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

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).

Table 1

Cladosporium species/strains reported for production of secondary metabolites.

Species/Strain	Substrate	Location	Refs.
C. cladosporioides	-	-	[12]
C. cladosporioides	sediment of hypersaline lake	El Hamra, Egypt	[22]
C. cladosporioides	sponge (Cliona sp.)	Los Molles, Chile	[23]
C. cladosporioides	aphid (Aphis craccivora)	Egypt	[17,18]
C. cladosporioides	endophytic in Zygophyllum mandavillei	Al-Ahsa, Saudi Arabia	[24]
C. cladosporioides	endophytic in unspecified plant	Tifton, United States	[25]
C. cladosporioides	-	Japan	[26]
C. cladosporioides/CBUK20700	dead insect	Thailand	[27,28]
C. cladosporioides/FERMBP-1285	block fence	Osaka, Japan	[29,30]
C. cladosporioides/IPV-F167	-	Italy	[31]
C. cladosporioides/LWL5	endophytic in Helianthus annuus	Daegu, South Korea	[16]
C. cladosporioides/MA-299	endophytic in Bruguiera gymnorrhiza	Hainan, China	[32,33,34]
C. cladosporioides/MCCC3A00182	deep sea sediment	Pacific Ocean	[35]
C. cladosporioides/MUPGBIOCHEM-CC-07-2015	brown alga (Sargassum wightii)	Tamil Nadu, India	[21]
C. cladosporioides/NRRL5507	-	-	[36,37]
C. cladosporioides/CL-1	rhizosphere of red pepper	South Korea	[38]
C. cladosporioides/EN-399	red alga (Laurencia okamurai)	Qingdao, China	[39]
C. cladosporioides/HDN14-342	deep sea sediment	Indian Ocean	[40]
C. colocasiae/A801	endophytic in Callistemon viminalis	Guangzhou, China	[41]
C. delicatulum/EF33	endophytic in Terminalia pallida	Andhra Pradesh, India	[42]
C. halotolerans/GXIMD 02502	coral (Porites lutea)	Weizhou islands, China	[43]
C. herbarum	sponge (Callyspongia aerizusa)	Bali, Indonesia	[44,45]
C. herbarum/FC27P	endophytic in Beta vulgaris	Dublin, United States	[46]
C. herbarum/IFB-E002	endophytic in Cynodon dactylon	Yancheng reserve, China	[47]
C. oxysporum	endophytic in Aglaia odorata	Java, Indonesia	[14]
C. oxysporum	endophytic in Alyxia reinwardtii	Java, Indonesia	[48]
C. oxysporum/DH14	locust (Oxya chinensis)	Jinhua, China	[49]
C. oxysporum/HDN13-314	endophytic in Avicennia marina	Hainan, China	[50]
C. oxysporum/RM1	endophytic in Moringa oleifera	Tamil Nadu, India	[51]
C. perangustum/FS62	deep sea sediment	South China Sea	[52]
C. phlei/C-273 w	pathogenic on Phleum pratense	Hokkaido, Japan	[53]
C. phlei/CBS 358.69	pathogenic on Phleum pratense	Germany	[54]
C. sphaerospermum/2005-01-E3	deep sea sludge	Pacific Ocean	[55,56]
C. sphaerospermum/DK-1-1	endophytic in Glycine max	South Korea	[57]
C. sphaerospermum/EIODSF 008	deep sea sediment	Indian Ocean	[58]
C. sphaerospermum/L3P3	deep sea sediment	Mariana Trench	[59]
C. sphaerospermum/SW67	hydroid (Hydractinia echinata)	South Korea	[60,61,62]
C. sphaerospermum/WBS017	endophytic in Fritillaria unibracteata var. wabuensis	China	[63]
C. tenuissimum	soil	Karo-cho, Japan	[64]
C. tenuissimum/DMG 3	endophytic in Swietenia mahagoni	Sumatra, Indonesia	[65]
C. tenuissimum/ITT21	pine rust (Cronartium flaccidum)	Tuscany, Italy	[66]
C. tenuissimum/LR463	endophytic in Maytenus hookeri	Yunnan, China	[67]
C. tenuissimum/P1S11	endophytic in Pinus wallichiana	Kashmir, India	[68]
C. uredinicola	endophytic in Psidium guajava	São Carlos, Brazil	[69]
C. velox/TN-9S	endophytic in Tinospora cordifolia	Amritsar, India	[70]
Cladosporium sp.	sponge (Niphates rowi)	Gulf of Aqaba, Israel	[71]
Cladosporium sp./486	intertidal sediment	San Antonio Oeste, Argentina	[19]
Cladosporium sp./501-7w	-	Japan	[72,73,74]
Cladosporium sp./F14	sea water	Sai Kung, China	[13,75]
Cladosporium sp./HDN17-58	deep sea sediment	Pacific Ocean	[76]
Cladosporium sp./I(R)9-2	endophytic in Quercus variabilis	Nanjing, China	[77]
Cladosporium sp./IFB3lp-2	endophytic in Rhizophora stylosa	Hainan, China	[78]
Cladosporium sp./IFM 49189	-	Japan	[79,80]
Cladosporium sp./JJM22	endophytic in Ceriops tagal	Hainan, China	[81,82,83]
Cladosporium sp./JNU17DTH12-9-0	unknown	China	[84]
Cladosporium sp./JS1-2	endophytic in Ceriops tagal	Hainan, China	[85]
Cladosporium sp./KcFL6’	endophytic in Kandelia candel	Daya Bay, China	[86]
Cladosporium sp./KFD33	blood cockle	Hainan, China	[87]
Cladosporium sp./L037	brown alga (Actinotrichia fragilis)	Okinawa, Japan	[88]
Cladosporium sp./N5	red alga (Porphyra yezoensis)	Lianyungang, China	[15]
Cladosporium sp./OUCMDZ-1635	sponge	Xisha Islands, China	[89]
Cladosporium sp./RSBE-3	endophytic in Rauwolfia serpentina	Bangladesh	[90]
Cladosporium sp./SCNU-F0001	endophytic in unspecified mangrove	Zhuhai, China	[91]
Cladosporium sp./SCSIO z01	deep sea sediment	East China Sea	[92]
Cladosporium sp./TPU1507	unidentified sponge	Manado, Indonesia	[93]
Cladosporium sp./TZP-29	unidentified soft coral	Guangzhou, China	[94]
Cladosporium sp./KF501	water sample	Wadden Sea, Germany	[95]
Cladosporium sp./SCSIO z0025	deep sea sediment	Okinawa, Japan	[96]

Figure 1

Pie charts of the origin of the strains examined in the present review.

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].

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.

