Fungal Bioactive Anthraquinones and Analogues

Abstract

This review, covering the literature from 1966 to the present (2020), describes naturally occurring fungal bioactive anthraquinones and analogues biosynthesized by the acetate route and concerning several different functionalized carbon skeletons. Hydrocarbons, lipids, sterols, esters, fatty acids, derivatives of amino acids, and aromatic compounds are metabolites belonging to other different classes of natural compounds and are generated by the same biosynthetic route. All of them are produced by plant, microorganisms, and marine organisms. The biological activities of anthraquinones and analogues comprise phytotoxic, antibacterial, antiviral, anticancer, antitumor, algicide, antifungal, enzyme inhibiting, immunostimulant, antiplatelet aggregation, cytotoxic, and antiplasmodium activities. The review also covers some practical industrial applications of anthraquinones.

Full text

toxins
Review
Fungal Bioactive Anthraquinones and Analogues
Marco Masi and Antonio Evidente *
Dipartimento di Scienze Chimiche, Universitàdi Napoli Federico II, Complesso Universitario
Monte Sant’Angelo, Via Cintia 4, 80126 Napoli, Italy; marco.masi@unina.it
*Correspondence: evidente@unina.it; Tel.: +39-081-2539178
Received: 20 October 2020; Accepted: 7 November 2020; Published: 12 November 2020


Abstract:
This review, covering the literature from 1966 to the present (2020), describes naturally
occurring fungal bioactive anthraquinones and analogues biosynthesized by the acetate route
and concerning several different functionalized carbon skeletons. Hydrocarbons, lipids, sterols, esters,
fatty acids, derivatives of amino acids, and aromatic compounds are metabolites belonging to other
different classes of natural compounds and are generated by the same biosynthetic route. All of
them are produced by plant, microorganisms, and marine organisms. The biological activities of
anthraquinones and analogues comprise phytotoxic, antibacterial, antiviral, anticancer, antitumor,
algicide, antifungal, enzyme inhibiting, immunostimulant, antiplatelet aggregation, cytotoxic,
and antiplasmodium activities. The review also covers some practical industrial applications
of anthraquinones.
Keywords: anthraquinones; natural analogues; fungi; biological activity
Key Contribution:
This review, covering the literature from 1966 to the present (2020), concerns
fungal anthraquinones and their biological activity including phytotoxic, antibacterial, antiviral,
anticancer, algicide, antifungal, enzyme inhibiting, immunostimulant, antiplatelet aggregation,
and antiplasmodium activities. The review also covers some practical industrial applications
of anthraquinones.
1. Introduction
Anthraquinones are a group of natural compounds with a plethora of biological activities
and potential practical applications. Most of them are produced by plant and micro-organisms among
the living organisms [
1
,
2
]. They are acetate-derivative metabolites biosynthesized starting from
a polyketide containing eight C2 units, which generates in turn with three aldol type condensations
the carbon skeleton of anthraquinones except for the two carbonyl oxygens of the central ring.
The latter are introduced by successive steps with an oxidation process. One example of this kind
of biosynthesis is reported in Figure 1for endocrin, a fungal anthraquinone produced by several
Penicillium and Aspergillus species [3].
Among secondary metabolites anthraquinones are the most investigated natural products
for their mechanism of action [
4
]. Plants, microorganisms, lichens, and algae are producers of
metabolites possessing diverse biological activities such as phytotoxic, antibacterial, antiviral, anticancer,
antitumor, algicide, antifungal, enzyme inhibiting, immunostimulant, antiplatelet aggregation,
cytotoxic and antiplasmodium activities. Anthraquinones are frequently reported among the plethora
of different classes of natural compounds as alkaloids, hydrocarbons, lipids, sterols, esters, fatty acids,
derivatives of amino acids, terpenoids, and aromatic compounds [
5
–
7
]. The activity of several hydroxyl-
and amino-anthraquinones cannot be exploited due to their weak solubility in water. Thus, some
of them are converted into water-soluble analogues by biotransformation [
8
]. Anthraquinones have
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Toxins 2020,12, 714 2 of 30
also industrial application as natural dyes substituting synthetic chemicals in formulation to avoid
undesired collateral effects [9].
Some previous reviews have described fungal anthraquinones such as that published by Gessler
at al. (2013) [
10
], limited to 12 natural anthraquinones, and those on anthraquinones specifically
produced by derived marine fungi [
11
]; also among them the treatment of the anthraquinones
synthesized by a single fungal species such as Phoma was reported [12].
Toxins 2020, 12, x FOR PEER REVIEW 2 of 31
biotransformation [8]. Anthraquinones have also industrial application as natural dyes substituting
synthetic chemicals in formulation to avoid undesired collateral effects [9].
Some previous reviews have described fungal anthraquinones such as that published by
Gessler at al. (2013) [10], limited to 12 natural anthraquinones, and those on anthraquinones
specifically produced by derived marine fungi [11]; also among them the treatment of the
anthraquinones synthesized by a single fungal species such as Phoma was reported[12].
Figure 1. Biosynthesis of the anthraquinone carbon skeleton.
This review describes an advanced overview on anthraquinones, and related analogues
grouped for the first time according to their natural sources. In particular, in addition to the isolation
from fungal sources and their chemical characterization, their potential applications in different
fields such as agriculture, medicine and the dyes industry are considered on the basis of their
biological activities.
The first section chronologically describes the fungal anthraquinones starting from 1966 to the
present day focusing on their sources, structures, and biological activities. The second section treats
the industrial application of anthraquinones in a different field essentially as natural dyes. This part
is focused on the comparison between natural and synthetic anthraquinone based dyes, their
chemical derivatization and classification, and the advanced methods used in the treatment of the
relative industrial wastewater to avoid severe negative environmental pollution. Finally, the main
points described are summarized in the conclusion.
2. Fungal Anthraquinones and Analogues
Dothistromin (1, Figure 2, Table 1) was isolated as the main phytotoxin produced by
Dothistroma pini (Hulbary), a pathogen inducing necrotic disease characterized by the formation of
red bands on the infected needles of Pinus radiata and other pines [13]. The same fungus also
produced six other anthraquinones: bisdeoxydothistromin; bisdeoxydehydrodothistromin;
Figure 1. Biosynthesis of the anthraquinone carbon skeleton.
This review describes an advanced overview on anthraquinones, and related analogues grouped
for the first time according to their natural sources. In particular, in addition to the isolation from
fungal sources and their chemical characterization, their potential applications in different fields such
as agriculture, medicine and the dyes industry are considered on the basis of their biological activities.
The first section chronologically describes the fungal anthraquinones starting from 1966 to
the present day focusing on their sources, structures, and biological activities. The second section treats
the industrial application of anthraquinones in a different field essentially as natural dyes. This part is
focused on the comparison between natural and synthetic anthraquinone based dyes, their chemical
derivatization and classification, and the advanced methods used in the treatment of the relative
industrial wastewater to avoid severe negative environmental pollution. Finally, the main points
described are summarized in the conclusion.
2. Fungal Anthraquinones and Analogues
Dothistromin (
1
, Figure 2, Table 1) was isolated as the main phytotoxin produced by Dothistroma
pini (Hulbary), a pathogen inducing necrotic disease characterized by the formation of red bands
on the infected needles of Pinus radiata and other pines [
13
]. The same fungus also produced six
other anthraquinones: bisdeoxydothistromin; bisdeoxydehydrodothistromin; 6-deoxyversicolorin C;

