, cladosporol B–E (122–125) [66]. Their absolute configurations were revised some years later from (4’R) to (4’S) when five new dimeric tetralones (i.e., cladosporols F–J) and the known cladosporol C (123) were isolated from an algal endophytic strain of C. cladosporioides [39]. Four new dimeric tetralones, namely clindanones A and B (133,134) and cladosporols F and G (126,127), were identified by a deep-sea derived strain of C. cladosporioides along with the known isosclerone (138), which is the only monomeric tetralone isolated from the Cladosporium species so far [40]. Clindanones (133,134) possess new dimeric forms of the skeleton composed by the coupling of indanone and 1-tetralone units. As introduced in chapter 2, cladosporol G (128) produced by the algal strain [39] is different from the compound (127) with the same name previously discovered as a product of the deep-sea derived strain.
Some cladosporols (i.e., 121, 123 and 124) were also isolated from a strain of Cladosporium sp. derived from the mangrove plant Kandelia candel, along with the new dimeric tetralone named cladosporone A (132) [86].

2.20. Naphtoquinones and Anthraquinones

Naphthoquinones and anthraquinones have been widely identified as metabolites from various plants, microbes and marine organisms [102,119,120]. Two anthraquinones, namely anhydrofusarubin (142) and methyl ether of fusarubin (143), were isolated from Cladosporium sp. from the bark of the plant Rauwolfia serpentina [90]. The only naphthoquinone known from Cladosporium, plumbagin (144), was isolated from a strain of Cladosporium delicatulum, which resulted as the most potent producer of this valuable drug after a dedicated screening of endophytic fungi carried out to find strains able to synthesize this valuable drug (Figure 22) [42].

2.21. Perylenquinones

The first member of the family of perylenquinones (Figure 23), named phleichrome (154), was reported as a new phytotoxic compound produced by Cladosporium phlei [53,99]. The stereochemistry of phleichrome was investigated in detail in a subsequent study, which reports the conversion of 154 in isophleichrome, highlighting the similarity in behavior and physical data with another couple of fungal perylenquinones, cercosporin and isocercosporin [54]. In fact, perylenquinones show intriguing stereochemical features, such as axial chirality due to the helical shape of the constrained pentacyclic ring, combined with asymmetric carbons in the side chains. Even if it was indicated that phleichrome can be thermally converted in its unnatural diastereoisomer named isophleichrome [54], the production by C. cladosporioides of ent-isophleichrome (152) was reported [46]. Moreover, several esters of 152, belonging to the series of calphostins, were isolated from a strain of Cladosporium sp. Calphostin C and I (151,153) [30,121] have also been incorrectly reported as new products with the names cladochromes E and D [31]. In fact, these compounds had been previously isolated, and their physico-chemical properties investigated in the course of screening the potential inhibitors of protein kinase C (PKC) from a strain of C. cladosporioides, along with several other calphostins (149–153) [29,30]. Moreover, four new perylenquinones, altertoxins VIII-XI (145–148), were isolated from the fermentation broth of a marine-derived strain of Cladosporium sp. [87]. These new metabolites partially share structures with a series of metabolites originally isolated from the Alternaria species [122].

2.22. Pyrones

Pyrones represent a family of six-membered unsaturated cyclic compounds containing oxygen that naturally occurs in two isomeric forms, either as 2-pyrone or 4-pyrone. 2-pyrone is extremely prevalent in numerous natural products isolated from plants, animals, marine organisms, bacteria, fungi, and insects [123,124]. Two new 2-pyrones (i.e., herbarins A and B (156,157)) were obtained from a spongiculous strain of C. herbarum isolated (Figure 24) [45].

2.23. Seco Acids

The 12 membered seco acids reported in Figure 25 were found to be produced by strains of C. cladosporioides and C. tenuissimum, along with members of the families of lactones or macrolides [33,67,68,94]. It can be speculated that these compounds are intermediates in the biosynthesis of cyclic compounds because seco acids are the starting material for the production of lactones [125].

2.24. Sterols

Sterols are a class of lipids involved in several metabolic reactions since they are components of the membrane of eukaryotic organisms playing a crucial role in permeability and fluidity [126]. They are modified triterpenoids containing the tetracyclic ring system of lanosterol but lacking the three methyl groups at C-4 and C14. The predominant sterol found in fungi is ergosterol, which has frequently been investigated in human pathogenic fungal strains [127]. Ergosterol (170) was also identified as product of a strain of Cladosporium sp., along with 23,24,25,26,27-pentanorlanost-8-ene-3β,22-diol (172), peroxyergosterol (173) and four new pentanorlanostane derivatives named cladosporides A–D (164–167) (Figure 26) [79,80].

2.25. Tetramic Acids

Tetramic acids are compounds containing 2,4-pyrrolidinedione backbone obtained by the fusion of an amino acid with polyketide units. The series of cladosporimins and cladosins belong to this class, with the latter reported exclusively from C. sphaerospermum (Figure 27 and Figure 28). In fact, six novel cladosins, the structures of which are constituted by a tetramic acid core and 6(3)-enamino-8,10-dihydroxy or 6(3)-enamino-7(8)-en-10-ol side chains, named cladosins A–D (177–180) and F–G (181,182), were reported from a strain of C. sphaerospermum from sediments collected in the Pacific Ocean [55,56]. Each compound exists as two tautomeric forms differing in configuration of the enamine. Moreover, investigation into the fermentation extracts of another isolate of C. sphaerospermum from marine sediments led to the discovery of cladosins H–K (183–186) [89]. Finally, cladosins L–O (187, 189–191), together with another tetramic acid named cladodionen (176), were isolated from a strain of this species obtained from healthy bulbs of Fritillaria unibracteata var. wabuensis [63].
Two structurally different compounds were reported as cladosin L (187,188) in two papers published almost at the same time [60,63]. In fact, a second product labeled with this name (188) was identified from a Hydractinia-associated strain of C. sphaerospermum.
Even in the cladosporiumin series (Figure 28) there are some compounds that were given the same name because of the contemporaneous publication of work dealing with the structural identification of novel tetramic acids. In fact, Liang et al. [58] and Risher et al. [61] identified two tetramic acids continuing the series of cladosporiumins (192–209), and both research teams named their new compounds cladosporiumins I and J (201,203). Furthermore, cladosporiumin L (206), reported by Liang et al. [58], is a metal complex of tetramic acid. In fact, considering that the formation of metal complexes of tetramic acid derivatives (e.g., harzianic acid [128,129]) affect the chemical shifts of H-5 an N-methyl proton or NH, the authors can speculate that the structure of cladosporiumin L is a Mg2 complex. The authors also reported the structure of cladosporiumins F (198) and H (200) as their Na complexes.

2.26. Tropolones

Malettinins A–C (210–212) were isolated and structurally elucidated from a marine strain of Cladosporium sp., along with the new malettinin E (213) (Figure 29) [95]. This represents the first isolation of tropolones from a fungus belonging to the genus Cladosporium. In fact, malettinins A–C were originally isolated from an unidentified fungus, which additionally produced a fourth metabolite, named malettinin D. This latter compound was not identified in the culture extracts of Cladosporium sp.; instead, its new 13-epimer was detected (213).

2.27. Volatile Terpenes

An isolate of C. cladosporioides obtained from the rhizosphere of red pepper has been investigated for the production of volatile terpenes using solid phase microextraction (SPME) coupled to GC-MS (Figure 30) [38]. Identification of volatiles revealed mainly (−)-trans-caryophyllene, dehydroaromadendrene, α-pinene and (+)-sativene (214–217). In previous research on Plant Growth Promoting Rhizobacteria (PGPR) and Plant Growth Promoting Fungi (PGPF), it was reported that volatile terpenes play important chemo-ecological roles in the interactions between plants and their environments [130]. In fact, this strain seems to be able to improve the growth of tobacco seedlings and their root development through the production of volatile terpenes [38].

2.28. Xanthones

The class of xanthones includes compounds with a backbone designated as dibenzo-7-pyrone. A huge number of xanthones have been isolated from natural sources of higher plants, fungi, ferns, and lichens [131]. A strain of C. halotolerans symbiotic with the coral Porites lutea produces nine metabolites (218–225,227) belonging to this class (Figure 31) [43]. Furthermore, a dimeric tetrahydroxanthone (226), where two tetrahydroxanthone monomers are connected through a 2,2’-biphenol linkage, was also isolated from an endophytic strain of Cladosporium sp. [85].

2.29. Miscellaneous

Finally, a number of products of Cladosporium are placed in a miscellaneous class because they have no structural affinity with previous groups (Figure 32). This is the case for a new abscisic acid analogue named cladosacid (230) [96], sumiki’s acids (229,241) [44], the new pentenoic acid derivative named 1,1′-dioxine-2,2′-dipropionic acid (233) [85] and two new ribofuranose phenol derivatives named 4-O-α-d-ribofuranose-3-hydroxymethyl-2-pentylphenol (239) and 4-O-α-d-ribofuranose-2-pentyl-3-phemethylol (238) [81,82].