Code	Name	Formula	Nominal Mass (U)	Refs.
Alkaloids
1	Aspernigrin A	C13H12N2O2	228	[47]
2	Aspidospermidin-20-ol, 1-acetyl-17-methoxy	C22H30N2O3	370	[24]
3	Cladosin E	C13H17NO4	251	[55]
4	Cladosporine A	C28H39NO2	421	[84]
5	Cytochalasin D	C30H37NO6	507	[85]
6	2-Methylacetate-3,5,6-trimethylpyrazine	C10H14N2O2	194	[85]
7	Nonanal oxime	C9H19NO	157	[17]
8	2-Piperidinone methyl	C6H11NO	113	[17]
Azaphilones
9	Bicyclic diol	C11H14O4	210	[52]
10	Lunatoic acid A	C21H24O7	388	[49]
11	Perangustol A	C11H14O4	210	[52]
12	Perangustol B	C11H14O4	210	[52]
Benzofluoranthenones
13	(6bS,7R,8S)-4,9-Dihydroxy-7,8- dimethoxy-1,6b,7,8-tetra-hydro-2H- benzo[J]fluoranthen-3-one	C23H22O4	362	[27]
14	(6bS,7R)-4,9-Dihydroxy-7- methoxy-1,2,6b,7-tetrahydrobenzo[J]fluoranthen-3,8-dione	C22H18O4	346	[27]
15	(6bR,7R,8S)-7- Methoxy-4,8,9-trihydroxy- 1,6b,7,8-tetrahydro-2H- benzo[J]fluoranthen-3-one	C22H20O4	348	[27]
16	(6bS,7R,8S)-7- Methoxy-4,8,9-trihydroxy- 1,6b,7,8-tetrahydro-2H- benzo[J]fluoranthen-3-one	C22H20O4	348	[27,28]
Benzopyranones
17	Coniochaetone A	C13H10O4	230	[43]
18	Coniochaetone B	C13H12O4	232	[43]
19	Coniochaetone K	C13H10O6	262	[43]
Binaphthopyrones
20	Cladosporinone	C33H30O14	650	[22]
21	Viriditoxin	C34H30O14	662	[22]
22	Viriditoxin SC-28763	C34H30O13	646	[22]
23	Viriditoxin SC-30532	C34H30O12	630	[22]
Butenolides and butanolides
24	Cladospolide F	C12H22O4	230	[94]
25	Cladospolide G	C14H24O5	272	[32]
26	Cladospolide H	C12H18O3	210	[32]
27	ent-Cladospolide F	C12H22O4	230	[32]
28	11-Hydroxy-γ-dodecalactone	C12H20O3	212	[94]
29	iso-Cladospolide B	C12H20O4	228	[32,44,50,67,71,94]
Cinnamic acid derivatives
30	Chlorogenic acid	C16H18O9	354	[70]
31	Caffeic acid	C9H8O4	180	[70]
32	Coumaric acid	C9H8O3	164	[70]
Citrinin derivatives
33	Citrinin H1	C25H30O7	442	[85]
34	Cladosporin A	C13H15NO3	233	[92]
35	Cladosporin B	C13H15NO3	233	[92]
36	Cladosporin C	C14H16O4	248	[92]
37	Cladosporin D	C12H16O4	224	[92]
Coumarins and Isocoumarins
38	Asperentin-8-methyl ether (= cladosporin-8-methyl ether)	C17H22O6	322	[25]
39	Cladosporin (= asperentin)	C16H20O5	292	[12,24,25,36,37]
40	5′-Hydroxyasperentin	C16H20O6	308	[24,25]
41	7-Hydroxy-4-methoxy-5-methylcoumarin	C11H10O4	206	[47]
42	Isocladosporin	C16H20O5	292	[24,25,37]
43	Kotanin	C24H22O8	438	[47]
44	Orlandin	C22H18O8	410	[47]
45	Phomasatin	C10H8O5	208	[35]
46	Umbelliferone	C9H6O3	162	[70]
Cyclohexene derivatives
47	Cladoscyclitol A	C12H20O5	244	[82]
48	Cladoscyclitol B	C13H22O7	290	[82]
49	Cladoscyclitol C	C12H22O4	230	[82]
50	Cladoscyclitol D	C12H22O5	246	[82]
Despsides
51	3-Hydroxy-2,4,5-trimethylphenyl 2,4-dihydroxy-3,6-dimethylbenzoate	C18H20O5	316	[69,98]
52	3-Hydroxy-2,4,5-trimethylphenyl 4-[(2,4-dihydroxy-3,6-dimethylbenzoyl)oxy]-2-hydroxy-3,6-dimethylbenzoate	C27H28O8	480	[69,98]
53	3-Hydroxy-2,5-dimethylphenyl 2,4-dihydroxy- 3,6-dimethylbenzoate	C17H18O5	302	[69,98]
54	3-Hydroxy-2,5-dimethylphenyl 4-[(2,4-dihydroxy-3,6-dimethylbenzoyl)oxy]-2-hydroxy-3,6-dimethylbenzoate	C26H26O8	466	[69,98]
Diketopiperazines
55	(3R,8aR)-Cyclo(leucylprolyl)	C11H18N2O2	210	[17]
56	(3S,8aS)-Cyclo(leucylprolyl)	C11H18N2O2	210	[17]
57	(3R,8aR)-Cyclo(phenylalanylprolyl)	C14H16N2O2	244	[17]
58	(3S,8aS)-Cyclo(phenylalanylprolyl)	C14H16N2O2	244	[17]
Flavonoids
59	(2S)-7,4′-Dihydroxy-5-methoxy-8-(γ,γ-dimethylallyl)-flavanone	C21H22O5	354	[93]
60	Catechin	C15H14O6	290	[70]
61	Epicatechin	C15H14O6	290	[70]
Gibberelines
62	GA3	C19H22O6	346	[57]
63	GA4	C19H24O5	332	[57]
64	GA5	C19H22O5	330	[57]
65	GA7	C19H22O5	330	[57]
66	GA15	C20H26O4	330	[57]
67	GA19	C20H26O6	362	[57]
68	GA24	C20H26O5	346	[57]
Fusicoccane diterpene glycosides
69	Cotylenin A	C33H50O11	622	[72,73,74]
70	Cotylenin B	C33H51ClO11	659	[73,74]
71	Cotylenin C	C33H52O11	624	[73]
72	Cotylenin D	C33H52O12	640	[73]
73	Cotylenin E	C28H46O9	526	[73]
Lactones
74	Cladosporactone A	C10H12O4	196	[35]
75	Cladosporamide A	C14H11NO5	273	[93]
76	5-Decanolide	C10H18O2	170	[17]
77	Herbaric acid	C10H8O6	224	[45]