Toxins 2020,12, 714 3 of 30
averufin; nidurufin; averythrin (
6
–
11
, Figure 2, Table 1). No biological activity was reported for
2
–
7
[
14
].
More recently, averythrin was also isolated from the marine derived fungus Aspergillus versivolor [
15
].
Toxins 2020, 12, x FOR PEER REVIEW 3 of 31
6-deoxyversicolorin C; averufin; nidurufin; averythrin (6–11, Figure 2, Table 1). No biological
activity was reported for 2–7 [14]. More recently, averythrin was also isolated from the marine
derived fungus Aspergillus versivolor [15].
O
O
O
O
OH
O
H
O
O
H
3
CO
OH
O
O
R
1, R
1
=R
2
=R
3
=OH
2, R
1
=OH, R
2
=R
3
=H
5, R=H
6, R=OH
O
O
H
3
CO
OH
R
1
OH
OH
R
2
12, R
1
=H, R
2
=OH
13, R
1
=R
2
=H
O
O
H
3
CO
R
OH
8, R=OH
9, R=H
O
O
H
3
CO
OH
O
OH
OH
OH
10
O
O
H
3
CO
OH
O
OH
OH
11
H
H
R
1
R
2
R
3
O
O
O
O
OH
O
H
R
3, R=OH
4, R=H
O
O
HO OH
OH
7
O
O
OH
OH
H
HO
H
OH
14
Figure 2. Bioactive anthraquinones and analogues produced by Dothistroma pini, Aspergillus
versicolor, Alternaria porri, Alternaria solani, Alternaria cucumerina, Alternaria bataticola, Diaporthe
angelicae and Stemphyfium botryosum.
Macrosporin and 6-methylxanthopurpurin 3-methyl ether (8 and 9, Figure 2, Table 1) are two
anthraquinones produced by Alternaria bataticola, the causal agent of a black spot of sweet potato
[16]. Compound 8 was also isolated from other fungi of the same genus as A. porri, A. solani and
A. cucumerina while 9 was isolated also from A. solani [16]. Then macrosporin was isolated together
with another two anthraquinones, named altersolanols A and J (10 and 11, Figure 2, Table 1), as well
as nectriapyrone, an α-pyrone, from the culture filtrates of Diaporthe angelicae (anamorph Phomopsis
Figure 2.
Bioactive anthraquinones and analogues produced by Dothistroma pini, Aspergillus
versicolor, Alternaria porri, Alternaria solani, Alternaria cucumerina, Alternaria bataticola, Diaporthe angelicae
and Stemphyfium botryosum.
Macrosporin and 6-methylxanthopurpurin 3-methyl ether (
8
and
9
, Figure 2, Table 1) are two
anthraquinones produced by Alternaria bataticola, the causal agent of a black spot of sweet potato [
16
].
Compound
8
was also isolated from other fungi of the same genus as A. porri,A. solani and A. cucumerina
while
9
was isolated also from A. solani [
16
]. Then macrosporin was isolated together with another two
anthraquinones, named altersolanols A and J (
10
and
11
, Figure 2, Table 1), as well as nectriapyrone,

Toxins 2020,12, 714 4 of 30
an
α
-pyrone, from the culture filtrates of Diaporthe angelicae (anamorph Phomopsis foeniculi), the causal
agent of serious disease on fennel (Foeniculum vulgare) in Bulgaria. These four metabolites were tested
on detached tomato leaves and only nectriapyrone and altersolanols A and J showed a modulate
phytotoxicity while macrosporin was not toxic [17].
Stemphylin, is a phytotoxin (
12
, Figure 2, Table 1) produced by Stemphyfium botryosum, a fungal
pathogen inducing a destructive disease in lettuce. The first structure of compound
12
was wrongly
assigned by Barash et al. (1975 and 1978) [
18
,
19
], and then corrected when it was isolated from the same
fungus together with two other phytotoxic anthraquinones, the above cited macrosporin and dactylariol
(
13
, Figure 2, Table 1) [
20
]. The latter compound (
13
) showed anti Adenosine TriPhosphate (ATP)
catabolism in Erlich I ascite tumor cells while stemphylin showed a weak antitumor activity on
the treated animal at a dose of 40 mg/kg [
20
]. Stemphylium botryosum, inducing leaf spot disease on beet
plants, also synthesized macrosporin and dactylariol (
8
and
13
), together with other anthraquinones
identified as stemphyrperylenol (
14
, Figure 2), alteroporiol, and stemphynols A and B (
15
–
17
, Figure 3,
Table 1). The phytotoxicity of all the metabolites (
8
,
13
–
17
) was tested on lettuce and beet evaluating
the seeds elongation. Compound
13
was the most active while compound
14
exhibited a moderate
inhibition while the other ones were inactive [21].
Cryphonectria (Endothia)parasitica (Murr.) Barr, the causal agent of chestnut (Castanea sativa) canker
disease and other species produces diaporthin, a phytotoxic benzopyranone pigment, together with
phytotoxic anthraquinones. The hundreds of fungal strains were grouped into virulent, intermediate
and hypervirulent and produced, respectively, diaporthin, rugulosin and skirin (
18
and
19
, Figure 3,
Table 1), crysophanol (
20
, Figure 3, Table 1) and emodin (
21
, Figure 3, Table 1) [
22
]. Virulent
and hypovirulent strains of C. parasitica also produced a main polysaccharide identified as pullulan (a
polymer constituted of
α
-1,4- and
α
-1,6-glucan) and a minor fraction which gave phytotoxicity on both
the host plant and tomato (Lycopersicon escultem L.) leaves. One component of this minor fraction was
identified as a galactan and consisted of the repeat unit: [→6)-β-d-Galf-(1→5)-β-d-Galf-(1→]n[23].
Rugulosin (
18
) was isolated together with emodin and skyrin from Hormonema dematioides
and showed activity against survival of budworm larvae while the other two anthraquinones were
inactive [24].
Aspergillus fumigatus, which is responsible for a lung disease, produced a plethora of
secondary metabolites belonging to different classes of natural compounds. Among them, emodin,
2-chloro-emodin (
21
and
22
Figure 3), and physcion (
23
, Figure 3) were also isolated. However,
compound 23 appeared not to have a role in the fungal infection [25].
Physcion (
23
) was also isolated from the organic culture extract of the marine derived fungus
Microsporum sp. and showed a cytotoxic effect on human cervical carcinoma HeLa cells and its
apoptosis induction was deeply investigated. Physcion also caused the formation of reactive oxygen
species (ROS) in the same cells [26].
Many Drechslera species, which are important pathogens on gramineous plants and their seeds,
produced colored pigments [
27
]. The red pigment exudated from Drechslera teres,D. graminea,D.
tritici-repentis,D. phlei,D. dictyoides,D. avenae was identified as the anthraquinone catenarin (
24
, Figure 3,
Table 1) while that from D. avenae and Bipolaris sorokiniana were two other anthraquinones recognized
as helminthosporin and cynodontin (
25
and
26
, Figure 3, Table 1). Catenarin (
24
) showed a total
inhibition of Bacillus subtilis (Gram+) growth but had no effect on the Gram- bacterium Ervinia carotova
but in part inhibited the mycelium growth of D. teres [
28
]. In particular, catanerin and emodin (
24
and
21
) were also found in kernels infected by Pyrenophora tritici-repentis (Died.) Drechs. (anamorph:
Drechslera tritici-repentis (Died.) Shoem.), the causal agent of tan spot of wheat. Compound
24
caused the reddish discoloration with red smudge of kernels, while compound
21
indicated that
P. tritici-repentis is a mycotoxigenic fungus. Compound
24
also induced non-specific leaf necrosis
and appeared moderately active against some of the fungi associated with P. tritici-repentis suggesting
its possible role in the life strategy of the pathogen [29].