3. Biological Activities of Secondary Metabolites

Most secondary metabolites reported in Table 3 have been investigated for biological properties, including antifungal, antibacterial cytotoxic and phytotoxic activities, which are summarized in Table 3. For some well-known compounds (e.g., the tetracyclic diterpenoid taxol and the funicone compound vermistatin), which have been extensively investigated and have been the subject of dedicated reviews [132], this table only considers data resulting from reports concerning the isolation of these compounds from Cladosporium strains.
Particularly valuable in the study of the bioactivities of natural products is the structure–activity relationship (SAR), but this aspect has only been taken into account in few research papers on Cladosporium compounds. An interesting evaluation of the relationships between structures and bioactivity was reported for cladosporin analogues by Wang et al. [25], who considered the presence of several essential positions in the chemical structures of these compounds that might be responsible for their antifungal activity. As a consequence, the antifungal activity of the parent compound seems to be influenced by the R configuration of C-6′. This configuration greatly decreased the antifungal activity of isocladosporin against the Colletotrichum species but slightly increased the antifungal activity against the Phomopsis species. Comparing the structures of cladosporin and 5′-hydroxyasperentin, the hydroxylation of the C-5′ position causes the loss of the antifungal activity against the Colletotrichum species and decreases the selectivity against the Phomopsis species. Comparison of 5′-hydroxyasperentin and the synthesized 6,5′-diacetyl derivative revealed that the replacement of the hydrogen in the hydroxyl group at C-6 and the hydrogen at C-5′ in the acetyl groups greatly increased selectivity toward the two Phomopsis species. Furthermore, the C-8 position also seems to be responsible for antifungal activity, demonstrated by the inactivity of asperentin-8-methyl ether against all the tested fungi [25].
Another interesting correlation between chemical structure and bioactivity arises from the investigation on the inhibitory activity of cladosporol towards β-l,3-glucan synthetase. In fact, the epoxy-alcohol moiety in cladosporol is very similar to another β-l,3-glucan biosynthesis inhibitor, (+)-isoepoxydon; hence, the epoxy-alcohol structure seems to play an important role in the inhibitory activity of β-l,3-glucan synthetase [26].

4. Conclusions

As resulting from the available information examined in this review, data concerning secondary metabolite production and properties in Cladosporium are notable in quantitative terms. Indeed, the biosynthetic aptitudes of these fungi are quite original, with several series of products for which they represent the only source known so far. At the same time, at least some strains have resulted in the sharing of genetic bases for producing bioactive compounds previously reported from other fungal genera, such as cytochalasin D, brefeldin A, vermistatin, zeaenol, the coniochaetones, the malettinins and the viridotoxins, or even from plants, such as the gibberellins, plumbagin and taxol, which represent a direction for their possible biotechnological exploitation.
Besides implications deriving from the bioactive properties of some valuable products, metabolomics has been also used as a tool for species description and discrimination in several fungal genera, such as Penicillium, Talaromyces, Aspergillus [133], Alternaria [134] and Trichoderma [135]. The great diversity of secondary metabolites reported from Cladosporium spp. could represent a notable base material for verifying if a similar approach can be consistent for this genus as well. So far, the number of isolates that have been examined in this respect is too small, with as many as 23 of them not having been ascribed to any definite species, and the only consistent aspect resulting from the analysis of the available literature is represented by the production of tetramic acids by C. sphaerospermum. However, it is to be expected that the likely accumulation of new reports based on accurate molecular identification referring to the most recent taxonomic schemes may pave the way to a chemotaxonomic perspective for Cladosporium too.