78	Isochracinic acid	C10H8O5	208	[35]
Macrolides
79	Brefeldin A	C16H24O4	280	[77]
80	Cladocladosin A	C13H18O3	222	[34]
81	Cladospamide A	C13H20N2O4	268	[91]
82	Cladospolide A	C12H20O4	228	[41,64,67,78,91]
83	Cladospolide B	C12H20O4	228	[44,64,67,78]
84	Cladospolide C	C12H20O4	228	[64]
85	4,5-Dihydroxy-12-methyloxacyclododecan-2-one	C12H22O4	230	[67]
86	(6R,12S)-6-Hydroxy-12-methyl- oxacyclodoecane-2,5-dione	C12H20O4	228	[67]
87	(10S,12S)-10-Hydroxy-12-methyloxacyclododecane-2,5-dione	C12H20O4	228	[67]
88	4-Hydroxy-12-methyloxacyclododecane-2,5,6-trione	C12H18O5	242	[41]
89	(E)-(3R,6S)-6-Hydroxy-12-methyl-2,5-dioxooxacyclododecan-3-yl 4,11-dihydroxydodec-2-enoate	C24H40O8	456	[78]
90	5R-Hydroxyrecifeiolide	C12H20O3	212	[32]
91	5S-Hydroxyrecifeiolide	C12H20O3	212	[32]
92	12-Methyloxacyclododecane-2,5,6-trione	C12H18O4	226	[41]
93	Methyl 2-(((4R,6S,12R)-6-hydroxy-12-methyl-2,5-dioxooxacyclododecan-4-yl)thio)acetate	C15H24O6S	332	[78]
94	5Z-7-Oxozeaenol	C19H22O7	362	[49]
95	Pandangolide 1	C12H20O5	244	[32,41,48,71,78]
96	Pandangolide 1a	C12H20O5	244	[71,78]
97	Pandangolide 2	C14H22O6S	318	[44,78]
98	Pandangolide 3	C16H26O7S	362	[33,44,50,78]
99	Pandangolide 4	C24H38O8S	486	[44]
100	Patulolide B	C13H20O3	224	[41]
101	Sporiolide A	C19H24O6	348	[88]
102	Sporiolide B	C14H24O4	256	[88]
103	Thiocladospolide A	C16H26O6S	346	[33,50]
104	Thiocladospolide B	C16H24O7S	360	[33]
105	Thiocladospolide C	C15H22O6S	330	[33]
106	Thiocladospolide D	C16H28O7S	364	[33]
107	Thiocladospolide E	C14H26O5S	306	[91]
108	Thiocladospolide F	C16H28O5S	332	[34]
109	Thiocladospolide F bis	C24H38O8S	486	[50]
110	Thiocladospolide G	C16H28O6S	348	[34]
111	Thiocladospolide G bis	C15H24O7S	348	[50]
112	Thiocladospolide H	C15H24O6S	332	[50]
113	Thiocladospolide I	C27H44O10S	560	[50]
114	Thiocladospolide J	C27H42O10S	558	[50]
115	Zeaenol	C19H24O7	364	[49]
Naphthalene derivatives
116	Cladonaphchrom A	C22H22O4	350	[83]
117	Cladonaphchrom B	C22H22O4	350	[83]
118	1,8-Dimethoxynaphthalene	C12H12O2	188	[81,83]
119	8-Methoxynaphthalen-1-ol	C11H10O2	174	[83]
Naphtalenones
120	Altertoxin XII	C20H18O4	322	[87]
121	Cladosporol A	C20H16O6	352	[26,66,86]
122	Cladosporol B	C20H14O6	350	[66]
123	Cladosporol C	C20H18O5	338	[35,39,40,66,85,86]
124	Cladosporol D	C20H18O6	354	[66,86]
125	Cladosporol E	C20H18O7	370	[40,66,85]
126	Cladosporol F	C21H20O5	352	[39,40]
127	Cladosporol G	C20H17ClO6	388	[40]
128	Cladosporol G bis	C21H20O5	352	[39]
129	Cladosporol H	C20H16O5	336	[39]
130	Cladosporol I	C20H18O5	338	[39,92]
131	Cladosporol J	C20H18O5	338	[39]
132	Cladosporone A	C20H16O6	352	[86]
133	Clindanone A	C22H18O7	394	[40]
134	Clindanone B	C22H18O7	394	[40]
135	(3R,4R)-3,4-Dihydro-3,4,8-trihydroxy-1(2H)-napthalenone	C10H10O4	194	[81]
136	4,8-Dihydroxy-1-tetralone	C10H10O3	178	[52]
137	(3S)-3,8-Dihydroxy-6,7-dimethyl-α-tetralone	C12H14O3	206	[81]
138	Isosclerone	C10H10O3	178	[40]
139	Scytalone	C10H10O4	194	[68]
140	(−)-(4R)-Regiolone	C10H10O3	178	[81]
141	(−)-trans-(3R,4R)-3,4,8-Trihydroxy-6,7-dimethyl-3,4- dihydronaphtha- len-1(2H)-one	C12H14O4	222	[81]
Naphthoquinones and anthraquinones
142	Anhydrofusarubin	C15H12O6	288	[90]
143	Methyl ether of fusarubin	C16H16O7	320	[90]
144	Plumbagin	C11H8O3	188	[42]
Perylenequinones
145	Altertoxin VIII	C20H16O3	304	[87]
146	Altertoxin IX	C20H18O2	290	[87]
147	Aterotoxin X	C20H18O2	290	[87]
148	Altertoxin XI	C21H20O2	304	[87]
149	Calphostin A (= UCN-1028A)	C44H38O12	758	[29,30]
150	Calphostin B	C37H34O11	654	[30]
151	Calphostin C (= Cladochrome E)	C44H38O14	790	[30,31]
152	Calphostin D (= ent-isophleinchrome)	C30H30O10	550	[30,46]
153	Calphostin I (= Cladochrome D)	C44H38O15	806	[30,31]
154	Phleichrome	C30H30O10	550	[53,54,99]
Pyrones
155	Citreoviridin A	C23H30O6	402	[45]
156	Herbarin A	C12H12O5	236	[45]
157	Herbarin B	C10H10O5	210	[45]
158	5-Hydroxy-2-oxo-2H-piran-4-yl) methyl acetate	C8H8O5	184	[65]
Seco acids
159	Cladospolide E	C12H20O4	228	[94]
160	11-Hydroxy-4,5-dioxododecanoic acid	C12H20O5	244	[78]