Toxins 2020,12, 714 5 of 30
Toxins 2020, 12, x FOR PEER REVIEW 5 of 31
O
O
OH
O
O
MeO OH
OH
OH
OH
MeO
R
2
15, R
1
=R
2
=OH
16, R
1
=OH, R
2
=H
R
1
O
O
OH
OH
O
O
OH OH
18, R
1
=Me, R
2
=H
27, R
1
=OMe, R
2
=H
29, R
1
=Me, R
2
=H
HO
OH
O
O
R
2
R
3
OH
20, R
1
=R
2
=R
3
=H
21, R
1
=H, R
2
=OH, R
3
=Me
22, R
1
=H, R
2
=Cl, R
3
=Me
O
O
O
HO HO
O
OH OH
OH
HO
R
1
R
1
19
R
1
O
O
R
1
R
5
OH
OH
R
2
R
3
R
4
23, R
1
=Me, R
2
=R
3
=H, R
4
=OH, R
5
=OMe
24, R
1
=R
3
=OH, R
2
=R
4
=R
5
=H
25, R
1
=R
3
=R
4
=R
5
=H, R
2
=OH
26, R
2
=R
3
=OH, R
1
=R
4
=R
5
=H
O
O
OH
O
O
MeO OH
OH
OH
O
H
MeO
OH
17
R
2
R
2
O
O
OH
OH
O
O
OH OH
OH
OMe
MeO
28
O
Figure 3. Bioactive anthraquinones and analogues produced by Stemphyfium botryosum, Cryphonectria
parasitica, Hormonema dematioides, Microsporum sp., Aspergillus claucus, Pyrenophora tritici-repentis,
Gliocladium sp. T31, Aspergillus fumigatus, Drechslera teres, Drechslera graminea, Drechslera
tritici-repentis, Drechslera phlei, Drechslera dictyoides, Drechslera avenae, Bipolaris sorokinana and
Cytospora CR200.
Cryphonectria (Endothia) parasitica (Murr.) Barr, the causal agent of chestnut (Castanea sativa)
canker disease and other species produces diaporthin, a phytotoxic benzopyranone pigment,
together with phytotoxic anthraquinones. The hundreds of fungal strains were grouped into
virulent, intermediate and hypervirulent and produced, respectively, diaporthin , rugulosin and
skirin (18 and 19, Figure 3, Table 1), crysophanol (20, Figure 3, Table 1) and emodin (21, Figure 3,
Table 1) [22]. Virulent and hypovirulent strains of C. parasitica also produced a main polysaccharide
identified as pullulan (a polymer constituted of α-1,4- and α-1,6-glucan) and a minor fraction which
Figure 3.
Bioactive anthraquinones and analogues produced by Stemphyfium botryosum, Cryphonectria
parasitica, Hormonema dematioides, Microsporum sp., Aspergillus claucus, Pyrenophora tritici-repentis,
Gliocladium sp. T31, Aspergillus fumigatus, Drechslera teres, Drechslera graminea, Drechslera tritici-repentis,
Drechslera phlei, Drechslera dictyoides, Drechslera avenae, Bipolaris sorokinana and Cytospora CR200.
Cytoskyrins A and B (
27
and
28
, Figure 3, Table 1) are two closely related bisanthraquinones
obtained from large-scale cultures of an endophytic fungus, CR200 (Cytospora sp.), isolated from
the branch of a Conocarpus erecta tree in the Guanacaste Conservation Area of Costa Rica. Previously,
a substituted benzopryrone, named cytosporone, was isolated from the same fungus and showed
antibiotic activity [
30
]. Cytoskyrin A showed strong BIA activity down to 12.5 ng in the standard assay

Toxins 2020,12, 714 6 of 30
while cytoskyrin B was inactive at the concentrations tested (<50 mg) [
31
]. The biochemical induction
assay (BIA) measures the induction of the SOS response in bacteria and is used to identify compounds
that inhibit DNA synthesis, either directly by inhibiting the DNA replication machinery or more often
indirectly by modifying DNA [
32
–
34
]. BIA activity is highly dependent on the three-dimensional
structure and not a general property of these polyphenolic compounds. In fact, close bisanthraquinones
such as luteoskyrin (
29
, Figure 3) and rugulosin (
18
) are known to interact with DNA. The structural
basis of these differences is not yet clear [31].
Dendryols A–D (
30–33
, Figure 4, Table 1), four phytotoxic anthraquinones, were produced
by Dendryphiella sp. [
35
], a fungus isolated from an infected sample of the paddy weed Eleocharis
kuroguwai (Cyperaceae) in Japan [
36
]. The dendryols
30
–
33,
when tested for the phytotoxic activity by
leaf-puncture assay on weeds (kuroguwai, barnyardgrass, and velvetleaf) and cultivated crops (rice,
corn, and cowpea), showed toxicity only against barnyardgrass and the nercrotic area appeared to be
dose-dependent. Compound 30 caused similar necrosis only on velvetleaf [35].
Toxins 2020, 12, x FOR PEER REVIEW 7 of 31
Figure 4. Bioactive anthraquinones and analogues produced by Dendryphiella sp., Ramularia
collo-cygni, Trichoderma harzianum and Ramularia uredinicola.
Rubellin A (34, Figure 4, Table 1) was isolated from the culture filtrates of Ramularia collocygni,
the causal agent of leaf-spot disease of barley in central Europe [37]. From the same fungus rubellins
B–F and 14-deydro rubellin D (35–38, Figure 4, Table 1) were also isolated. Biosynthetic studies
carried out by the incorporation of both [1-13C]-acetate and [2-13C]-acetate into the rubellins
demonstrated that such anthraquinone derivatives were biosynthesized via the polyketide pathway.
Rubellin A (34) increased photodynamic oxygen activation [38], while rubellins B–E exhibited
antibacterial activity, as well as light-dependent, antiproliferative and cytotoxic activity in a series of
human tumor cell lines [39]. Closely related anthraquinones were isolated from the same fungus and
from Ramularia uredinicola and identified as uridinetubellins I and II, and caeruleoramulin (40–42,
Figure 4 and Table I). Both uredinorubellins (40 and 41) showed photodynamic activity comparable
to rubellin D, whereas caeruleoramularin did not display such activity [40].
1-Hydroxy-3-methyl-anthraquinone and 1,8-dihydroxy-3-methyl-anthraquinone (43 and 44,
Figure 5, Table 1), were isolated together with other bioactive metabolites from Trichoderma
harzianum in a study aimed to improve the production and application of novel biopesticides and
Figure 4.
Bioactive anthraquinones and analogues produced by Dendryphiella sp., Ramularia collo-cygni,
Trichoderma harzianum and Ramularia uredinicola.