Author Contributions

Conceptualization, R.N. and A.A.; writing—original draft preparation, M.M.S.; writing—review and editing, M.M.S., R.N. and A.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Molecules 26 03959 g001 550
Figure 1. Pie charts of the origin of the strains examined in the present review.
Figure 1. Pie charts of the origin of the strains examined in the present review.
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Figure 2. Structures of alkaloids.
Figure 2. Structures of alkaloids.
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Figure 3. Structures of azaphilones.
Figure 3. Structures of azaphilones.
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Figure 4. Structures of benzofluoranthenones.
Figure 4. Structures of benzofluoranthenones.
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Figure 5. Structures of benozopyranones.
Figure 5. Structures of benozopyranones.
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Figure 6. Structures of binaphthopyrones.
Figure 6. Structures of binaphthopyrones.
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Figure 7. Structures of butanolides and butenolides.
Figure 7. Structures of butanolides and butenolides.
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Figure 8. Structures of cinnamic acid derivatives.
Figure 8. Structures of cinnamic acid derivatives.
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Figure 9. Structures of citrinin derivatives.
Figure 9. Structures of citrinin derivatives.
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Figure 10. Structures of coumarins and isocoumarins.
Figure 10. Structures of coumarins and isocoumarins.
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Figure 11. Structures of cyclohexene derivatives.
Figure 11. Structures of cyclohexene derivatives.
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Figure 12. Structures of depsides.
Figure 12. Structures of depsides.
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Figure 13. Structures of diketopiperazines.
Figure 13. Structures of diketopiperazines.
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Figure 14. Structures of flavonoids.
Figure 14. Structures of flavonoids.
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Figure 15. Structures of gibberellins.
Figure 15. Structures of gibberellins.
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Figure 16. Structures of fusicoccane diterpene glycosides.
Figure 16. Structures of fusicoccane diterpene glycosides.
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Figure 17. Structures of lactones.
Figure 17. Structures of lactones.
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Figure 18. Structures of macrodiolides.
Figure 18. Structures of macrodiolides.
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Figure 19. Structures of thiocladospolides.
Figure 19. Structures of thiocladospolides.
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Figure 20. Structures of naphthalene derivatives.
Figure 20. Structures of naphthalene derivatives.
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Figure 21. Structures of naphthalenones.
Figure 21. Structures of naphthalenones.
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Figure 22. Structures of naphthoquinones and anthraquinones.
Figure 22. Structures of naphthoquinones and anthraquinones.
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Figure 23. Structures of perylenequinones.
Figure 23. Structures of perylenequinones.
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Figure 24. Structures of pyrones.
Figure 24. Structures of pyrones.
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Figure 25. Structures of seco acids.
Figure 25. Structures of seco acids.
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Figure 26. Structures of sterols.
Figure 26. Structures of sterols.
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Figure 27. Structures of tetramic acids.
Figure 27. Structures of tetramic acids.
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Figure 28. Structures of cladosporiumins.
Figure 28. Structures of cladosporiumins.
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Figure 29. Structures of tropolones.
Figure 29. Structures of tropolones.
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Figure 30. Structures of volatile terpenes.
Figure 30. Structures of volatile terpenes.
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Figure 31. Structures of xanthones.
Figure 31. Structures of xanthones.
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Figure 32. Structures of compounds from the group “miscellaneous”.
Figure 32. Structures of compounds from the group “miscellaneous”.
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Table
Table 1. Cladosporium species/strains reported for production of secondary metabolites.
Table 1. Cladosporium species/strains reported for production of secondary metabolites.
Species/StrainSubstrateLocationRefs.
C. cladosporioides--[12]
C. cladosporioidessediment of hypersaline lakeEl Hamra, Egypt[22]
C. cladosporioidessponge (Cliona sp.)Los Molles, Chile[23]
C. cladosporioidesaphid (Aphis craccivora)Egypt[17,18]
C. cladosporioidesendophytic in Zygophyllum mandavilleiAl-Ahsa, Saudi Arabia[24]
C. cladosporioidesendophytic in unspecified plantTifton, United States[25]
C. cladosporioides-Japan[26]
C. cladosporioides/CBUK20700dead insectThailand[27,28]
C. cladosporioides/FERMBP-1285block fenceOsaka, Japan[29,30]
C. cladosporioides/IPV-F167-Italy[31]
C. cladosporioides/LWL5endophytic in Helianthus annuusDaegu, South Korea[16]
C. cladosporioides/MA-299endophytic in Bruguiera gymnorrhizaHainan, China[32,33,34]
C. cladosporioides/MCCC3A00182deep sea sedimentPacific Ocean[35]
C. cladosporioides/MUPGBIOCHEM-CC-07-2015brown alga (Sargassum wightii)Tamil Nadu, India[21]
C. cladosporioides/NRRL5507--[36,37]
C. cladosporioides/CL-1rhizosphere of red pepperSouth Korea[38]
C. cladosporioides/EN-399red alga (Laurencia okamurai)Qingdao, China[39]
C. cladosporioides/HDN14-342deep sea sedimentIndian Ocean[40]
C. colocasiae/A801endophytic in Callistemon viminalisGuangzhou, China[41]
C. delicatulum/EF33endophytic in Terminalia pallidaAndhra Pradesh, India[42]
C. halotolerans/GXIMD 02502coral (Porites lutea)Weizhou islands, China[43]
C. herbarumsponge (Callyspongia aerizusa)Bali, Indonesia[44,45]
C. herbarum/FC27Pendophytic in Beta vulgarisDublin, United States[46]
C. herbarum/IFB-E002endophytic in Cynodon dactylonYancheng reserve, China[47]
C. oxysporumendophytic in Aglaia odorataJava, Indonesia[14]
C. oxysporumendophytic in Alyxia reinwardtiiJava, Indonesia[48]
C. oxysporum/DH14locust (Oxya chinensis)Jinhua, China[49]