161	seco-Patulolide A	C12H20O4	228	[94]
162	seco-Patulolide C	C12H22O4	230	[33,41,50,94]
163	(3S,5S, 11S)-Trihydroxydodecanoic acid	C12H24O5	248	[68]
Sterols
164	Cladosporide A	C25H40O3	388	[79]
165	Cladosporide B	C25H38O3	386	[80]
166	Cladosporide C	C25H40O3	388	[80]
167	Cladosporide D	C25H38O3	386	[80]
168	Cladosporisteroid B	C21H30O3	330	[35]
169	(22E,24R)-3β,5α-Dihydroxyergosta-7,22-dien-6-one	C28H44O3	428	[35]
170	Ergosterol	C28H44O	396	[79]
171	3α-Hydroxy-pregn-7-ene-6,20-dione	C21H30O3	330	[62]
172	23,24,25,26,27-Pentanorlanost-8-ene-3β,22-diol	C28H42O5	458	[79]
173	Peroxyergosterol (= (22E)-5α,8α-epidioxyergosta-6,22-dien-3β-ol)	C28H44O3	428	[23,35,79]
174	3β,5α,6β-Trihydroxyergosta-7,22-diene	C29H48O3	444	[47]
175	3β,5α,9α-Trihydroxy-(22E,24R)-ergosta-6-one	C28H44O4	444	[35]
Tetramic acids
176	Cladodionen	C13H15NO3	233	[58,63,89,96]
177	Cladosin A	C13H20N2O4	268	[55]
178	Cladosin B	C12H18N2O4	254	[55,60,63]
179	Cladosin C	C12H16N2O3	236	[55,60,63]
180	Cladosin D	C13H18N2O3	250	[55]
181	Cladosin F	C12H18N2O4	254	[56,60,63]
182	Cladosin G	C13H20N2O4	268	[56]
183	Cladosin H	C20H26N2O4	358	[89]
184	Cladosin I	C20H26N2O4	358	[89]
185	Cladosin J	C25H29N3O3	419	[89]
186	Cladosin K	C25H29N3O3	419	[89]
187	Cladosin L	C13H22N2O4	270	[60]
188	Cladosin L bis	C14H13NO3	243	[63]
189	Cladosin M	C13H17NO4	251	[63]
190	Cladosin N	C13H17NO4	251	[63]
191	Cladosin O	C9H12N2O	164	[63]
192	Cladosporicin A	C21H27N3O5	401	[61]
193	Cladosporiumin A	C19H27NO5	349	[59]
194	Cladosporiumin B	C19H27NO5	349	[59]
195	Cladosporiumin C	C19H27NO5	349	[59]
196	Cladosporiumin D	C14H21NO3	251	[59]
197	Cladosporiumin E	C13H17NO4	251	[58,59]
198	Cladosporiumin F	C13H19NO5	269	[59]
199	Cladosporiumin G	C13H19NO4	253	[58,59]
200	Cladosporiumin H	C14H23NO5	285	[59]
201	Cladosporiumin I	C13H19NO3	237	[58]
202	Cladosporiumin I bis	C19H27NO5	349	[61]
203	Cladosporiumin J	C13H17NO4	251	[58]
204	Cladosporiumin J bis	C19H27NO5	349	[61]
205	Cladosporiumin K	C13H17NO4	251	[58]
206	Cladosporiumin L	(C13H20NO5)3Mg2	889	[58]
207	Cladosporiumin M	C13H15NO3	233	[58]
208	Cladosporiumin N	C13H19NO4	253	[58]
209	Cladosporiumin O	C13H17NO4	251	[58]
Tropolones
210	Malettinin A	C16H16O5	288	[95]
211	Malettinin B	C16H20O5	292	[95]
212	Malettinin C	C16H20O5	292	[95]
213	Malettinin E	C16H20O5	292	[95]
Volatile terpenes
214	(−)-trans-Caryophyllene	C15H24	204	[38]
215	Dehydro aromdendrene	C15H22	202	[38]
216	α-Pinene	C10H16	136	[38]
217	(+)-Sativene	C15H24	204	[38]
Xanthones
218	Conioxanthone A	C16H12O7	316	[43]
219	3,8-Dihydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate	C16H12O6	300	[43]
220	α-Diversonolic ester	C16H16O7	320	[43]
221	β-Diversonolic ester	C16H16O7	320	[43]
222	8-Hydroxy-6-methylxanthone-1-carboxylic acid	C15H12O5	272	[43]
223	Methyl 8-hydroxy-6-(hydroxymethyl)- 9-oxo-9H-xanthene-1-carboxylate	C16H12O6	300	[43]
224	Methyl 8-hydroxy-6-methyl-9-oxo-9H-xanthene-1- carboxylate	C16H12O5	284	[43]
225	8-(Methoxycarbonyl)-1-hydroxy-9-oxo-9H-xanthene-3-carboxylic acid	C16H10O7	314	[43]
226	Secalonic acid D	C32H30O14	638	[85]
227	Vertixanthone	C15H10O5	270	[43]
Miscellaneous
228	α-Acetylorcinol	C9H10O3	166	[52]
229	Acetyl Sumiki’s acid	C9H10O4	182	[44]
230	Cladosacid	C15H22O3	250	[96]
231	(2R*,4R*)-3,4-dihydro-5-methoxy-2-methyl-1(2H)-benzopyran-4-ol	C10H12O2	164	[81]
232	1-(3,5-Dihydroxy-4-methylphenyl)propan-2-one	C10H12O3	180	[52]
233	1,1′-Dioxine-2,2′-dipropionic acid	C10H12O6	228	[85]
234	Ellagic acid	C14H6O8	302	[70]
235	Fonsecinone A	C32H26O10	570	[47]
236	5-Hydroxy-2-methyl-4H-chromen-4-one	C10H8O3	176	[83]
237	(2S)-5-Hydroxy-2-methyl-chroman-4-one	C10H10O2	162	[81,83]
238	4-O-α -d-Ribofuranose-2-pentyl-3-phemethylol	C17H26O6	326	[82]
239	4-O-α-d-Ribofuranose-3-hydroxymethyl-2-pentylphenol	C17H26O7	342	[81]
240	Rubrofusarin B	C16H14O5	286	[47]
241	Sumiki’s acid	C6H6O4	142	[44]
242	Taxol	C47H51NO14	853	[51]
243	tert-Butylhydroquinone	C10H14O2	166	[70]
244	Vermistatin	C18H16O6	328	[85]