Toxins 2020,12, 714 7 of 30
Rubellin A (
34
, Figure 4, Table 1) was isolated from the culture filtrates of Ramularia collocygni,
the causal agent of leaf-spot disease of barley in central Europe [
37
]. From the same fungus rubellins
B–F and 14-deydro rubellin D (
35
–
38
, Figure 4, Table 1) were also isolated. Biosynthetic studies carried
out by the incorporation of both [1-
13
C]-acetate and [2-
13
C]-acetate into the rubellins demonstrated
that such anthraquinone derivatives were biosynthesized via the polyketide pathway. Rubellin A (
34
)
increased photodynamic oxygen activation [
38
], while rubellins B–E exhibited antibacterial activity,
as well as light-dependent, antiproliferative and cytotoxic activity in a series of human tumor cell
lines [
39
]. Closely related anthraquinones were isolated from the same fungus and from Ramularia
uredinicola and identified as uridinetubellins I and II, and caeruleoramulin (
40
–
42
, Figure 4and Table I).
Both uredinorubellins (
40
and
41
) showed photodynamic activity comparable to rubellin D, whereas
caeruleoramularin did not display such activity [40].
1-Hydroxy-3-methyl-anthraquinone and 1,8-dihydroxy-3-methyl-anthraquinone (
43
and
44
, Figure 5,
Table 1), were isolated together with other bioactive metabolites from Trichoderma harzianum in a study
aimed to improve the production and application of novel biopesticides and biofertilizers and thus to
help in the management of crop plant diseases. However, the two anthraquinones had no role in this
activity [41].
Five anthraquinones named averantin, methyl-averantin, averufin, nidurufin, and versiconol
(
45
–
49
, Figure 5, Table 1) were isolated from Aspergillus versicolor, a sponge-derived fungus. Methyl
averatin and nidurufin (
45
and
48
) showed strong cytotoxicity against five human solid tumor cell lines
(A-549, SK-OV-3, SK-MEL-2, XF-498, and HCT-15) with IC50 values in the range of 0.41–4.61 µg/mL.
Averatin and nidurufin (
45
and
48
) had antibacterial activity against several clinical isolates of
Gram +strains with MIC values of 0.78–6.25
µ
g/mL [
42
]. Successively, a new anthraquinone, named
isorhodoptilometrin-1-methyl ether (
50
, Figure 5, Table 1), was isolated together with the already
known emodin, 1-methyl emodin, evariquinone, 7-hydroxyemodin, 6,8-methyl ether, siderin, arugosin
C, and variculanol from the same fungus but obtained from the Red Sea green alga Halimeda opuntia.
Compound
50
and siderin showed moderate antibacterial activity against B. subtilis,B. cereus, and S.
aureus at 50
µ
g/disk, while, tested at 3
µ
g, only compound
50
exhibited mild solid tumor selectivity
HEP-G2 with respect to the human normal cells (CFU) [43].
Phoma is a genus well known as producer of phytotoxin belonging to different classes of
natural compounds including anthraquinones [
44
]. In fact, from Phoma foevata, the causal agent
of gangrene in potatoes, several anthraquinones were isolated such as the already cited emodin
and crysophanol, together with pachybasin and phomarin (
51
and
52
, Figure 5, Table 1) but no
biological activity was reported [
45
]. Furthermore, a phytotoxic anthraquinone, which was identified
as anhydropseudophlegmacin-9,10-quinone-3
0
-amino-8
0
-O-methyl ether (
53
, Figure 5, Table 1), was
isolated from Phoma herbarum FGCC#54, a phytopathogenic fungus, investigated for herbicidal potential.
Compound 53 showed phytotoxic activity against the prominent weeds of Central India [46].
Fungi belonging to the Alternaria genus are also well known as producers of a plethora of bioactive
metabolites. In fact, five new hydroanthraquinone derivatives, named tetrahydroaltersolanols C–F
(
54
–
57
, Figure 6, Table 1) and dihydroaltersolanol A (
58
, Figure 6, Table 1), and five new alterporriol-type
anthranoid dimers, named alterporriols N
−
R (
59
–
63
, Figure 6), were isolated from the culture broth
and the mycelia of Alternaria sp. ZJ-2008003.
The fungus also produced seven known analogues as tetrahydroaltersolanol B, altersolanol B,
altersolanol C, altersolanol L, ampelanol, macrosporin (
8
, Figure 2) and alterporriol C. The fungus
was isolated from Sarcophyton sp. soft coral collected from the South China Sea. All the compounds
were assayed against the porcine reproductive and respiratory syndrome virus (PRRSV) and
54
and
62
showed antiviral activity with IC
50
values of 65 and 39
µ
M, respectively. Compound
61
exhibited cytotoxic activity against PC-3 and HCT-116 cell lines, with IC
50
values of 6.4 and 8.6
µ
M,
respectively [47].

Toxins 2020,12, 714 8 of 30
Toxins 2020, 12, x FOR PEER REVIEW 8 of 31
biofertilizers and thus to help in the management of crop plant diseases. However, the two
anthraquinones had no role in this activity [41].
Five anthraquinones named averantin, methyl-averantin, averufin, nidurufin, and versiconol
(45–49, Figure 5, Table 1) were isolated from Aspergillus versicolor, a sponge-derived fungus. Methyl
averatin and nidurufin (45 and 48) showed strong cytotoxicity against five human solid tumor cell
lines (A-549, SK-OV-3, SK-MEL-2, XF-498, and HCT-15) with IC50 values in the range of
0.41–4.61 μg/mL.
O
O
OH
R
3
R
1
43, R
1
=R
2
=R
3
=H
44, R
1
=R
3
=H, R
2
=OH
44, R
1
=OMe, R
2
=
45, R
1
=R
2
=H, R
3
=Me
46, R
1
=H, R
2
=OH, R
3
=Me
O
O
O
H
OH
O
H
R
HO
45, R=
46, R=
49, R=
OH
( )
4
OMe
( )
4
OH
OH
O
O
OHOH
47, R=H
48, R=OH
HO O
O
R
R
2
OH
R
3
=OH
O
O
OHO
50
R
1
OH
O
O
OH
51, R
2
=R
3
=H
52, R
1
=OH, R
2
=H
R
1
R
2
OH O
NH
2
COMe
O
O
HO
OH OH
53
O
MeO
R
3
R
4
OH
OH
R
1
R
2
R
5
R
6
54, R
1
=R
5
=OH, R
2
=R
6
=H, R
3
=αH, R
4
=βH,
55, R
1
=R
6
=OH, R
2
=R
5
=H, R
3
=βH, R
4
=αH,
56, R
1
=R
5
=H, R
2
=R
6
=OH, R
3
=αH, R
4
=βH
57, R
1
=O
A
c, R
2
=R
5
=H, R
3
=αH, R
4
=βH, R
6
=OH
Figure 5. Bioactive anthraquinones and analogues produced by Aspergillus versicolor, Phoma foevata,
Coniothyrium sp., Phoma herbarum, Ascochyta lentis and Alternaria sp.
Figure 5.
Bioactive anthraquinones and analogues produced by Aspergillus versicolor, Phoma foevata,
Coniothyrium sp., Phoma herbarum, Ascochyta lentis and Alternaria sp.

Toxins 2020,12, 714 9 of 30
Toxins 2020, 12, x FOR PEER REVIEW 10 of 31
Figure 6. Bioactive anthraquinones and analogues produced by Alternaria sp.
The fungus also produced seven known analogues as tetrahydroaltersolanol B, altersolanol B,
altersolanol C, altersolanol L, ampelanol, macrosporin (8, Figure 2) and alterporriol C. The fungus
was isolated from Sarcophyton sp. soft coral collected from the South China Sea. All the compounds
were assayed against the porcine reproductive and respiratory syndrome virus (PRRSV) and 54 and
62 showed antiviral activity with IC50 values of 65 and 39 μM, respectively. Compound 61 exhibited
cytotoxic activity against PC-3 and HCT-116 cell lines, with IC50 values of 6.4 and 8.6 μM,
respectively [47].
Holoroquinone (64, Figure 7, Table 1), is an anthraquinone isolated from a marine-derived
fungus Halorosellinia sp., which showed antitumor activity. Its biosynthesis was elucidated by
incorporation of [2-13C]malonate and [1,2,3-13C]malonate followed by 13C-NMR investigation [48].
Figure 6. Bioactive anthraquinones and analogues produced by Alternaria sp.
Holoroquinone (
64
, Figure 7, Table 1), is an anthraquinone isolated from a marine-derived fungus
Halorosellinia sp., which showed antitumor activity. Its biosynthesis was elucidated by incorporation of
[2-13C]malonate and [1,2,3-13C]malonate followed by 13C-NMR investigation [48].
Two new dimeric anthraquinones with a rare chemical skeleton, named torrubiellins A and B
(
65
and
66
, Figure 7, Table 1), were isolated from Torrubiella sp. BCC 28517 (family Clavicipitaceae)
belonging to a genus of fungus that attacks spiders, scale-insects, and hoppers. Torrubiellin B (
66
)
exhibited a broad range of biological activities including strong antimalarial (Plasmodium falciparum),
antifungal (Candida albicans), antibacterial (Bacillus cereus) activities, and cytotoxicity to cancer cell lines.
Its biological activity was always higher than that of torrubiellin A (65) [49].
Two new xanthone–anthraquinone heterodimers, named acremoxanthones C and D (
67
and
68
, Figure 7, Table 1), were isolated from an unidentified fungus of the Hypocreales order (MSX
17022). The fungus also produced the close and already known acremonidins A and C, benzophenone,
and moniliphenone. All the metabolites showed moderate cytotoxic activity
in vitro
. In addition,
acremoxanthone D (
68
), and acremonidins A and C exhibited moderate 20S proteasome inhibitory
activity [50].