C. oxysporum/HDN13-314endophytic in Avicennia marinaHainan, China[50]
C. oxysporum/RM1endophytic in Moringa oleiferaTamil Nadu, India[51]
C. perangustum/FS62deep sea sedimentSouth China Sea[52]
C. phlei/C-273 wpathogenic on Phleum pratenseHokkaido, Japan[53]
C. phlei/CBS 358.69pathogenic on Phleum pratenseGermany[54]
C. sphaerospermum/2005-01-E3deep sea sludgePacific Ocean[55,56]
C. sphaerospermum/DK-1-1endophytic in Glycine maxSouth Korea[57]
C. sphaerospermum/EIODSF 008deep sea sedimentIndian Ocean[58]
C. sphaerospermum/L3P3deep sea sedimentMariana Trench[59]
C. sphaerospermum/SW67hydroid (Hydractinia echinata)South Korea[60,61,62]
C. sphaerospermum/WBS017endophytic in Fritillaria unibracteata
var. wabuensis		China[63]
C. tenuissimumsoilKaro-cho, Japan[64]
C. tenuissimum/DMG 3endophytic in Swietenia mahagoniSumatra, Indonesia[65]
C. tenuissimum/ITT21pine rust (Cronartium flaccidum)Tuscany, Italy[66]
C. tenuissimum/LR463endophytic in Maytenus hookeriYunnan, China[67]
C. tenuissimum/P1S11endophytic in Pinus wallichianaKashmir, India[68]
C. uredinicolaendophytic in Psidium guajavaSão Carlos, Brazil[69]
C. velox/TN-9Sendophytic in Tinospora cordifoliaAmritsar, India[70]
Cladosporium sp.sponge (Niphates rowi)Gulf of Aqaba, Israel[71]
Cladosporium sp./486intertidal sedimentSan Antonio Oeste, Argentina[19]
Cladosporium sp./501-7w-Japan[72,73,74]
Cladosporium sp./F14sea waterSai Kung, China[13,75]
Cladosporium sp./HDN17-58deep sea sedimentPacific Ocean[76]
Cladosporium sp./I(R)9-2endophytic in Quercus variabilisNanjing, China[77]
Cladosporium sp./IFB3lp-2endophytic in Rhizophora stylosaHainan, China[78]
Cladosporium sp./IFM 49189-Japan[79,80]
Cladosporium sp./JJM22endophytic in Ceriops tagalHainan, China[81,82,83]
Cladosporium sp./JNU17DTH12-9-0unknownChina[84]
Cladosporium sp./JS1-2endophytic in Ceriops tagalHainan, China[85]
Cladosporium sp./KcFL6’endophytic in Kandelia candelDaya Bay, China[86]
Cladosporium sp./KFD33blood cockleHainan, China[87]
Cladosporium sp./L037brown alga (Actinotrichia fragilis)Okinawa, Japan[88]
Cladosporium sp./N5red alga (Porphyra yezoensis)Lianyungang, China[15]
Cladosporium sp./OUCMDZ-1635spongeXisha Islands, China[89]
Cladosporium sp./RSBE-3endophytic in Rauwolfia serpentinaBangladesh[90]
Cladosporium sp./SCNU-F0001endophytic in unspecified mangroveZhuhai, China[91]
Cladosporium sp./SCSIO z01deep sea sedimentEast China Sea[92]
Cladosporium sp./TPU1507unidentified spongeManado, Indonesia[93]
Cladosporium sp./TZP-29unidentified soft coralGuangzhou, China[94]
Cladosporium sp./KF501water sampleWadden Sea, Germany[95]
Cladosporium sp./SCSIO z0025 deep sea sedimentOkinawa, Japan[96]
Table
Table 2. List of secondary metabolites produced by Cladosporium species. The Latin suffix “bis” is added when the same name has been previously introduced for another compound. The names of novel compounds are underlined.
Table 2. List of secondary metabolites produced by Cladosporium species. The Latin suffix “bis” is added when the same name has been previously introduced for another compound. The names of novel compounds are underlined.
CodeNameFormulaNominal Mass (U)Refs.
Alkaloids
1Aspernigrin AC13H12N2O2228[47]
2Aspidospermidin-20-ol, 1-acetyl-17-methoxyC22H30N2O3370[24]
3Cladosin EC13H17NO4251[55]
4Cladosporine AC28H39NO2421[84]
5Cytochalasin DC30H37NO6507[85]
62-Methylacetate-3,5,6-trimethylpyrazineC10H14N2O2194[85]
7Nonanal oximeC9H19NO157[17]
82-Piperidinone methylC6H11NO113[17]
Azaphilones
9Bicyclic diolC11H14O4210[52]
10Lunatoic acid AC21H24O7388[49]
11Perangustol AC11H14O4210[52]
12Perangustol BC11H14O4210[52]
Benzofluoranthenones
13(6bS,7R,8S)-4,9-Dihydroxy-7,8-
dimethoxy-1,6b,7,8-tetra-hydro-2H-
benzo[J]fluoranthen-3-one		C23H22O4362[27]
14(6bS,7R)-4,9-Dihydroxy-7-
methoxy-1,2,6b,7-tetrahydrobenzo[J]fluoranthen-3,8-dione		C22H18O4346[27]
15(6bR,7R,8S)-7-
Methoxy-4,8,9-trihydroxy-
1,6b,7,8-tetrahydro-2H-
benzo[J]fluoranthen-3-one		C22H20O4348[27]
16(6bS,7R,8S)-7-
Methoxy-4,8,9-trihydroxy-
1,6b,7,8-tetrahydro-2H-
benzo[J]fluoranthen-3-one		C22H20O4348[27,28]
Benzopyranones
17Coniochaetone AC13H10O4230[43]
18Coniochaetone BC13H12O4232[43]
19Coniochaetone KC13H10O6262[43]
Binaphthopyrones
20CladosporinoneC33H30O14650[22]
21ViriditoxinC34H30O14662[22]
22Viriditoxin SC-28763C34H30O13646[22]
23Viriditoxin SC-30532C34H30O12630[22]
Butenolides and butanolides
24Cladospolide FC12H22O4230[94]
25Cladospolide GC14H24O5272[32]
26Cladospolide HC12H18O3210[32]
27ent-Cladospolide FC12H22O4230[32]
2811-Hydroxy-γ-dodecalactoneC12H20O3212[94]
29iso-Cladospolide BC12H20O4228[32,44,50,67,71,94]
Cinnamic acid derivatives
30Chlorogenic acidC16H18O9354[70]
31Caffeic acidC9H8O4180[70]
32Coumaric acidC9H8O3164[70]
Citrinin derivatives
33Citrinin H1C25H30O7442[85]
34Cladosporin AC13H15NO3233[92]
35Cladosporin BC13H15NO3233[92]
36Cladosporin CC14H16O4248[92]
37Cladosporin DC12H16O4224[92]
Coumarins and Isocoumarins
38Asperentin-8-methyl ether (= cladosporin-8-methyl ether)C17H22O6322[25]
39Cladosporin (= asperentin) C16H20O5292[12,24,25,36,37]
405′-HydroxyasperentinC16H20O6308[24,25]
417-Hydroxy-4-methoxy-5-methylcoumarinC11H10O4206[47]
42IsocladosporinC16H20O5292[24,25,37]
43KotaninC24H22O8438[47]
44OrlandinC22H18O8410[47]
45PhomasatinC10H8O5208[35]
46UmbelliferoneC9H6O3162[70]
Cyclohexene derivatives
47Cladoscyclitol AC12H20O5244[82]
48Cladoscyclitol BC13H22O7290[82]
49Cladoscyclitol CC12H22O4230[82]
50Cladoscyclitol DC12H22O5246[82]
Despsides
513-Hydroxy-2,4,5-trimethylphenyl 2,4-dihydroxy-3,6-dimethylbenzoateC18H20O5316[69,98]
523-Hydroxy-2,4,5-trimethylphenyl 4-[(2,4-dihydroxy-3,6-dimethylbenzoyl)oxy]-2-hydroxy-3,6-dimethylbenzoateC27H28O8480[69,98]
533-Hydroxy-2,5-dimethylphenyl 2,4-dihydroxy- 3,6-dimethylbenzoateC17H18O5302[69,98]
543-Hydroxy-2,5-dimethylphenyl 4-[(2,4-dihydroxy-3,6-dimethylbenzoyl)oxy]-2-hydroxy-3,6-dimethylbenzoateC26H26O8466[69,98]
Diketopiperazines
55(3R,8aR)-Cyclo(leucylprolyl) C11H18N2O2210[17]
56(3S,8aS)-Cyclo(leucylprolyl)C11H18N2O2210[17]
57(3R,8aR)-Cyclo(phenylalanylprolyl) C14H16N2O2244[17]
58(3S,8aS)-Cyclo(phenylalanylprolyl)C14H16N2O2244[17]
Flavonoids
59(2S)-7,4′-Dihydroxy-5-methoxy-8-(γ,γ-dimethylallyl)-flavanoneC21H22O5354[93]
60CatechinC15H14O6290[70]
61EpicatechinC15H14O6290[70]
Gibberelines
62GA3C19H22O6346[57]
63GA4C19H24O5332[57]
64GA5C19H22O5330[57]
65GA7C19H22O5330[57]
66GA15C20H26O4330[57]
67GA19C20H26O6362[57]
68GA24C20H26O5346[57]
Fusicoccane diterpene glycosides
69Cotylenin AC33H50O11622[72,73,74]
70Cotylenin BC33H51ClO11659[73,74]
71Cotylenin CC33H52O11624[73]
72Cotylenin DC33H52O12640[73]
73Cotylenin EC28H46O9526[73]
Lactones
74Cladosporactone AC10H12O4196[35]
75Cladosporamide AC14H11NO5273[93]
765-DecanolideC10H18O2170[17]
77Herbaric acidC10H8O6224[45]