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].

Figure 2

Structures of alkaloids.

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].

Figure 3

Structures of azaphilones.

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].

Figure 4

Structures of benzofluoranthenones.

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].

Figure 5

Structures of benozopyranones.

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].

Figure 6

Structures of binaphthopyrones.

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].

Figure 7

Structures of butanolides and butenolides.

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].

Figure 8

Structures of cinnamic acid derivatives.

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].

Figure 9

Structures of citrinin derivatives.

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].

Figure 10

Structures of coumarins and isocoumarins.

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].

Figure 11

Structures of cyclohexene derivatives.

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].

Figure 12

Structures of depsides.

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.

Figure 13

Structures of diketopiperazines.

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].

Figure 14

Structures of flavonoids.

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].

Figure 15

Structures of gibberellins.

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].

Figure 16

Structures of fusicoccane diterpene glycosides.

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].

Figure 17

Structures of lactones.

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].

Figure 18

Structures of macrodiolides.

Figure 19

Structures of thiocladospolides.

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].

Figure 20

Structures of naphthalene derivatives.

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].

Figure 21

Structures of naphthalenones.

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].

Figure 22

Structures of naphthoquinones and anthraquinones.

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].

Figure 23

Structures of perylenequinones.

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].

Figure 24

Structures of pyrones.

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].

Figure 25

Structures of seco acids.

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].

Figure 26

Structures of sterols.

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].

Figure 27

Structures of tetramic acids.

Figure 28

Structures of cladosporiumins.

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).

Figure 29

Structures of tropolones.

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].

Figure 30

Structures of volatile terpenes.

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].

Figure 31

Structures of xanthones.

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].

Figure 32

Structures of compounds from the group “miscellaneous”.

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.

Table 3

Bioactivities of secondary metabolites produced by the Cladosporium species.