Toxins 2020,12, 714 10 of 30
Toxins 2020, 12, x FOR PEER REVIEW 11 of 31
Figure 7. Bioactive anthraquinones and analogues produced by Halorosellinia sp., Torrubiella sp. BBC
28517, Hypocreales sp. MSX 17022, Penicillium citrinum PSU-F51 and Stemphylium sp. 33231.
Two new dimeric anthraquinones with a rare chemical skeleton, named torrubiellins A and B
(65 and 66, Figure 7, Table 1), were isolated from Torrubiella sp. BCC 28517 (family Clavicipitaceae)
belonging to a genus of fungus that attacks spiders, scale-insects, and hoppers. Torrubiellin B (66)
exhibited a broad range of biological activities including strong antimalarial (Plasmodium falciparum),
antifungal (Candida albicans), antibacterial (Bacillus cereus) activities, and cytotoxicity to cancer cell
lines. Its biological activity was always higher than that of torrubiellin A (65) [49].
Two new xanthone–anthraquinone heterodimers, named acremoxanthones C and D (67 and 68,
Figure 7, Table 1), were isolated from an unidentified fungus of the Hypocreales order (MSX 17022).
The fungus also produced the close and already known acremonidins A and C, benzophenone, and
moniliphenone. All the metabolites showed moderate cytotoxic activity in vitro. In addition,
acremoxanthone D (68), and acremonidins A and C exhibited moderate 20S proteasome inhibitory
activity [50].
Two new anthraquinone citrinin derivatives, named penicillanthranins A and B (69 and 70,
Figure 7, Table 1), were isolated together with 3R,4S-dihydrocitrinin from the mycelium extract of
the sea fan-derived fungus Penicillium citrinum PSU-F51. Penicillanthranin A (69) showed moderate
Figure 7.
Bioactive anthraquinones and analogues produced by Halorosellinia sp., Torrubiella sp. BBC
28517, Hypocreales sp. MSX 17022, Penicillium citrinum PSU-F51 and Stemphylium sp. 33231.
Two new anthraquinone citrinin derivatives, named penicillanthranins A and B (
69
and
70
, Figure 7,
Table 1), were isolated together with 3R,4S-dihydrocitrinin from the mycelium extract of the sea
fan-derived fungus Penicillium citrinum PSU-F51. Penicillanthranin A (
69
) showed moderate
antibacterial activity against Staphylococcus aureus ATCC25923 with MIC values of 16
µ
g/mL
and methicillin-resistant S. aureus SK1. Compounds
69
also exhibited mild cytotoxicity toward KB cells
with IC
50
values of 30
µ
g/mL [
51
]. Two new benzopyranones and one isochroman together with several
known compounds as methyl 2-(2-acetyl-3,5-dihydroxy-4,6-dimethylphenyl)acetate, coniochaetone A,
decarboxydihydrocitrinin, 1-acetonyl-7-carboxyl-6,8-dihydroxy-3,4,5-trimethylisochroman 6,8-dihydroxy
-3,4,5,7-tetramethyl-3,4-dihydroisocoumarin, methyl 8-hydroxy-6-methylxanthone -1-carboxylate,
sydowinin A, pinselin, conioxanthone A, chrysophanol, emodin, and
ω
-hydroxyemodin were isolated
from the culture filtrates of the same fungus [51].

Toxins 2020,12, 714 11 of 30
Four new anthraquinone derivatives, named auxarthrol C, macrosporin 2-O-(6
0
-acetyl)-
α
-d-glucopyranoside (
71
and
72
, Figure 7), 2-O-acetylaltersolanol B, and 2-O-acetylaltersolanol L
(
73
and
74
, Figure 8), and four new alterporriol-type anthranoid dimers, named alterporriols T–W
(
75
–
78
, Figure 8), were isolated along with 17 analogues from the rice culture of Stemphylium sp. 33,231
obtained from the mangrove Bruguiera sexangula var. rhynchopetala collected from the South China
Sea [
52
]. The already known compounds were identified as dihydroaltersolanol A, macrosporin,
macrosporin-7-O-sulfate, altersolanols A–C and L, ampelanol, tetrahydroaltersolanol B and alterporriols
A–E, N, and Q. Compounds
78
, showed only weak antibacterial activity against E. coli,S. aureus,
and B. subtilis, suggesting that anthraquinone derivatives showed better antibacterial activities than
anthraquinone dimers in these assays. Compounds
78
also showed a moderate lethality, with an LD
50
value of 10 µM when tested on brine shrimp lethality using Artemia salina [52].
Toxins 2020, 12, x FOR PEER REVIEW 13 of 31
O
O
MeO
OH
OH
MeO
OH
OH
OAc
73
74
OH
OH
OAC
H
H
O
O
OH
OH
MeO
OH
R
OH
O
O
MeO
OH
OH
75, R=OH
76, R=H
O
HO
OH
OMe
O
O
HO
OMe
77
O
O
HO
OH
OMe
O
O
OMe
OH
OH
HO
HO
78
O
O
OHMeO
OMe
79
OH OMe
O
O
MeO
OMe
80
OH
O
O
O
O
OHMeO
OMe OH
O
81
Figure 8. Bioactive antharaquinones and analogues produced by Stemphylium sp. 33231, Penicillium
purpurogenum, the endophytic fungus ZSUH-36 and A. versicolor.
Asperversin, A, 9ξ-O-2(2,3-dimethylbut-3-brevianamide Q, brevianamide K, brevianamide M,
6,8-5α,8α-epidioxyergosta-6,22-dien-3β-ol, ergosta-7,22-diene3β,5α,6β-triol, and
6β-methoxyergosta-7,22-diene-3β,5α-diol were isolated from the same fungus. Compound 81
exhibited antibacterial activity against Escherichia coli and S. aureus, and lethality against brine
shrimp (Artemia salina) with an LC50 value of 0.5 μg/mL [56].
Two anthraquinones identified as questin and isorhodoptilometrin (88 and 89, Figure 9,
Table 1) were produced together with chaetominine, (+)-alantrypinone, and
4-hydroxybenzaldehyde from the endophytic fungus Aspergillus sp. YL-6, isolated from the
allelopathic plant Pleioblastus amarus. When all the metabolites were tested on wheat (Triticum
aestivum) and radish (Raphanus sativus) at concentrations of 10 and 20 ppm, they inhibited the
germination and growth of the two plant seeds completely. Among them (+)-alantrypinone, an
indole-3-acetic acid (IAA), showed the best effects similar to that induced by glyphosate, a
broad-spectrum systemic herbicide. Furthermore, questin (88), inhibited shoot and root elongation
of wheat, always similar to glyphosate [57]. Questin was previously isolated together with another
Figure 8.
Bioactive antharaquinones and analogues produced by Stemphylium sp. 33231, Penicillium
purpurogenum, the endophytic fungus ZSUH-36 and A. versicolor.