78Isochracinic acidC10H8O5208[35]
Macrolides
79Brefeldin AC16H24O4280[77]
80Cladocladosin AC13H18O3222[34]
81Cladospamide AC13H20N2O4268[91]
82Cladospolide AC12H20O4228[41,64,67,78,91]
83Cladospolide BC12H20O4228[44,64,67,78]
84Cladospolide CC12H20O4228[64]
854,5-Dihydroxy-12-methyloxacyclododecan-2-oneC12H22O4230[67]
86(6R,12S)-6-Hydroxy-12-methyl-
oxacyclodoecane-2,5-dione		C12H20O4228[67]
87(10S,12S)-10-Hydroxy-12-methyloxacyclododecane-2,5-dioneC12H20O4228[67]
884-Hydroxy-12-methyloxacyclododecane-2,5,6-trioneC12H18O5242[41]
89(E)-(3R,6S)-6-Hydroxy-12-methyl-2,5-dioxooxacyclododecan-3-yl 4,11-dihydroxydodec-2-enoateC24H40O8456[78]
905R-HydroxyrecifeiolideC12H20O3212[32]
915S-HydroxyrecifeiolideC12H20O3212[32]
9212-Methyloxacyclododecane-2,5,6-trione C12H18O4226[41]
93Methyl 2-(((4R,6S,12R)-6-hydroxy-12-methyl-2,5-dioxooxacyclododecan-4-yl)thio)acetateC15H24O6S332[78]
945Z-7-OxozeaenolC19H22O7362[49]
95Pandangolide 1C12H20O5244[32,41,48,71,78]
96Pandangolide 1aC12H20O5244[71,78]
97Pandangolide 2C14H22O6S318[44,78]
98Pandangolide 3C16H26O7S362[33,44,50,78]
99Pandangolide 4C24H38O8S486[44]
100Patulolide BC13H20O3224[41]
101Sporiolide AC19H24O6348[88]
102Sporiolide BC14H24O4256[88]
103Thiocladospolide AC16H26O6S346[33,50]
104Thiocladospolide BC16H24O7S360[33]
105Thiocladospolide CC15H22O6S330[33]
106Thiocladospolide DC16H28O7S364[33]
107Thiocladospolide EC14H26O5S306[91]
108Thiocladospolide FC16H28O5S332[34]
109Thiocladospolide F bisC24H38O8S486[50]
110Thiocladospolide GC16H28O6S348[34]
111Thiocladospolide G bisC15H24O7S348[50]
112Thiocladospolide HC15H24O6S332[50]
113Thiocladospolide IC27H44O10S560[50]
114Thiocladospolide JC27H42O10S558[50]
115ZeaenolC19H24O7364[49]
Naphthalene derivatives
116Cladonaphchrom AC22H22O4350[83]
117Cladonaphchrom BC22H22O4350[83]
1181,8-DimethoxynaphthaleneC12H12O2188[81,83]
1198-Methoxynaphthalen-1-olC11H10O2174[83]
Naphtalenones
120Altertoxin XIIC20H18O4322[87]
121Cladosporol AC20H16O6352[26,66,86]
122Cladosporol BC20H14O6350[66]
123Cladosporol CC20H18O5338[35,39,40,66,85,86]
124Cladosporol DC20H18O6354[66,86]
125Cladosporol EC20H18O7370[40,66,85]
126Cladosporol FC21H20O5352[39,40]
127Cladosporol G C20H17ClO6388[40]
128Cladosporol G bisC21H20O5352[39]
129Cladosporol HC20H16O5336[39]
130Cladosporol IC20H18O5338[39,92]
131Cladosporol JC20H18O5338[39]
132Cladosporone AC20H16O6352[86]
133Clindanone AC22H18O7394[40]
134Clindanone BC22H18O7394[40]
135(3R,4R)-3,4-Dihydro-3,4,8-trihydroxy-1(2H)-napthalenoneC10H10O4194[81]
1364,8-Dihydroxy-1-tetraloneC10H10O3178[52]
137(3S)-3,8-Dihydroxy-6,7-dimethyl-α-tetraloneC12H14O3206[81]
138IsoscleroneC10H10O3178[40]
139ScytaloneC10H10O4194[68]
140(−)-(4R)-RegioloneC10H10O3178[81]
141(−)-trans-(3R,4R)-3,4,8-Trihydroxy-6,7-dimethyl-3,4- dihydronaphtha- len-1(2H)-oneC12H14O4222[81]
Naphthoquinones and anthraquinones
142AnhydrofusarubinC15H12O6288[90]
143Methyl ether of fusarubinC16H16O7320[90]
144PlumbaginC11H8O3188[42]
Perylenequinones
145Altertoxin VIIIC20H16O3304[87]
146Altertoxin IX C20H18O2290[87]
147Aterotoxin XC20H18O2290[87]
148Altertoxin XIC21H20O2304[87]
149Calphostin A (= UCN-1028A)C44H38O12758[29,30]
150Calphostin BC37H34O11654[30]
151Calphostin C (= Cladochrome E)C44H38O14790[30,31]
152Calphostin D (= ent-isophleinchrome)C30H30O10550[30,46]
153Calphostin I (= Cladochrome D) C44H38O15806[30,31]
154PhleichromeC30H30O10550[53,54,99]
Pyrones
155Citreoviridin AC23H30O6402[45]
156Herbarin AC12H12O5236[45]
157Herbarin BC10H10O5210[45]
1585-Hydroxy-2-oxo-2H-piran-4-yl) methyl acetateC8H8O5184[65]
Seco acids
159Cladospolide EC12H20O4228[94]
16011-Hydroxy-4,5-dioxododecanoic acidC12H20O5244[78]
161seco-Patulolide AC12H20O4228[94]
162seco-Patulolide CC12H22O4230[33,41,50,94]
163(3S,5S, 11S)-Trihydroxydodecanoic acidC12H24O5248[68]
Sterols
164Cladosporide AC25H40O3388[79]
165Cladosporide BC25H38O3386[80]
166Cladosporide CC25H40O3388[80]
167Cladosporide DC25H38O3386[80]
168Cladosporisteroid BC21H30O3330[35]
169(22E,24R)-3β,5α-Dihydroxyergosta-7,22-dien-6-oneC28H44O3428[35]
170ErgosterolC28H44O396[79]
1713α-Hydroxy-pregn-7-ene-6,20-dioneC21H30O3330[62]
17223,24,25,26,27-Pentanorlanost-8-ene-3β,22-diolC28H42O5458[79]
173Peroxyergosterol (= (22E)-5α,8α-epidioxyergosta-6,22-dien-3β-ol)C28H44O3428[23,35,79]
1743β,5α,6β-Trihydroxyergosta-7,22-dieneC29H48O3444[47]
1753β,5α,9α-Trihydroxy-
(22E,24R)-ergosta-6-one		C28H44O4444[35]
Tetramic acids
176CladodionenC13H15NO3233[58,63,89,96]
177Cladosin AC13H20N2O4268[55]
178Cladosin BC12H18N2O4254[55,60,63]
179Cladosin CC12H16N2O3236[55,60,63]
180Cladosin DC13H18N2O3250[55]
181Cladosin FC12H18N2O4254[56,60,63]
182Cladosin GC13H20N2O4268[56]
183Cladosin H C20H26N2O4358[89]
184Cladosin I C20H26N2O4358[89]
185Cladosin JC25H29N3O3419[89]
186Cladosin KC25H29N3O3419[89]
187Cladosin LC13H22N2O4270[60]
188Cladosin L bisC14H13NO3243[63]
189Cladosin MC13H17NO4251[63]
190Cladosin NC13H17NO4251[63]
191Cladosin OC9H12N2O164[63]
192Cladosporicin AC21H27N3O5401[61]
193Cladosporiumin AC19H27NO5349[59]
194Cladosporiumin BC19H27NO5349[59]
195Cladosporiumin CC19H27NO5349[59]
196Cladosporiumin DC14H21NO3251[59]
197Cladosporiumin E C13H17NO4251[58,59]
198Cladosporiumin FC13H19NO5269[59]
199Cladosporiumin G C13H19NO4253[58,59]
200Cladosporiumin HC14H23NO5285[59]
201Cladosporiumin IC13H19NO3237[58]
202Cladosporiumin I bisC19H27NO5349[61]
203Cladosporiumin JC13H17NO4251[58]
204Cladosporiumin J bisC19H27NO5349[61]
205Cladosporiumin KC13H17NO4251[58]
206Cladosporiumin L(C13H20NO5)3Mg2889[58]
207Cladosporiumin MC13H15NO3233[58]
208Cladosporiumin NC13H19NO4253[58]
209Cladosporiumin OC13H17NO4251[58]
Tropolones
210Malettinin AC16H16O5288[95]
211Malettinin BC16H20O5292[95]
212Malettinin CC16H20O5292[95]
213Malettinin EC16H20O5292[95]
Volatile terpenes
214(−)-trans-CaryophylleneC15H24204[38]
215Dehydro aromdendreneC15H22202[38]
216α-PineneC10H16136[38]
217(+)-SativeneC15H24204[38]
Xanthones
218Conioxanthone AC16H12O7316[43]
2193,8-Dihydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylateC16H12O6300[43]
220α-Diversonolic esterC16H16O7320[43]
221β-Diversonolic esterC16H16O7320[43]
2228-Hydroxy-6-methylxanthone-1-carboxylic acidC15H12O5272[43]
223Methyl 8-hydroxy-6-(hydroxymethyl)- 9-oxo-9H-xanthene-1-carboxylateC16H12O6300[43]
224Methyl 8-hydroxy-6-methyl-9-oxo-9H-xanthene-1- carboxylateC16H12O5284[43]
2258-(Methoxycarbonyl)-1-hydroxy-9-oxo-9H-xanthene-3-carboxylic acidC16H10O7314[43]
226Secalonic acid DC32H30O14638[85]
227VertixanthoneC15H10O5270[43]
Miscellaneous
228α-AcetylorcinolC9H10O3166[52]
229Acetyl Sumiki’s acidC9H10O4182[44]
230CladosacidC15H22O3250[96]
231(2R*,4R*)-3,4-dihydro-5-methoxy-2-methyl-1(2H)-benzopyran-4-olC10H12O2164[81]
2321-(3,5-Dihydroxy-4-methylphenyl)propan-2-oneC10H12O3180[52]