Name (Code)	Biological Activity	Concentration	Results	Ref.
Alkaloids
Aspidospermidin-20-ol, 1-acetyl-17-methoxy (2)	Antimicrobial	125 µg mL−1;	Xanthomonas oryzae (MIC);	[24]
		62.50 µg mL−1;	Pseudomonas syringae (MIC);
		320.5 µg mL−1	Aspergillus flavus (MIC)
Cladosporine A (4)	Antimicrobial	4 μg mL−1;	Staphylococcus aureus (MIC);	[84]
		16 μg mL−1	Candida albicans (MIC)
Cytochalasin D (5)	Antibacterial	25 μg mL–1	S. aureus (MIC)	[85]
2-Methylacetate-3,5,6-trimethylpyrazine (6)	Antibacterial	12.5 μg mL–1	S. aureus (MIC)	[85]
Azaphilones
Lunatoic acid A (10)	Phytotoxic	100 μg mL–1	Brassica 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 IL2	2.4 µM	IC50	[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 IL2	2.5 µM	IC50	[27]
	Abl tyrosine kinase	0.76 µM	IC50
(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 IL2	0.4 µM	IC50	[27]
	Abl tyrosine kinase	0.06 µM	IC50
Benzopyranones
Coniochaetone A (17)	Cytotoxic	10 µM	22RV1 (67.4%), C4-2B (13.87%), RWPE-1 (17.3%)	[43]
Coniochaetone B (18)	Cytotoxic	10 µM	22RV1 (32.7%), C4-2B (2.9%), RWPE-1 (19.7%)	[43]
Coniochaetone K (19)	Cytotoxic	10 µM	22RV1 (64.6%), C4-2B (7.2%), RWPE-1 (11.7%)	[43]
Binaphthopyrones
Cladosporinone (20)	Cytotoxic	53.7 µM	L5178Y (IC50)	[22]
	Antibacterial	64 µg mL−1	S. aureus (MIC)
Viriditoxin (21)	Cytotoxic	0.1 µM	L5178Y (IC50)	[22]
	Antibacterial	0.015 µg mL−1	S. aureus (MIC)
Viriditoxin SC-28763 (22)	Cytotoxic	0.25 µM	L5178Y (IC50)	[22]
	Antibacterial	2 µg mL−1	S. aureus (MIC)
Viriditoxin SC-30532 (23)	Antibacterial	16 µg mL−1	S. aureus (MIC)	[22]
Butenolides and butanolides
Cladospolide F (24)	Lipid accumulation	10 µM	Oleic acid	[94]
Cladospolide G (25)	Antimicrobial	32 µg mL−1;	E. coli (MIC);	[32]
		1 µg mL−1;	Glomerella cingulata (MIC);
		32 µg mL−1;	Bipolaris sorokiniana (MIC);
		1 µg mL−1	Fusarium oxysporum f. sp. cucumerinum (MIC)
ent-Cladospolide F (27)	Antibacterial	8 µg mL−1;	S. aureus (MIC);	[32]
		16 µg mL−1;	Edwardsiella ictarda (MIC);
		64 µg mL−1	P. aeruginosa (MIC)
	Acetylcholinesterase	40.46 µM	IC50
11-Hydroxy-γ-dodecalactone (28)	Lipid accumulation	10 µM	Oleic acid	[94]
iso-Cladospolide B (29)	Antimicrobial	32 µg mL−1;	E. coli (MIC);	[32]
		32 µg mL−1;	Edwardsiella tarda (MIC);
		16 µg mL−1;	E. ictarda (MIC);
		64 µg mL−1	G. cingulata (MIC)
	Antimicrobial	16 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−1	F. oxysporum f. sp. cucumerinum (MIC)
Citrinin dervatives
Citrinin H1 (33)	Antibacterial	6.25 μg mL−1;	S. aureus (MIC);	[85]
		12.5 μg mL−1;	E. coli (MIC);
		12.5 μg mL−1	B. cereus (MIC)
Cladosporin A (34)	Toxic	72.0 µM	brine shrine nauplii (IC50)	[92]
Cladosporin B (35)	Toxic	81.7 µM	brine shrine nauplii (IC50)	[92]
Cladosporin C (36)	Toxic	49.9 µM	brine shrine nauplii (IC50)	[92]
Cladosporin D (37)	Antioxidant	16.4 µM	DPPH radicals (IC50)	[92]
	Toxic	81.4 µM	brine shrine nauplii (IC50)
Coumarins and isocoumarins
Cladosporin (39)	Antimicrobial	75 µg mL−1;	dermatophytes (100%);	[12]
		40 µg mL−1	spore germination of Penicillium sp. (100%) and Aspergillus sp. (100%)
		30 µM	Colletotrichum 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−1	Fusarium solani (MIC)
	Phytotoxic	10−3 M	etiolated wheat (81%)	[37]
5′-Hydroxyasperentin (40)	Antimicrobial	15.62 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−1	F. solani (MIC)
		30 µM	P. viticola (53.9%), Phomopsis obscurans (25.6%)	[25]
Isocladosporin (41)	Antimicrobial	30 µM	C. 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−1	F. solani (MIC)
	Phytotoxic	10−3 M	etiolated wheat (100%)	[37]
Cyclohexene derivatives
Cladoscyclitol B (48)	Inhibition of α-glucosidase	2.95 µM	IC50	[82]
Depsides
3-Hydroxy-2,4,5-trimethylphenyl 4-[(2,4-dihydroxy-3,6-dimethylbenzoyl)oxy]-2-hydroxy-3,6-dimethylbenzoate (51)	Antimicrobial	25 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−1	S. aureus (bacteriostatic)
3-Hydroxy-2,5-dimethylphenyl 2,4-dihydroxy-3,6-dimethylbenzoate (53)	Antimicrobial	25 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)	Antimicrobial	250 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−1	S. aureus (bacteriostatic)
Flavonoids
(2S)-7,4′-Dihydroxy-5-methoxy-8-(γ,γ-dimethylallyl)- flavanone (59)	Enzymatic inhibitory	11 µM;	PTP1B (IC50);	[93]
		27 µM	TCPTP (IC50)
Lactones
Cladosporamide A (75)	Enzymatic inhibitory	48 µM;	PTP1B (IC50);	[93]
		54 µM	TCPTP (IC50)
Macrolides
Cladocladosin A (80)	Antimicrobial	16 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−1	Harpophora maydis (MIC)
Cladospolide B (83)	Phytotoxic	1 µg plant−1	Oryza sativa (37.8%)	[64]
5R-Hydroxyrecifeiolide (90)	Antimicrobial	32 µg mL−1;	E. ictarda (MIC);	[32]
		32 µg mL−1	P. aeruginosa (MIC)
5S-Hydroxyrecifeiolide (91)	Antimicrobial	16 µg mL−1	G. cingulata (MIC)	[32]
5Z-7-Oxozeaenol (94)	Phytotoxic	4.8 µg mL−1	Amaranthus retroflexus (IC50)	[49]
Pandangolide 1 (95)	Antimicrobial	32 µg mL−1;	S. aureus (MIC);	[32]
		4 µg mL−1;	E. ictarda (MIC);
		1 µg mL−1;	G. cingulata (MIC);
		32 µg mL−1	P. aeruginosa (MIC)
Pandangolide 3 (98)	Antimicrobial	2 µg mL−1;	C. gloeosporioides (MIC);	[33]
		8 µg mL−1	B. 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−1	F. oxysporum f. sp. cucumerinum (MIC)
Sporiolide A (101)	Antimicrobial	16.7 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−1	Neurospora crassa (MIC)
	Cytotoxic	0.13 µg mL−1	L1210 (IC50)
Sporiolide B (102)	Antimicrobial	16.7 µg mL−1	M. luteus (MIC)	[88]
	Cytotoxic	0.81 µg mL−1	L1210 (IC50)
Thiocladospolide A (103)	Antimicrobial	1 µg mL−1;	E. tarda (MIC);	[33]
		8 µg mL−1;	E. ictarda (MIC);
		2 µg mL−1	C. glecosporioides (MIC)
		32 µg mL−1;	E. tarda (MIC);	[50]
		32 µg mL−1;	E. ictarda (MIC);