Toxins 2020,12, 714 12 of 30
Eight known anthraquinone derivatives such as 6,8,10-tri-O-methyl averantin,
6,8-di-O-methyl averufnin, 6,8-di-O-methyl averufanin (
79
–
81
, Figure 8, Table 1) aversin,
1,3-dihydroxy-6,8-dimethoxy-9,10-anthraquinone, 6,8-di-O-methylnidurufin, 6,8-di-O-methyl
versiconol and 5-methyoxysterigmatocystin (
82
–
86
, Figure 9, Table 1) were isolated from the extracts
of Penicillium purpurogenum together with (S)-ornidazole. Only compounds
79
and
86
exhibited strong
toxicity against brine shrimp (Artemia salina) at 10 mM, with lethality rates of 100% comparable to
the positive control toosendanin. Compounds
79
,
82,
and
85
moderately inhibited the growth of
Botrytis cinerea. Compound
82
showed moderate antifungal activity against Gibberella saubinettii, while
compounds
84
,
85
and (S)-ornidazole exhibited phytotoxicity on radish seedlings at 100 mM [
53
].
6,8,1
0
-Tri-O-methyl averantin (
79
), 6,8-di-O-methyl averufanin (
80
), and 6,8-di-O-methyl averufin (
81
),
together with three known anthraquinones 1-O-methyl averantin, averufin (
9
), and versicolorin C were
also produced by the endophytic fungus ZSUH-36 isolated from a mangrove collected from the South
China Sea. At that time, only the unambiguous structure of
79
, being a new anthraquinone, was
determined by advanced NMR spectra while no activity was described [
54
]. Previously, compounds
82
and
85,
together with the two xanthones 5-methoxysterigmatocystin and sterigmatocystin (
86
and
87
, Figure 9, Table 1), had been isolated from the same fungus and only the unambiguous structure
of compound
85
, which at that time was a new anthraquinone, was determined by advanced NMR
spectra [
55
]. Compounds
80
–
82
and
84
were previously isolated from the culture of Aspergillus
versicolor, an endophytic fungus obtained from the marine brown alga Sargassum thunbergii.
Asperversin, A, 9
ξ
-O-2(2,3-dimethylbut-3-brevianamide Q, brevianamide K, brevianamide M,
6,8-5
α
,8
α
-epidioxyergosta-6,22-dien-3
β
-ol, ergosta-7,22-diene3
β
,5
α
,6
β
-triol, and 6
β
-methoxyergosta
-7,22-diene-3
β
,5
α
-diol were isolated from the same fungus. Compound
81
exhibited antibacterial activity
against Escherichia coli and S. aureus, and lethality against brine shrimp (Artemia salina) with an LC
50
value
of 0.5 µg/mL [56].
Two anthraquinones identified as questin and isorhodoptilometrin (
88
and
89
, Figure 9, Table 1)
were produced together with chaetominine, (+)-alantrypinone, and 4-hydroxybenzaldehyde from
the endophytic fungus Aspergillus sp. YL-6, isolated from the allelopathic plant Pleioblastus amarus.
When all the metabolites were tested on wheat (Triticum aestivum) and radish (Raphanus sativus)
at concentrations of 10 and 20 ppm, they inhibited the germination and growth of the two
plant seeds completely. Among them (+)-alantrypinone, an indole-3-acetic acid (IAA), showed
the best effects similar to that induced by glyphosate, a broad-spectrum systemic herbicide.
Furthermore, questin (
88
), inhibited shoot and root elongation of wheat, always similar to
glyphosate [
57
]. Questin was previously isolated together with another three anthraquinones,
identified as fallacinol, citreorosein, and questinol (
90
–
92
, Figure 9, Table 1), and protocatechuic
acid, (+)-catechin, 2,5-dimethyl-7-hydroxy chromone, 7-hydroxy-4-methoxy-5-methylcoumarin,
torachrysone-8-O-d-glucoside, and 2-methoxy-6-acetyl-7-methyljuglone from the dried roots of
Polygonum cuspidatum, a plant extensively used in Chinese and Japanese folk medicine [
58
].
Isorhodoptilometrin (
89
) was previously isolated together with secalonic acid D, emodin (
21
),
and citreorosein (
91)
, from a marine lichen-derived fungus Gliocladium sp. T31 with secalinic acid D
showing strong cytotoxic activity against human myeloid leukemia K562 cell line [59].
Engyodontochones A (
93
, Figure 9, Table 1) and B–F (
94
–
97
, Figure 10, Table 1) together with two
known polyketides as a betacolin-like metabolite (
99
, Figure 9, Table 1) and JBIR-99 (
100,
Figure 10,
Table 1), all belonging to the anthraquinone–xanthone subgroup of polyketides, were isolated from
mycelia and culture broth of Engyodontium album strain LF069. E. album, was found in soil extreme
environments, plant debris, and in indoor environments on paper, textile, jute, and painted walls.
It is a pathogenic fungus, inducing serious human diseases. Engyodontochones A–E (
93, 94
–
96
)
and betacolin-like metabolite (
99
) exhibited inhibitory activity, 10-fold stronger than chloramphenicol,
against methicillin resistant S. aureus (MRSA) [60].

Toxins 2020,12, 714 13 of 30
Toxins 2020, 12, x FOR PEER REVIEW 14 of 31
three anthraquinones, identified as fallacinol, citreorosein, and questinol (90–92, Figure 9, Table 1),
and protocatechuic acid, (+)-catechin, 2,5-dimethyl-7-hydroxy chromone,
7-hydroxy-4-methoxy-5-methylcoumarin, torachrysone-8-O-D-glucoside, and
2-methoxy-6-acetyl-7-methyljuglone from the dried roots of Polygonum cuspidatum, a plant
extensively used in Chinese and Japanese folk medicine [58]. Isorhodoptilometrin (89) was
previously isolated together with secalonic acid D, emodin (21), and citreorosein (91), from a marine
lichen-derived fungus Gliocladium sp. T31 with secalinic acid D showing strong cytotoxic activity
against human myeloid leukemia K562 cell line [59].
O
O
R2R4
88,R
1=OH, R2=Me, R3=OMe, R4=CH2OH
89,R
1=R2=R3=OH, R4=CH2(OH)CH3)
90,R
1=R3=OH, R2=OMe, R4=CH2OH
91,R
1=R2=R3=OH, R4=CH2OH,
92,R
1=OMe, R2=R3=OH, R4=CH2OH
R3
R1
O
O
O
OH
OAC
HO
OH
OH
AcO
R
O
MeO
OMe OH
O
O
H
H
82
O
O
MeO
OMe OH
O
O
OH
OO
O
OHMeO
OMe H
83
84
O
MeO
OMe OH
OH
O
OH
OH
85
O
OOH OMe
R
O
O
H
H
86,R=H
87,R=OMe
93,R= OH
99,R= OH
Figure 9. Bioactive anthraquinones and analogues produced by P. purpurogenum, the endophytic
fungus ZSUH-36, A. versicolor, Aspergillus sp. YL-6, Gliocladium sp. T31 and Engyodontium album.
Engyodontochones A (93, Figure 9, Table 1) and B–F (94–97, Figure 10, Table 1) together with
two known polyketides as a betacolin-like metabolite (99, Figure 9, Table 1) and JBIR-99 (100,
Figure 10, Table 1), all belonging to the anthraquinone–xanthone subgroup of polyketides, were
isolated from mycelia and culture broth of Engyodontium album strain LF069. E. album, was found in
soil extreme environments, plant debris, and in indoor environments on paper, textile, jute, and
painted walls. It is a pathogenic fungus, inducing serious human diseases. Engyodontochones A–E
Figure 9.
Bioactive anthraquinones and analogues produced by P. purpurogenum, the endophytic
fungus ZSUH-36, A. versicolor, Aspergillus sp. YL-6, Gliocladium sp. T31 and Engyodontium album.
Seven anthraquinone derivatives identified as 1,2,8-trihydroxyanthraquinone, 1,3,8-trihydroxy
anthraquinone, 1,3,6-trihydroxy-8-methylanthraquinone, rheoemodin, aloesaponarin II, isozyganein,
1-acetyl-4,5-dihydroxy-anthraquinone (
101
–
107
, Figure 10, Table 1) were isolated together with
cis-4-hydroxyscytalone, and cerebroside B from the culture filtrates of the endophytic fungus
Nigrospora sp. cis-4-Hydroxyscytalone showed strong antibacterial activities against E. coli and B.
subtilis with MIC values of 64 and 128
µ
g/mL, respectively. 1,3,8-Trihydroxyanthraquinone,
1,3,6-trihydroxy-8-methylanthraquinone, and aloesaponarin II (
102
,
103
, and
105
) exhibited inhibitory
activity against P. oryzae with MIC values of 128
µ
g/mL, while 1,3,8-trihydroxyanthraquinone (
102
)
showed moderate antifungal activity against C. albicans with MIC value of 128
µ
g/mL. Rheoemodin
(
104)
exhibited weak antimicrobial activity only against E. coli with MIC values of 256
µ
g/mL [
61
].
Isozyganein (106) was also previously synthesized and showed weak antioxidative activity [62].
Aspetritones A and B (
108
and
109
, Figure 10, Table 1) were isolated from the culture of
the coral-derived fungus Aspergillus tritici SP2-8-1, together with 4-methyl-candidusin A and fifteen
known metabolites belonging to different classes of natural compounds as prenylcandidusin,