2331,1′-Dioxine-2,2′-dipropionic acidC10H12O6228[85]
234Ellagic acidC14H6O8302[70]
235Fonsecinone AC32H26O10570[47]
2365-Hydroxy-2-methyl-4H-chromen-4-oneC10H8O3176[83]
237(2S)-5-Hydroxy-2-methyl-chroman-4-oneC10H10O2162[81,83]
2384-O-α-d-Ribofuranose-2-pentyl-3-phemethylolC17H26O6326[82]
2394-O-α-d-Ribofuranose-3-hydroxymethyl-2-pentylphenolC17H26O7342[81]
240Rubrofusarin BC16H14O5286[47]
241Sumiki’s acidC6H6O4142[44]
242TaxolC47H51NO14853[51]
243tert-ButylhydroquinoneC10H14O2166[70]
244VermistatinC18H16O6328[85]
Table
Table 3. Bioactivities of secondary metabolites produced by the Cladosporium species.
Table 3. Bioactivities of secondary metabolites produced by the Cladosporium species.
Name (Code)Biological ActivityConcentrationResultsRef.
Alkaloids
Aspidospermidin-20-ol, 1-acetyl-17-methoxy (2)Antimicrobial125 µg mL−1;Xanthomonas oryzae (MIC);[24]
62.50 µg mL−1;Pseudomonas syringae (MIC);
320.5 µg mL−1Aspergillus flavus (MIC)
Cladosporine A (4)Antimicrobial4 μg mL−1;Staphylococcus aureus (MIC);[84]
16 μg mL−1Candida albicans (MIC)
Cytochalasin D (5)Antibacterial25 μg mL–1S. aureus (MIC)[85]
2-Methylacetate-3,5,6-trimethylpyrazine (6)Antibacterial12.5 μg mL–1S. aureus (MIC)[85]
Azaphilones
Lunatoic acid A (10)Phytotoxic100 μg mL–1Brassica rapa; Sorghum durra; Brassica campestris; Capsicum annuum; Raphanus sativus[49]
Benzofluoranthenones
(6bS,7R,8S)-4,9-Dihydroxy-7,8-dimethoxy-1,6b,7,8-tetra-hydro-2H-benzo[J]fluoranthen-3-one (13)Inhibition of anti-CD28-induced IL22.4 µMIC50[27]
(6bR,7R,8S)-7-Methoxy-4,8,9-trihydroxy-1,6b,7,8-tetrahydro-2H-benzo[J]fluoranthen-3-one (15)Inhibition of anti-CD28-induced IL22.5 µMIC50[27]
Abl tyrosine kinase0.76 µMIC50
(6bS,7R,8S)-7-Methoxy-4,8,9-trihydroxy-1,6b,7,8-tetrahydro-2H-benzo[J]fluoranthen-3-one (16)Inhibition of anti-CD28-induced IL20.4 µMIC50[27]
Abl tyrosine kinase0.06 µMIC50
Benzopyranones
Coniochaetone A (17)Cytotoxic10 µM22RV1 (67.4%), C4-2B (13.87%), RWPE-1 (17.3%)[43]
Coniochaetone B (18)Cytotoxic10 µM22RV1 (32.7%), C4-2B (2.9%), RWPE-1 (19.7%)[43]
Coniochaetone K (19)Cytotoxic10 µM22RV1 (64.6%), C4-2B (7.2%), RWPE-1 (11.7%)[43]
Binaphthopyrones
Cladosporinone (20)Cytotoxic53.7 µML5178Y (IC50)[22]
Antibacterial64 µg mL−1S. aureus (MIC)
Viriditoxin (21)Cytotoxic0.1 µML5178Y (IC50)[22]
Antibacterial0.015 µg mL−1S. aureus (MIC)
Viriditoxin SC-28763 (22)Cytotoxic0.25 µML5178Y (IC50)[22]
Antibacterial2 µg mL−1S. aureus (MIC)
Viriditoxin SC-30532 (23)Antibacterial16 µg mL−1S. aureus (MIC)[22]
Butenolides and butanolides
Cladospolide F (24)Lipid accumulation10 µMOleic acid[94]
Cladospolide G (25)Antimicrobial32 µg mL−1;E. coli (MIC);[32]
1 µg mL−1;Glomerella cingulata (MIC);
32 µg mL−1;Bipolaris sorokiniana (MIC);
1 µg mL−1Fusarium oxysporum f. sp. cucumerinum (MIC)
ent-Cladospolide F (27)Antibacterial8 µg mL−1;S. aureus (MIC);[32]
16 µg mL−1;Edwardsiella ictarda (MIC);
64 µg mL−1P. aeruginosa (MIC)
Acetylcholinesterase40.46 µMIC50
11-Hydroxy-γ-dodecalactone (28)Lipid accumulation10 µMOleic acid[94]
iso-Cladospolide B (29)Antimicrobial32 µg mL−1;E. coli (MIC);[32]
32 µg mL−1;Edwardsiella tarda (MIC);
16 µg mL−1;E. ictarda (MIC);
64 µg mL−1G. cingulata (MIC)
Antimicrobial16 µg mL−1;E. tarda (MIC);[50]
8 µg mL−1;E. ictarda (MIC);
8 µg mL−1;Clematis mandshurica Miura (MIC);
16 µg mL−1;Colletotrichum gloeosporioides (MIC);
32 µg mL−1;B. sorokiniana (MIC);
32 µg mL−1F. oxysporum f. sp. cucumerinum (MIC)
Citrinin dervatives
Citrinin H1 (33)Antibacterial6.25 μg mL−1;S. aureus (MIC);[85]
12.5 μg mL−1;E. coli (MIC);
12.5 μg mL−1B. cereus (MIC)
Cladosporin A (34)Toxic72.0 µMbrine shrine nauplii (IC50)[92]
Cladosporin B (35)Toxic81.7 µMbrine shrine nauplii (IC50)[92]
Cladosporin C (36)Toxic49.9 µMbrine shrine nauplii (IC50)[92]
Cladosporin D (37)Antioxidant16.4 µMDPPH radicals (IC50)[92]
Toxic81.4 µMbrine shrine nauplii (IC50)
Coumarins and isocoumarins
Cladosporin (39)Antimicrobial75 µg mL−1;dermatophytes (100%);[12]
40 µg mL−1spore germination of Penicillium sp. (100%) and Aspergillus sp. (100%)
30 µMColletotrichum acutatum (92.7%), Colletotrichum fragariae (90.1%), C. gloeosporioides (95.4%), Plasmopara viticola (79.9%)[25]
500 µg mL−1;X. oryzae (MIC), A. flavus (MIC);[24]
62.50 µg mL−1Fusarium solani (MIC)
Phytotoxic10−3 Metiolated wheat (81%)[37]
5′-Hydroxyasperentin (40)Antimicrobial15.62 µg mL−1;X. oryzae (MIC);[24]
62.50 µg mL−1;P. syringae (MIC);
15.62 µg mL−1;A. flavus (MIC);
7.81 µg mL−1F. solani (MIC)
30 µMP. viticola (53.9%), Phomopsis obscurans (25.6%)[25]
Isocladosporin (41)Antimicrobial30 µMC. fragariae (50.4%), C. gloeosporioides (60.2%), P. viticola (83.0%)[25]
15.62 µg mL−1;X. oryzae (MIC), P. syringae (MIC);[24]
125 µg mL−1;A. flavus (MIC);
62.50 µg mL−1F. solani (MIC)
Phytotoxic10−3 Metiolated wheat (100%)[37]
Cyclohexene derivatives
Cladoscyclitol B (48)Inhibition of α-glucosidase2.95 µMIC50[82]
Depsides
3-Hydroxy-2,4,5-trimethylphenyl 4-[(2,4-dihydroxy-3,6-dimethylbenzoyl)oxy]-2-hydroxy-3,6-dimethylbenzoate (51)Antimicrobial25 µg mL−1;B. subtilis (bacteriostatic);[69,98]
25 µg mL−1;P. aeruginosa (bacteriostatic);
250 µg mL−1;E. coli (bacteriostatic);
250 µg mL−1S. aureus (bacteriostatic)
3-Hydroxy-2,5-dimethylphenyl 2,4-dihydroxy-3,6-dimethylbenzoate (53)Antimicrobial25 µg mL−1;B. subtilis (MIC);[69,98]
25 µg mL−1;P. aeruginosa (MIC);
250 µg mL−1;E. coli (MIC);
250 µg mL−1;S. aureus (MIC)
3-Hydroxy-2,5-dimethylphenyl 4-[(2,4-dihydroxy-3,6-dimethylbenzoyl)oxy]-2-hydroxy-3,6-dimethylbenzoate (54)Antimicrobial250 µg mL−1;B. subtilis (bacteriostatic);[69,98]
250 µg mL−1;P. aeruginosa (bacteriostatic);
250 µg mL−1;E. coli (bacteriostatic);
250 µg mL−1S. aureus (bacteriostatic)
Flavonoids
(2S)-7,4′-Dihydroxy-5-methoxy-8-(γ,γ-dimethylallyl)- flavanone (59)Enzymatic inhibitory11 µM;PTP1B (IC50);[93]
27 µMTCPTP (IC50)
Lactones
Cladosporamide A (75)Enzymatic inhibitory48 µM;PTP1B (IC50);[93]
54 µMTCPTP (IC50)
Macrolides
Cladocladosin A (80)Antimicrobial16 µg mL−1;E. coli (MIC);[34]
1 µg mL−1;E. tarda (MIC);
4 µg mL−1;P. aeruginosa (MIC);
2 µg mL−1;Vibrio anguillarum (MIC);
32 µg mL−1;F. oxysporium f. sp. momordicae (MIC);
32 µg mL−1;Penicillium digitatum (MIC);
8 µg mL−1Harpophora maydis (MIC)
Cladospolide B (83)Phytotoxic1 µg plant−1Oryza sativa (37.8%)[64]
5R-Hydroxyrecifeiolide (90)Antimicrobial32 µg mL−1;E. ictarda (MIC);[32]
32 µg mL−1P. aeruginosa (MIC)
5S-Hydroxyrecifeiolide (91)Antimicrobial16 µg mL−1G. cingulata (MIC)[32]
5Z-7-Oxozeaenol (94)Phytotoxic4.8 µg mL−1Amaranthus retroflexus (IC50)[49]
Pandangolide 1 (95)Antimicrobial32 µg mL−1;S. aureus (MIC);[32]
4 µg mL−1;E. ictarda (MIC);
1 µg mL−1;G. cingulata (MIC);
32 µg mL−1P. aeruginosa (MIC)
Pandangolide 3 (98)Antimicrobial2 µg mL−1;C. gloeosporioides (MIC);[33]
8 µg mL−1B. sorokiniana (MIC)
32 µg mL−1;E. tarda (MIC);[50]