		16 µg mL−1	C. gloeosporioides (MIC)
Thiocladospolide B (104)	Antimicrobial	2 µg mL−1;	C. gloeosporioides (MIC);	[33]
		32 µg mL−1;	Physalospora piricola (MIC);
		1 µg mL−1ù	F. oxysporum (MIC)
Thiocladospolide C (105)	Antimicrobial	1 µg mL−1;	C. gloeosporioides (MIC);	[33]
		32 µg mL−1;	P. piricola (MIC);
		32 µg mL−1	F. oxysporum (MIC)
Thiocladospolide D (106)	Antimicrobial	1 µg mL−1;	E. ictarda (MIC);	[33]
		1 µg mL−1;	C. gloeosporioides (MIC);
		32 µg mL−1;	P. piricola (MIC);
		1 µg mL−1	F. oxysporum (MIC)
Thiocladospolide F (108)	Antimicrobial	16 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−1	H. maydis (MIC)
Thiocladospolide F bis (109)	Antimicrobial	32 µg mL−1;	E. tarda (MIC);	[50]
		16 µg mL−1;	E. ictarda (MIC);
		16 µg mL−1	B. sorokiniana (MIC)
Thiocladospolide G (110)	Antimicrobial	2 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−1	H. maydis (MIC)
Thiocladospolide G bis (111)	Antimicrobial	4 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−1	F. oxysporum f. sp. cucumerinum (MIC)
Thiocladospolide H (112)	Antimicrobial	16 µg mL−1;	E. tarda (MIC);	[50]
		8 µg mL−1;	E. ictarda (MIC);
		16 µg mL−1;	C. gloeosporioides (MIC);
		16 µg mL−1	B. sorokiniana (MIC)
Thiocladospolide I (113)	Antimicrobial	32 µg mL−1;	E. tarda (MIC);	[50]
		32 µg mL−1;	E. ictarda (MIC);
		16 µg mL−1	F. oxysporum f. sp. cucumerinum (MIC)
Thiocladospolide J (114)	Antimicrobial	16 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−1	F. oxysporum f. sp. cucumerinum (MIC)
Zeaenol (115)	Phytotoxic	8.16 µg mL−1	A. retroflexus (IC50)	[49]
Naphthalene derivatives
Cladonaphchrom A (116)	Antimicrobial	1.25 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)	Antibacterial	2.5 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−1	C. paradoxa (MIC)
Naphtalenones
Altertoxin XII (120)	Quorum sensing inhibitory	20 µg well−1	Chromobacterium violaceum (MIC)	[87]
Cladosporol A (121)	Antifungal	100 ppm	Uromyces appendiculatus (84.2%)	[66]
	Β-1,3-glucan biosynthesis inhibitor	10 µg ml	IC50	[26]
Cladosporol B (122)	Antifungal	100 ppm	U. appendiculatus (100%)	[66]
Cladosporol C (123)	Antifungal	100 ppm	U. appendiculatus (77.6%)	[66]
	Antibacterial	8 µg mL−1;	E. coli (MIC);	[39]
		64 µg mL−1;	M. luteus (MIC);
		16 µg mL−1	Vibrio harveyi (MIC)
	Cytotoxic	33.9 µM;	A549 (100%);	[86]
		45.6 µM;	H1975 (100%);
		72.5 µM;	HL60 (100%);
		11.4 µM	MOLT-4 (100%)
		14 µM;	A549 (IC50);	[39]
		4 µM	H446 (IC50)
Cladosporol D (124)	Antifungal	100 ppm	U. appendiculatus (69.4%)	[66]
	Anti-COX-2	60.2 µM	IC50	[86]
Cladosporol E (125)	Antifungal	100 ppm	U. appendiculatus (74.8%)	[66,85]
Cladosporol F (126)	Antibacterial	32 µg mL−1;	E. coli (MIC);	[39]
		64 µg mL−1;	M. luteus (MIC);
		32 µg mL−1	V. harveyi (MIC)
	Cytotoxic	15 µM;	A549 (IC50);	[39,40]
		10 µM;	HeLa (IC50);
		23 µM;	K562 (IC50);
		23 µM	HCT-116 (IC50)
Cladosporol G (127)	Cytotoxic	3.9 µM;	HeLa (IC50);	[40]
		8.8 µM;	K562 (IC50);
		19.5 µM	HCT-116 (IC50)
Cladosporol G bis (128)	Antibacterial	64 µg mL−1;	E. coli (MIC);	[39]
		128 µg mL−1;	M. luteus (MIC);
		64 µg mL−1	V. harveyi (MIC)
	Cytotoxic	13 µM;	A549 (IC50);
		11 µM;	HeLa (IC50);
		10 µM;	Huh7 (IC50);
		11 µM;	L02 (IC50);
		14 µM;	LM3 (IC50);
		15 µM	SW1990 (IC50)
Cladosporol H (129)	Antibacterial	32 µg mL−1;	E. coli (MIC);	[39]
		64 µg mL−1;	M. luteus (MIC);
		4 µg mL−1	V. harveyi (MIC)
	Cytotoxic	5 µM;	A549 (IC50);
		10 µM;	H446 (IC50);
		1 µM;	Huh7 (IC50);
		4.1 µM;	LM3 (IC50);
		10 µM;	MCF-7 (IC50);
		14 µM	SW1990 (IC50)
Cladosporol I (130)	Quorum sensing inhibitory	30 µg well−1	C. violaceum (MIC)	[87]
	Antibacterial	64 µg mL−1;	E. coli (MIC);	[39]
		64 µg mL−1;	M. luteus (MIC);
		16 µg mL−1	V. harveyi (MIC)
	Cytotoxic	10.8 µM	HeLa (IC50)
Cladosporol J (131)	Antibacterial	16 µg mL−1;	E. coli (MIC);	[39]
		64 µg mL−1;	M. luteus (MIC);
		32 µg mL−1	V. harveyi (MIC)
	Cytotoxic	15 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 µM	SW1990 (IC50)
Cladosporone A (132)	Cytotoxic	14.3 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 µM	MOLT-4 (100%)
	Anti-COX-2	49.1 µM	IC50
(3S)-3,8-Dihydroxy-6,7-dimethyl-α- tetralone (137)	Antibacterial	20 µM	S. aureus, B. cereus, E. coli, Vibrio alginolyticus, Vibrio parahemolyticus, methicillin-resistant S. aureus	[81]
Scytalone (139)	Antibacterial	63.6 µg mL−1;	Bacillus cereus (IC50);	[68]
		95.5 µg mL−1	E. coli (IC50)
Naphtoquinones and anthraquinones
Anhydrofusarubin (142)	Cytotoxic	3.97 μg mL–1	K-562 (IC50)	[90]
Methyl ether of fusarubin (143)	Cytotoxic	3.58 μg mL–1	K-562 (IC50)	[90]
	Antibacterial	40 μg disc–1	S. aureus (27 mm), Bacillus megaterium (22 mm), E coli (25 mm), P. aeruginosa (24 mm)
	Toxic	81.4 µM	brine shrine naupalii (IC50)
Perylenequinones
Altertoxin VIII (145)	Quorum sensing inhibitory	30 µg well−1	C. violaceum (MIC)	[87]
Altertoxin IX (146)	Quorum sensing inhibitory	30 µg well−1	C. violaceum (MIC)	[87]
Aterotoxin X (147)	Quorum sensing inhibitory	20 µg well−1	C. violaceum (MIC)	[87]
Altertoxin XI (148)	Quorum sensing inhibitory	30 µg well−1	C. violaceum (MIC)	[87]
Calphostin A (=UCN-1028A) (149)	PK inhibition	0.19 µg mL−1;	PKC (IC50);	[29,30]
		40 µg mL−1	PKA (IC50)
	Cytotoxic	0.29 µg mL−1;	HeLa S3 (IC50);
		0.21 µg mL−1	MCF-7 (IC50)
Calphostin B (150)	PK inhibition	1.04 µg mL−1;	PKC (IC50);	[7]
		22.9 µg mL−1	PKA (IC50)
	Cytotoxic	2.56 µg mL−1;	HeLa S3 (IC50);
		1.61 µg mL−1	MCF-7 (IC50)
Calphostin C (=cladochrome E) (151)	PK inhibition	0.05 µg mL−1	PKC (IC50)	[30]
	Cytotoxic	0.23 µg mL−1;	HeLa S3 (IC50);
		0.18 µg mL−1	MCF-7 (IC50)
Calphostin D (= ent-isophleinchrome) (152)	PK inhibition	6.36 µg mL−1;	PKC (IC50);	[30]