Toxins 2020,12, 714 14 of 30
candidusin, and terphenyllin derivatives and anthraquinones. Bostrocyn (
110
, Figure 10, Table 1)
and other four anthraquinones (
111
–
114
, Figure 10, Table 1) were isolated. Aspetritone A (
108
) showed
the most significant activity against methicillin-resistant strains of S. aureus in respect to that of
the positive control chloramphenicol and exhibited strong cytotoxicity against human cancer cell lines
HeLa, A549, and Hep G2 [63].
A new anthraquinone glycoside derivative namely, 1-O-methyl-6-O-(
α
-d-ribofuranosyl)-emodin
(
115
, Figure 11, Table 1), was produced together with two new resorcinol glycoside
derivatives as resorcinol 2-butyl-5-pentyl-4-C-6-deoxy-
β
-d-gulopyranoside and resorcinol 2-butyl
-5-pentyl-4-C-
α
-l-rhamnoside, named stemphols C and D, and eight already known compounds
from the culture filtrates of the endophytic fungus Gaeumannomyces sp. isolated from the rhizome
of a halophyte, Phragmites communis, in Suncheon bay, South Korea [
64
]. In particular, among
the known compounds, 1-O-methylemodin (
116
, Figure 11, Table 1) was also identified. Compound
116
was first isolated together with 5-chloro-6,8-dihydroxy-1-methoxy-3-methylanthraquinone,
7-chloro-6,8-dihydroxy-1-methoxy-3-methylanthraquinone, 5-chloro-6,8,10-trihydroxy-1-methoxy-3
-methyl-9(10H) anthracenone and 5-chloro-8,10-dihydroxy-l,6-dimethoxy-3-metbyl-9(10H)-anthracenone
(
117
–
120
, Figure 11, Table 1), from Phialophora alba, a fungus that might protect the aspen from attack
by other fungi [
65
]. Compounds
115
as well as the two glycosyl derivatives of resorcinol showed
anti-inflammatory properties while 1-O-methylemodin (
116
) reduced NO production by LPS-treated
cells by 43% and 31%, respectively, without inducing cell death [64].
Compound
115
also inhibited the growth of the tree decaying fungus Phellinus tremulae [
66
],
the secretion of IL-625 [67], and of protein tyrosine phosphatase 1B [68].
Rubrumol (
121
, Figure 11, Table 1) was isolated together with four known analogues as emodin
and catenarin (
21
and
24
), rubrocristin, 2-methyleurotinone, and conyothyrinone A (
122
–
124
, Figure 11,
Table 1) from the solid culture of Eurotium rubrum, a fungus obtained from the salt-tolerance wild
plant Suaeda salsa L. which was collected from ‘BoHai’ seaside. Among all the compounds, only
121
showed activity when tested on Topo I to relax supercoiled pBR322 DNA and it did not show cytotoxic
activities against A549, MDA-MB-231, PANC-1, and HepG2 human cancer cell [
69
]. Rubrocristin
(
122
) was previously isolated from the mycelia of Aspergillus glaucus together with physcion (
23
)
emodin, and catenarin (
21
and
24
), questin (
88
), erythroglaucin, physcion-9-anthrone, viocristin,
and isoviocristin (
125
–
128
, Figure 11, Table 1). Compounds
21
,
24
,
127,
and
128
showed antibacterial
activity with minimal inhibitory concentrations ranging from 1–10 pg/mL, while compounds
21
,
24,
and
127
inhibited the incorporation of uridine and thymidine in Ehrlich ascites carcinoma cells while
24
and to a lesser extent compound
21
also inhibited
in vitro
DNA-dependent RNA polymerase from
Escherichia coli [
70
]. Conyothyrinone A (
124
, Figure 11, Table 1) was also isolated from the culture of
Coniothyrium sp. together with conyothyrinones B–D (
129
–
131
, Figure 11, Table 1) and the already known
ones pachybasin and phomarin (
51
and
52
) as well as 1,7-dihydroxy-3-methyl-9,10-anthraquinone
and 1-hydroxy-3-hydroxymethyl-9,10-anthraquinone (
132
and
133
, Figure 11, Table 1), an endophytic
fungus isolated from Salsola oppostifolia from Gomera in the Canary islands. All these metabolites were
tested for their antifungal, antibacterial, and algicidal properties. Compound
132
showing a strong
antibacterial activity against Bacillus magaterium and E. coli. Phomarin and conyothyryrinone A (
52
and
124
) exhibited strong antifungal activity against Mycrobotryum violaceum and B. cinerea, while
pachybasin (51), which is the main metabolite, showed weak activity against B. megaterium [71].
Three new anthraquinones, identified as (-)-2
0
R-1-hydroxyisorhodoptilometrin, methyl
3,4,8-trihydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate, and methyl 6,8-dihydroxy-3-methyl
-9-oxo-9H-xanthene-1-carboxylate (
134
–
136
, Figure 11, Table 1) were isolated from the culture filtrates,
Penicillium sp. OUCMDZ-4736, on the effect of acid stress conditions. The fungus was isolated
from the sediment around the roots of the mangrove (Acanthus ilicifolius). The new anthraquinones
were isolated together with ten already known compounds including asterric acid, parietinic acid,
endocrocin, and monochlorsulochrin [
72
]. Compound
134
, on comparison with the control lamivudine

Toxins 2020,12, 714 15 of 30
showed a stronger anti-hepatitis B virus inhibiting HBsAg and HBeAg secretion from HepG2.2.15
cells [73].
Toxins 2020, 12, x FOR PEER REVIEW 16 of 31
97, R=βOAc
98, R=αOAc
OOH
OAC
HO
O
OH
O
HO
COOH
RO
O
R
1
R
2
R
3
R
4
R
5
R
6
R
7
101, R
1
=R
4
=R
5
=OH, R
2
=R
3
=R
6
=R
7
=H
102, R
1
=R
4
=R
6
=OH, R
2
=R
3
=R
5
=R
7
=H,
103, R
1
=R
2
=R
6
=R
4
=OH, R
3
=R
5
=R
7
=H
104, R
1
= Me, R
2
=R
4
=R
6
=OH, R
3
=R
5
=R
7
=H
105, R
1
=R
2
=R
6
=H, R
3
=R
5
=OH, R
4
=R
7
=Me
106, R
1
=R
2
=R
3
=R
5
=R
6
=H, R
4
=Me, R
7
=OH
107, R
1
=R
2
=R
5
=R
6
=H, R
3
=R
7
=OH, R
4
=COCH
3
OH
OH
O
O
R
1
"R
R
3
108, R
1
=R
2
=OMe, R
3
=H
110, R
1
=H, R
2
=OMe, R
3
=bOH
O
O
MeO
MeO OH
OH
109
O
O
R
8
R
6
R
5
R
1
R
2
R
3
R
4
111, R
1
=R
3
=R
6
=R
8
=H, R
2
=R
4
=R
5
=OH, R
7
=Me
112, R
1
=R
2
=R
5
=R
6
=OMe, R
3
=OH, R
4
=R
7
=R
8
=H
113, R
1
=OMe, R
2
=CH
2
OH, R
3
=OH, R
4
=R
5
=R
6
=R
7
=R
8
=H
114, R
1
=R
2
=R
3
=OMe, R
4
=R
5
=R
6
=R
8
=H, R
7
=CH
2
OH
R
7
94, R=βOAc
100, R=αOAc
OOH
OAC
HO
O
OH
O
R
H
O
OH
95, R
1
=R
2
=H, R
3
=5-furanoyl, R
4
=αOAc
96, R
1
=βOAc, R2=5-furanyl, R
3
=R
4
=H
OOH
OAC
HO
O
OH
O
R
1
R
2
R
3
R
4
Figure 10. Bioactive anthraquinones and analogues produced by Engyodontium album, Nigrospora sp.
and Aspergillus tritici.
Figure 10.
Bioactive anthraquinones and analogues produced by Engyodontium album, Nigrospora sp.
and Aspergillus tritici.