32 µg mL−1;E. ictarda (MIC);
32 µg mL−1;C. gloeosporioides (MIC);
16 µg mL−1F. oxysporum f. sp. cucumerinum (MIC)
Sporiolide A (101)Antimicrobial16.7 µg mL−1;Micrococcus luteus (MIC);[88]
16.7 µg mL−1;C. albicans (MIC);
8.4 µg mL−1;Cryptococcus neoformans (MIC);
16.7 µg mL−1;Aspergillus niger (MIC);
8.4 µg mL−1Neurospora crassa (MIC)
Cytotoxic0.13 µg mL−1L1210 (IC50)
Sporiolide B (102)Antimicrobial16.7 µg mL−1M. luteus (MIC)[88]
Cytotoxic0.81 µg mL−1L1210 (IC50)
Thiocladospolide A (103)Antimicrobial1 µg mL−1;E. tarda (MIC);[33]
8 µg mL−1;E. ictarda (MIC);
2 µg mL−1C. glecosporioides (MIC)
32 µg mL−1;E. tarda (MIC);[50]
32 µg mL−1;E. ictarda (MIC);
16 µg mL−1C. gloeosporioides (MIC)
Thiocladospolide B (104)Antimicrobial2 µg mL−1;C. gloeosporioides (MIC);[33]
32 µg mL−1;Physalospora piricola (MIC);
1 µg mL−1ùF. oxysporum (MIC)
Thiocladospolide C (105)Antimicrobial1 µg mL−1;C. gloeosporioides (MIC);[33]
32 µg mL−1;P. piricola (MIC);
32 µg mL−1F. oxysporum (MIC)
Thiocladospolide D (106)Antimicrobial1 µg mL−1;E. ictarda (MIC);[33]
1 µg mL−1;C. gloeosporioides (MIC);
32 µg mL−1;P. piricola (MIC);
1 µg mL−1F. oxysporum (MIC)
Thiocladospolide F (108)Antimicrobial16 µg mL−1;E. coli (MIC);[34]
2 µg mL−1;E. tarda (MIC);
2 µg mL−1;V. anguillarum (MIC);
16 µg mL−1;F. oxysporium f. sp. momordicae (MIC);
16 µg mL−1;P. digitatum (MIC);
4 µg mL−1H. maydis (MIC)
Thiocladospolide F bis (109)Antimicrobial32 µg mL−1;E. tarda (MIC);[50]
16 µg mL−1;E. ictarda (MIC);
16 µg mL−1B. sorokiniana (MIC)
Thiocladospolide G (110)Antimicrobial2 µg mL−1;E. tarda (MIC);[34]
2 µg mL−1;V. anguillarum (MIC);
32 µg mL−1;F. oxysporium f. sp. momordicae (MIC);
32 µg mL−1;P. digitatum (MIC);
8 µg mL−1H. maydis (MIC)
Thiocladospolide G bis (111)Antimicrobial4 µg mL−1;E. tarda (MIC);[50]
32 µg mL−1;E. ictarda (MIC);
32 µg mL−1;C. mandshurica Miura (MIC);
16 µg mL−1;C. gloeosporioides (MIC);
32 µg mL−1F. oxysporum f. sp. cucumerinum (MIC)
Thiocladospolide H (112) Antimicrobial16 µg mL−1;E. tarda (MIC);[50]
8 µg mL−1;E. ictarda (MIC);
16 µg mL−1;C. gloeosporioides (MIC);
16 µg mL−1B. sorokiniana (MIC)
Thiocladospolide I (113)Antimicrobial32 µg mL−1;E. tarda (MIC);[50]
32 µg mL−1;E. ictarda (MIC);
16 µg mL−1F. oxysporum f. sp. cucumerinum (MIC)
Thiocladospolide J (114)Antimicrobial16 µg mL−1;E. tarda (MIC);[50]
16 µg mL−1;E. ictarda (MIC);
16 µg mL−1;C. mandshurica Miura (MIC);
16 µg mL−1;C. gloeosporioides (MIC);
32 µg mL−1;B. sorokiniana (MIC);
16 µg mL−1F. oxysporum f. sp. cucumerinum (MIC)
Zeaenol (115)Phytotoxic8.16 µg mL−1A. retroflexus (IC50)[49]
Naphthalene derivatives
Cladonaphchrom A (116)Antimicrobial1.25 µg mL−1;Scaphirhynchus albus (MIC);[83]
2.5 µg mL−1;E. coli (MIC);
10 µg mL−1;B. subtilis (MIC);
5 µg mL−1;Micrococcus tetragenus (MIC);
10 µg mL−1;M. luteus (MIC);
50 µg mL−1;Alternaria brassicicola (MIC);
50 µg mL−1;Phytophthora parasitica var. nicotianae (MIC);
25 µg mL−1;Colletotrichum capsici (MIC);
100 µg mL−1;B. oryzae (MIC);
50 µg mL−1;Diaporthe medusaea (MIC);
50 µg mL−1 Cyanophora paradoxa (MIC)
Cladonaphchrom B (117)Antibacterial2.5 µg mL−1;S. albus (MIC);[83]
2.5 µg mL−1;E. coli (MIC);
5 µg mL−1;B. subtilis (MIC);
5 µg mL−1;M. tetragenus (MIC);
10 µg mL−1;M. luteus (MIC);
25 µg mL−1;A. brassicicola (MIC);
50 µg mL−1;P. parasitica var. nicotianae (MIC);
25 µg mL−1;C. capsici (MIC);
100 µg mL−1;D. medusaea (MIC);
50 µg mL−1C. paradoxa (MIC)
Naphtalenones
Altertoxin XII (120)Quorum sensing inhibitory20 µg well−1Chromobacterium violaceum (MIC)[87]
Cladosporol A (121)Antifungal100 ppmUromyces appendiculatus (84.2%)[66]
Β-1,3-glucan biosynthesis inhibitor10 µg mlIC50[26]
Cladosporol B (122)Antifungal100 ppmU. appendiculatus (100%)[66]
Cladosporol C (123)Antifungal100 ppmU. appendiculatus (77.6%)[66]
Antibacterial8 µg mL−1;E. coli (MIC);[39]
64 µg mL−1;M. luteus (MIC);
16 µg mL−1Vibrio harveyi (MIC)
Cytotoxic33.9 µM;A549 (100%);[86]
45.6 µM;H1975 (100%);
72.5 µM;HL60 (100%);
11.4 µMMOLT-4 (100%)
14 µM;A549 (IC50);[39]
4 µMH446 (IC50)
Cladosporol D (124)Antifungal100 ppmU. appendiculatus (69.4%)[66]
Anti-COX-260.2 µMIC50[86]
Cladosporol E (125)Antifungal100 ppmU. appendiculatus (74.8%)[66,85]
Cladosporol F (126)Antibacterial32 µg mL−1;E. coli (MIC);[39]
64 µg mL−1;M. luteus (MIC);
32 µg mL−1V. harveyi (MIC)
Cytotoxic15 µM;A549 (IC50);[39,40]
10 µM;HeLa (IC50);
23 µM;K562 (IC50);
23 µMHCT-116 (IC50)
Cladosporol G (127)Cytotoxic3.9 µM;HeLa (IC50);[40]
8.8 µM;K562 (IC50);
19.5 µMHCT-116 (IC50)
Cladosporol G bis (128)Antibacterial64 µg mL−1;E. coli (MIC);[39]
128 µg mL−1;M. luteus (MIC);
64 µg mL−1V. harveyi (MIC)
Cytotoxic13 µM;A549 (IC50);
11 µM;HeLa (IC50);
10 µM;Huh7 (IC50);
11 µM;L02 (IC50);
14 µM;LM3 (IC50);
15 µMSW1990 (IC50)
Cladosporol H (129)Antibacterial32 µg mL−1;E. coli (MIC);[39]
64 µg mL−1;M. luteus (MIC);
4 µg mL−1V. harveyi (MIC)
Cytotoxic5 µM;A549 (IC50);
10 µM;H446 (IC50);
1 µM;Huh7 (IC50);
4.1 µM;LM3 (IC50);
10 µM;MCF-7 (IC50);
14 µMSW1990 (IC50)
Cladosporol I (130)Quorum sensing inhibitory30 µg well−1C. violaceum (MIC)[87]
Antibacterial64 µg mL−1;E. coli (MIC);[39]
64 µg mL−1;M. luteus (MIC);
16 µg mL−1V. harveyi (MIC)
Cytotoxic10.8 µMHeLa (IC50)
Cladosporol J (131)Antibacterial16 µg mL−1;E. coli (MIC);[39]
64 µg mL−1;M. luteus (MIC);
32 µg mL−1V. harveyi (MIC)
Cytotoxic15 µM;A549 (IC50);
4 µM;H446 (IC50);
4.9 µM;HeLa (IC50);
6.2 µM;Huh7 (IC50);
13 µM;L02 (IC50);
9.1 µM;LM3 (IC50);
1.8 µM;MCF-7 (IC50);
2.2 µMSW1990 (IC50)
Cladosporone A (132)Cytotoxic14.3 µM; K562 (100%); [86]
15.7 µM;A549 (100%);
29.9 µM;Huh-7 (100%);
40.6 µM;H1975 (100%);
21.3 µM;MCF-7 (100%):
10.5 µM;U937 (100%);
17.0 µM;BGC823 (100%);
10.1 µM;HL60 (100%);
53.7 µM;HeLa (100%)
14.6 µMMOLT-4 (100%)
Anti-COX-249.1 µMIC50
(3S)-3,8-Dihydroxy-6,7-dimethyl-α- tetralone (137)Antibacterial20 µMS. aureus, B. cereus, E. coli, Vibrio alginolyticus, Vibrio parahemolyticus, methicillin-resistant S. aureus[81]
Scytalone (139)Antibacterial63.6 µg mL−1;Bacillus cereus (IC50);[68]
95.5 µg mL−1E. coli (IC50)
Naphtoquinones and anthraquinones
Anhydrofusarubin (142)Cytotoxic3.97 μg mL–1K-562 (IC50)[90]
Methyl ether of fusarubin (143)Cytotoxic3.58 μg mL–1K-562 (IC50)[90]
Antibacterial40 μg disc–1S. aureus (27 mm), Bacillus megaterium (22 mm), E coli (25 mm), P. aeruginosa (24 mm)
Toxic81.4 µMbrine shrine naupalii (IC50)
Perylenequinones
Altertoxin VIII (145)Quorum sensing inhibitory30 µg well−1C. violaceum (MIC)[87]
Altertoxin IX (146)Quorum sensing inhibitory30 µg well−1C. violaceum (MIC)[87]
Aterotoxin X (147)Quorum sensing inhibitory20 µg well−1C. violaceum (MIC)[87]
Altertoxin XI (148)Quorum sensing inhibitory30 µg well−1C. violaceum (MIC)[87]
Calphostin A (=UCN-1028A) (149)PK inhibition0.19 µg mL−1;PKC (IC50);[29,30]
40 µg mL−1PKA (IC50)