		12.7 µg mL−1	PKA (IC50)
	Cytotoxic	8.45 µg mL−1;	HeLa S3 (IC50);
		2.69 µg mL−1	MCF-7 (IC50)
	Phytotoxic	5 µg L−1	Sugar beet cells(100% inhibition in the light, 37–64% inhibition in the dark)	[46]
		33 µg L−1	Necrosis on sugar beet leaves
Calphostin I (= Cladochrome D) (153)	PK inhibition	6.36 µg mL−1;	PKC (IC50);	[30]
		12.7 µg mL−1	PKA (IC50)
	Cytotoxic	0.24 µg mL−1;	HeLa S3 (IC50);
		0.16 µg mL−1	MCF-7 (IC50)
Phleichrome (154)	Invertase I inhibition	0.5 mM	62%	[99]
Seco acids
Cladospolide E (159)	Lipid accumulation	10 µM	Oleic acid;Triglycerides (~170 µg mg−1 protein);Total cholesterol (~3 µg mg−1 protein)	[94]
Seco-patulolide A (161)	Lipid accumulation	10 µM	Oleic acid;Triglycerides (~150 µg mg−1 protein);Total cholesterol (~3 µg mg−1 protein)	[94]
Seco-patulolide C (162)	Lipid accumulation	10 µM	Oleic acid;Triglycerides (~150 µg mg−1 protein);Total cholesterol (~3 µg mg−1 protein)	[94]
	Antimicrobial	32 µg mL−1;	E. tarda (MIC);	[50]
		32 µg mL−1;	E. ictarda (MIC);
		16 µg mL−1	C. gloeosporioides (MIC)
(3S,5S,11S)-Trihydroxydodecanoic acid (163)	Antibacterial	63.6 µg mL−1	B. cereus (MIC)	[68]
	Cytotoxic	42 µM;	MCF-7;
		82 µM	T47D
	Antibacterial	40 μg disc–1	S. aureus (27 mm), B. megaterium (22 mm), E coli (25 mm), P. aeruginosa (24 mm)
	Toxic	81.4 µM	brine shrine naupalii (IC50)
Sterols
Cladosporide A (164)	Antifungal	0.5 µg mL−1	Aspergillus fumigatus (IC50)	[79]
Cladosporide B (165)	Antifungal	3 µg disc−1	A. fumigatus (11 mm)	[80]
Cladosporide C (166)	Antifungal	1.5 µg disc−1	A. 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)	Cytotoxic	28.6 µM	HL-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 µM	MGC-803 (IC50)
		18.7 µM;	MCF-7 (IC50);	[96]
		19.1 µM;	HeLa (IC50);
		17.9 µM;	HCT-116 (IC50);
		9.1 µM	HL-60 (IC50)
		3.7 µM	L5178 (IC50)	[63]
	Antifungal	100 mg/plate;	Ustilago maydis (0.97 cm);
		100 mg/plate	Saccharomyces cerevisiae (3.27 cm)
Cladosin B (178)	Renoprotective effects against cisplatin-induced kidney cell damage	25 µM;50 µM;100 µM	LLC-PK1 (dose-dependent)	[60]
Cladosin C (179)	Antiviral	276 µM	H1N1 (IC50)	[55]
Cladosin F (181)	Renoprotective effects against cisplatin-induced kidney cell damage	25 µM;50 µM;100 µM	LLC-PK1 (dose-dependent)	[60]
Cladosin I (184)	Cytotoxic	4.1 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 µM	MGC-803 (IC50)
Cladosin J (185)	Cytotoxic	6.8 µM;	K562 (IC50);	[89]
		7.8 µM	HL-60 (IC50)
Cladosin K (186)	Cytotoxic	5.9 µM;	K562 (IC50);	[89]
		7.5 µM;	HL-60 (IC50);
		14 µM;	HCT-116 (IC50);
		18 µM	PC-3 (IC50)
Cladosin L (187)	Renoprotective effects against cisplatin-induced kidney cell damage	25 µM;50 µM;100 µM	LLC-PK1 (dose-indipendent)	[60]
Cladosin L bis (188)	Antibacterial	25 µM;	S. aureus ATCC 700699 (IC50);	[63]
		50 µM	S. aureus ATCC 29213 (IC50)
Cladosporicin A (192)	Cytotoxic	70.88 µM;	Bt549 (IC50);	[61]
		74.48 µM;	HCC70 (IC50);
		75.54 µM;	MDA-MB-231 (IC50);
		79.36 µM	MDA-MB-468 (IC50)
Cladosporiumin I bis (202)	Cytotoxic	76.18 µM;	Bt549 (IC50);	[61]
		85.29 µM;	HCC70 (IC50);
		82.37 µM;	MDA-MB-231 (IC50);
		81.44 µM	MDA-MB-468 (IC50)
Cladosporiumin J bis (204)	Cytotoxic	78.96 µM;	Bt549 (IC50);	[61]
		76.41 µM;	HCC70 (IC50);
		79.27 µM;	MDA-MB-231 (IC50);
		74.64 µM	MDA-MB-468 (IC50)
Tropolones
Malettinin A (210)	Antimicrobial	33.1 µM;	Trichophyton rubrum (IC50);	[95]
		100 µM	C. albicans (81%)
Malettinin B (211)	Antimicrobial	28.3 µM;	Xanthomonas campestris (IC50);	[95]
		60.6 µM;	T. rubrum (IC50);
		100 µM;	Staphylococcus epidermidis (<80%);
		100 µM;	B. subtilis (<80%);
		100 µM	C. albicans (<80%)
Malettinin C (212)	Antimicrobial	37.9 µM;	X. campestris (IC50);	[95]
		83.2 µM;	T. rubrum (IC50);
		100 µM;	S. epidermidis (<80%);
		100 µM;	B. subtilis (<80%);
		100 µM	C. albicans (<80%)
Malettinin E (213)	Antimicrobial	28.7 µM;	X. campestris (IC50);	[95]
		30.7 µM;	T. rubrum (IC50)
Xanthones
Conioxanthone A (218)	Cytotoxic	10 µM	22RV1 (36.8%), C4-2B (3.3%), RWPE-1 (20.3%)	[43]
3,8-Dihydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate (219)	Cytotoxic	10 µM	22RV1 (82.1%), C4-2B (77.7%), RWPE-1 (11.5%)	[43]
α-Diversonolic ester (220)	Cytotoxic	10 µM	22RV1 (28.8%), C4-2B (12.9%), RWPE-1 (24.3%)	[43]
β-Diversonolic ester (221)	Cytotoxic	10 µM	22RV1 (40.2%), C4-2B (2.8%), RWPE-1 (10.3%)	[43]
8-Hydroxy-6-methylxanthone-1-carboxylic acid (222)	Cytotoxic	10 µM	22RV1 (71.3%), C4-2B (60.7%), RWPE-1 (19.7%)	[43]
Methyl 8-hydroxy-6-(hydroxymethyl)- 9-oxo-9H-xanthene-1-carboxylate (223)	Cytotoxic	10 µM	22RV1 (68.1%), C4-2B (20.2%), RWPE-1 (19.0%)	[43]
Methyl 8-hydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate (224)	Cytotoxic	10 µM	22RV1 (55.8%), C4-2B (8.1%), RWPE-1 (5.3%)	[43]
8-(Methoxycarbonyl)-1-hydroxy-9-oxo-9H-xanthene-3-carboxylic acid (225)	Cytotoxic	10 µM	22RV1 (63.9%), C4-2B (12.2%), RWPE-1 (27.0%)	[43]
Vertixanthone (227)	Cytotoxic	10 µM	22RV1 (27.1%), RWPE-1 (25.0%)	[43]
Miscellaneous
Acetyl Sumiki’s acid (229)	Antibacterial	5 μg disc−1	B. subtilis (7 mm), S. aureus (7 mm)	[44]
1,1′-Dioxine-2,2′-dipropionic acid (233)	Antibacterial	25 μg mL−1;	S. aureus (MIC);	[85]
		25 μg mL−1;	E. coli (MIC);
		12.5 μg mL−1	B. cereus (MIC)
4-O-α-d-Ribofuranose-2-pentyl-3-phemethylol (238)	Inhibition of α-glucosidase	2.50 µM	IC50	[82]
Sumiki’s acid (241)	Antibacterial	5 μg disc−1	B. subtilis (7 mm), S. aureus (7 mm)	[44]
Taxol (242)	Cytotoxic	3.5 µM	HCT 15 (IC50)	[51]
	Antibacterial	30 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−1	Bacillus subtilis (1 mm)
Vermistatin (244)	Antibacterial	25 μg mL−1;	S. aureus (MIC);	[85]
		25 μg mL−1	B. cereus (MIC)

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.