Cytotoxic0.29 µg mL−1;HeLa S3 (IC50);
0.21 µg mL−1MCF-7 (IC50)
Calphostin B (150)PK inhibition1.04 µg mL−1;PKC (IC50);[7]
22.9 µg mL−1PKA (IC50)
Cytotoxic2.56 µg mL−1;HeLa S3 (IC50);
1.61 µg mL−1MCF-7 (IC50)
Calphostin C (=cladochrome E) (151)PK inhibition0.05 µg mL−1PKC (IC50)[30]
Cytotoxic0.23 µg mL−1;HeLa S3 (IC50);
0.18 µg mL−1MCF-7 (IC50)
Calphostin D (= ent-isophleinchrome) (152)PK inhibition6.36 µg mL−1;PKC (IC50);[30]
12.7 µg mL−1PKA (IC50)
Cytotoxic8.45 µg mL−1;HeLa S3 (IC50);
2.69 µg mL−1MCF-7 (IC50)
Phytotoxic5 µg L−1Sugar beet cells
(100% inhibition in the light, 37–64% inhibition in the dark)		[46]
33 µg L−1Necrosis on sugar beet leaves
Calphostin I (= Cladochrome D) (153)PK inhibition6.36 µg mL−1;PKC (IC50);[30]
12.7 µg mL−1PKA (IC50)
Cytotoxic0.24 µg mL−1;HeLa S3 (IC50);
0.16 µg mL−1MCF-7 (IC50)
Phleichrome (154)Invertase I inhibition0.5 mM62%[99]
Seco acids
Cladospolide E (159)Lipid accumulation10 µMOleic acid;
Triglycerides (~170 µg mg−1 protein);
Total cholesterol (~3 µg mg−1 protein)		[94]
Seco-patulolide A (161)Lipid accumulation10 µMOleic acid;
Triglycerides (~150 µg mg−1 protein);
Total cholesterol (~3 µg mg−1 protein)		[94]
Seco-patulolide C (162)Lipid accumulation10 µMOleic acid;
Triglycerides (~150 µg mg−1 protein);
Total cholesterol (~3 µg mg−1 protein)		[94]
Antimicrobial32 µg mL−1;E. tarda (MIC);[50]
32 µg mL−1;E. ictarda (MIC);
16 µg mL−1C. gloeosporioides (MIC)
(3S,5S,11S)-Trihydroxydodecanoic acid (163)Antibacterial63.6 µg mL−1B. cereus (MIC)[68]
Cytotoxic42 µM;MCF-7;
82 µMT47D
Antibacterial40 μg disc–1S. aureus (27 mm), B. megaterium (22 mm), E coli (25 mm), P. aeruginosa (24 mm)
Toxic81.4 µMbrine shrine naupalii (IC50)
Sterols
Cladosporide A (164)Antifungal0.5 µg mL−1Aspergillus fumigatus (IC50)[79]
Cladosporide B (165)Antifungal3 µg disc−1A. fumigatus (11 mm)[80]
Cladosporide C (166)Antifungal1.5 µg disc−1A. fumigatus (11 mm)[80]
3α-Hydroxy-pregn-7-ene-6,20-dione (171)Anti-adipogenic 1.25 – 10 µM 3T3-L1[62]
Tetramic acids
Cladodionen (176)Cytotoxic28.6 µMHL-60 (IC50)[58]
4.5 µM;K562 (IC50);[89]
6.6 µM;HL-60 (IC50);
12 µM;HCT-116 (IC50);
11 µM;PC-3 (IC50);
15 µM;SH-SYSY (IC50);
22 µMMGC-803 (IC50)
18.7 µM;MCF-7 (IC50);[96]
19.1 µM;HeLa (IC50);
17.9 µM;HCT-116 (IC50);
9.1 µMHL-60 (IC50)
3.7 µML5178 (IC50)[63]
Antifungal100 mg/plate;Ustilago maydis (0.97 cm);
100 mg/plateSaccharomyces cerevisiae (3.27 cm)
Cladosin B (178)Renoprotective effects against cisplatin-induced kidney cell damage25 µM;
50 µM;
100 µM		LLC-PK1 (dose-dependent)[60]
Cladosin C (179)Antiviral276 µMH1N1 (IC50)[55]
Cladosin F (181)Renoprotective effects against cisplatin-induced kidney cell damage25 µM;
50 µM;
100 µM		LLC-PK1 (dose-dependent)[60]
Cladosin I (184)Cytotoxic4.1 µM;K562 (IC50);[89]
2.8 µM;HL-60 (IC50);
11 µM;HCT-116 (IC50);
13 µM;PC-3 (IC50);
12 µM;SH-SYSY (IC50);
19 µMMGC-803 (IC50)
Cladosin J (185)Cytotoxic6.8 µM;K562 (IC50);[89]
7.8 µMHL-60 (IC50)
Cladosin K (186)Cytotoxic5.9 µM;K562 (IC50);[89]
7.5 µM;HL-60 (IC50);
14 µM;HCT-116 (IC50);
18 µMPC-3 (IC50)
Cladosin L (187)Renoprotective effects against cisplatin-induced kidney cell damage25 µM;
50 µM;
100 µM		LLC-PK1 (dose-indipendent)[60]
Cladosin L bis (188)Antibacterial25 µM;S. aureus ATCC 700699 (IC50);[63]
50 µMS. aureus ATCC 29213 (IC50)
Cladosporicin A (192)Cytotoxic70.88 µM;Bt549 (IC50);[61]
74.48 µM;HCC70 (IC50);
75.54 µM;MDA-MB-231 (IC50);
79.36 µMMDA-MB-468 (IC50)
Cladosporiumin I bis (202)Cytotoxic76.18 µM;Bt549 (IC50);[61]
85.29 µM;HCC70 (IC50);
82.37 µM;MDA-MB-231 (IC50);
81.44 µMMDA-MB-468 (IC50)
Cladosporiumin J bis (204)Cytotoxic78.96 µM;Bt549 (IC50);[61]
76.41 µM;HCC70 (IC50);
79.27 µM;MDA-MB-231 (IC50);
74.64 µMMDA-MB-468 (IC50)
Tropolones
Malettinin A (210)Antimicrobial33.1 µM;Trichophyton rubrum (IC50);[95]
100 µMC. albicans (81%)
Malettinin B (211)Antimicrobial28.3 µM;Xanthomonas campestris (IC50);[95]
60.6 µM;T. rubrum (IC50);
100 µM;Staphylococcus epidermidis (<80%);
100 µM;B. subtilis (<80%);
100 µMC. albicans (<80%)
Malettinin C (212)Antimicrobial37.9 µM;X. campestris (IC50);[95]
83.2 µM;T. rubrum (IC50);
100 µM;S. epidermidis (<80%);
100 µM;B. subtilis (<80%);
100 µMC. albicans (<80%)
Malettinin E (213)Antimicrobial28.7 µM;X. campestris (IC50);[95]
30.7 µM;T. rubrum (IC50)
Xanthones
Conioxanthone A (218)Cytotoxic10 µM22RV1 (36.8%), C4-2B (3.3%), RWPE-1 (20.3%)[43]
3,8-Dihydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate (219)Cytotoxic10 µM22RV1 (82.1%), C4-2B (77.7%), RWPE-1 (11.5%)[43]
α-Diversonolic ester (220)Cytotoxic10 µM22RV1 (28.8%), C4-2B (12.9%), RWPE-1 (24.3%)[43]
β-Diversonolic ester (221)Cytotoxic10 µM22RV1 (40.2%), C4-2B (2.8%), RWPE-1 (10.3%)[43]
8-Hydroxy-6-methylxanthone-1-carboxylic acid (222)Cytotoxic10 µM22RV1 (71.3%), C4-2B (60.7%), RWPE-1 (19.7%)[43]
Methyl 8-hydroxy-6-(hydroxymethyl)- 9-oxo-9H-xanthene-1-carboxylate (223)Cytotoxic10 µM22RV1 (68.1%), C4-2B (20.2%), RWPE-1 (19.0%)[43]
Methyl 8-hydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate (224) Cytotoxic10 µM22RV1 (55.8%), C4-2B (8.1%), RWPE-1 (5.3%)[43]
8-(Methoxycarbonyl)-1-hydroxy-9-oxo-9H-xanthene-3-carboxylic acid (225)Cytotoxic10 µM22RV1 (63.9%), C4-2B (12.2%), RWPE-1 (27.0%)[43]
Vertixanthone (227)Cytotoxic10 µM22RV1 (27.1%), RWPE-1 (25.0%)[43]
Miscellaneous
Acetyl Sumiki’s acid (229)Antibacterial5 μg disc−1B. subtilis (7 mm), S. aureus (7 mm)[44]
1,1′-Dioxine-2,2′-dipropionic acid (233)Antibacterial25 μg mL−1;S. aureus (MIC);[85]
25 μg mL−1;E. coli (MIC);
12.5 μg mL−1B. cereus (MIC)
4-O-α-d-Ribofuranose-2-pentyl-3-phemethylol (238)Inhibition of α-glucosidase2.50 µMIC50[82]
Sumiki’s acid (241)Antibacterial5 μg disc−1B. subtilis (7 mm), S. aureus (7 mm)[44]
Taxol (242)Cytotoxic3.5 µMHCT 15 (IC50)[51]
Antibacterial30 µL disc−1;Pseudomonas aeruginosa (2 mm);
20 µL disc−1;Escherichia coli (3 mm);
30 µL disc−1;Klebsiella pneumoniae (2 mm);
20 µL disc−1;Acetobacter sp. (2 mm);
40 µL disc−1Bacillus subtilis (1 mm)
Vermistatin (244)Antibacterial25 μg mL−1;S. aureus (MIC);[85]
25 μg mL−1B. cereus (MIC)
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Salvatore, M.M.; Andolfi, A.; Nicoletti, R. The Genus Cladosporium: A Rich Source of Diverse and Bioactive Natural Compounds. Molecules 2021, 26, 3959. https://doi.org/10.3390/molecules26133959

AMA Style

Salvatore MM, Andolfi A, Nicoletti R. The Genus Cladosporium: A Rich Source of Diverse and Bioactive Natural Compounds. Molecules. 2021; 26(13):3959. https://doi.org/10.3390/molecules26133959

Chicago/Turabian Style

Salvatore, Maria Michela, Anna Andolfi, and Rosario Nicoletti. 2021. "The Genus Cladosporium: A Rich Source of Diverse and Bioactive Natural Compounds" Molecules 26, no. 13: 3959. https://doi.org/10.3390/molecules26133959

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