Toxins 2020,12, 714 16 of 30
Toxins 2020, 12, x FOR PEER REVIEW 17 of 31
Figure 11. Bioactive anthraquinones and analogues produced by Gaeumannomyces sp., Phialophora
alba, Eurotium rubrum, A. glaucus, Coniothyrium sp., Penicillium sp. OUCMDZ-4736, Fusarium solani
and Paraconiothyrium sp.
Compound 115 also inhibited the growth of the tree decaying fungus Phellinus tremulae [66], the
secretion of IL-625 [67], and of protein tyrosine phosphatase 1B [68].
Rubrumol (121, Figure 11, Table 1) was isolated together with four known analogues as emodin
and catenarin (21 and 24), rubrocristin, 2-methyleurotinone, and conyothyrinone A (122–124,
Figure 11, Table 1) from the solid culture of Eurotium rubrum, a fungus obtained from the
salt-tolerance wild plant Suaeda salsa L. which was collected from ‘BoHai’ seaside. Among all the
compounds, only 121 showed activity when tested on Topo I to relax supercoiled pBR322 DNA and
it did not show cytotoxic activities against A549, MDA-MB-231, PANC-1, and HepG2 human cancer
cell [69]. Rubrocristin (122) was previously isolated from the mycelia of Aspergillus glaucus together
with physcion (23) emodin, and catenarin (21 and 24), questin (88), erythroglaucin,
physcion-9-anthrone, viocristin, and isoviocristin (125–128, Figure 11, Table 1). Compounds 21, 24,
127, and 128 showed antibacterial activity with minimal inhibitory concentrations ranging from
1–10 pg/mL, while compounds 21, 24, and 127 inhibited the incorporation of uridine and thymidine
Figure 11.
Bioactive anthraquinones and analogues produced by Gaeumannomyces sp., Phialophora
alba, Eurotium rubrum, A. glaucus, Coniothyrium sp., Penicillium sp. OUCMDZ-4736, Fusarium solani
and Paraconiothyrium sp.
Danthron (
137
, Figure 11, Table 1), characterized as 1,8-dihydroxyanthraquinone, was produced
as the main bioactive metabolite by the fungal endophyte Paraconiothyrium sp. isolated from
Zingiber officinale. Compound
137
showed antifungal activity against clinical pathogens and against
the phytopathogen Pythium myriotylum, which causes Pythium rot in ginger [
74
]. Danthron, also
called as chrysazin, was used as a stimulant laxative in some countries and showed antibacterial,
antifungal [75], and anticancer activities [76].
An aza-anthraquinone identified as bostrycoidin (
138
, Figure 11, Table 1) was produced
together with anhydrofusarubin, fusarubin, 3-deoxyfusarubin, ergosterol, 3,5,9-trihydroxy
ergosta-7,22-diene-6-one, and 4-hydroxybenzaldehyde from large scale cultivation of the endophytic
fungus Fusarium solani isolated from Cassia alata Linn. growing in Bangladesh.

Toxins 2020,12, 714 17 of 30
The crude organic extract of the fungal culture filtrates showed cytotoxicity, using “Brine Shrimp
Lethality Bioassay”, antimicrobial and antioxidant activity. Among the isolated metabolites, compound
138 appeared to be the most potent anticancer and antimicrobial metabolite [77].
Three new phytotoxic anthraquinones, named lentiquinones A–C (
139
–
141
, Figure 12, Table 1) were
isolated from the culture filtrates of Ascochyta lentis inducing Ascochyta blight on lentil (Lens culinaris
Medik.) [
78
]. Another new anthraquinone, named lentisone (
142
Figure 12, Table 1), together with
the known pachybasin (
51
), tyrosol, and pseurotin A, was previously isolated from the same fungus [
79
].
Pachybasin (
51
) was also isolated, as the main metabolite, from the fungal mycelium of the same
fungus together with other three known anthraquinones as
ω
-hydroxypachybasin (
143
, Figure 12,
Table 1), 1,7-dihydroxy-3-methylanthracene-9,10-dione (
144,
Figure 12, Table 1), and phomarin
(
52
) [
78
]. Tested by leaf-puncture on host and non-host plants, the three new anthraquinones
(
139
–
141
) and lentisone (
142
) caused severe necrosis, with lentiquinone A being the most active.
Compound
139
proved to be particularly active on cress (Lepidium sativum), in inhibiting root
elongation. Furthermore, all the compounds reduced the content of chlorophyll in Lemna minor,
with 1,7-dihyroxy-3-methylanthracene-9,10-dione (
144
) being the most active. The lentiquinones A–C
and lenstisone had antibiotic properties [78].
Two anthraquinone dimers (
145
and
146
, Figure 12, Table 1) were produced together with
another three known anthraquinones as 1
0
-O-methylaverantin and averantin (
147
and
148
, Figure 12,
Table 1), averythrin (
7
), and two xanthones as stergmatocystin and variecoxanthone from
the marine-derived fungus Aspergillus versicolor. Compounds
145
and
146,
showed selective
antibacterial activity against S. aureus, while stergmatocystin exhibited moderate cytotoxicity against
human cancer cell lines [
15
]. Averantin was also isolated from the marine-derived fungus
Aspergillus sp. SCSIO F063 together with its seven related chlorinated anthraquinones as
(1
0
S)-7-chloroaverantin, (1
0
S)-6-O-methyl-7-chloroaverantin, (1
0
S)-1
0
-O-methyl-7-chloroaverantin,
(1
0
S)-6,1
0
-O,O-dimethyl-7-chloroaverantin, (1
0
S)-7-chloroaverantin-1
0
-butyl ether, 7-chloroaverythrin,
and 6-O-methyl-7-chloroaverythrin (
149
–
155
, Figure 13, Table 1). Five known analogues, identified
as 1
0
-O-methylaverantin, 6-O-methylaverantin, averantin-1
0
-butyl ether, and averythrin (
7
) were
also isolated when the fungus was grown on sea salt-containing potato dextrose broth. When
sodium bromide was added to the culture medium also two new brominated anthraquinones
as (1
0
S)-6,1
0
-O,O-dimethyl-7-bromoaverantin and (1
0
S)-6-O-methyl-7-bromoaverantinone (
156
and
157
, Figure 13, Table 1) and a nonhalogenated anthraquinone, identified as (1
0
S)-6,1
0
-O,O
-dimethylaverantin (
158
, Figure 13, Table 1) were extracted from fungal mycelia. Among all thecompounds
isolated only 6-O-methyl-7-chloroaveratin (
155)
displayed inhibition activity against three human tumor
cell lines, SF-268, MCF-7, and NCI-H460, with IC50 values of 7.11, 6.64, and 7.42 µM, respectively [47].
A hydroanthraquinone with a hexacyclic spiro-fused ring system and two new anthraquinones
with a 4,5-disubstituted butylaminolate unit, named anthrininones A–C (
159
–
161
, Figure 13, Table 1)
were isolated from the deep-sea derived fungus Alternaria tenuissima DFFSCS013. They were isolated
together with six known analogues including 6-O-methylalaternin (
162
, Figure 13, Table 1), 10,11-
dihydroaltersolanol A, altersolanol L, ampelanol, (3R)-1-deoxyaustrocortilutein and altersolanol
B. Compounds
159
–
162
showed strong inhibition activity against indoleamine 2,3-dioxygenase 1
(IDO1), and compounds
160
–
162
also had selective inhibition activity against different protein tyrosine
phosphatase, while compound
159
stimulated intracellular calcium levels at a concentration of
10 µM [81].

Toxins 2020,12, 714 18 of 30
Toxins 2020, 12, x FOR PEER REVIEW 19 of 31
145, R=CH
3
146, R=H
OOH
HO
OH
O
OH
O
O
OH
OR
O
OH
140, R=αOH
141, R=βOH
OH
O
OH
OH OH
R
143, R
1
=H R
2
=CH
2
OH
144, R
1
=OH, R
2
=Me
O
O
OH
R
2
H
138
N
O
O
OH
O
H
H
3
CO
OH
142
O
O
OH
OH OH
OH
O
OH O
OH
OR
HO
147, R=CH
3
148, R=H
R
1
139
O
O
O
OH
O
H
O
H
Figure 12. Bioactive anthraquinones and analogues produced by Fusarium solani, Ascochyta lentis, A.
versicolor and Aspergillus sp. SCSIO F063.
Two anthraquinone dimers (145 and 146, Figure 12, Table 1) were produced together with
another three known anthraquinones as 1′-O-methylaverantin and averantin (147 and 148, Figure 12,
Table 1), averythrin (7), and two xanthones as stergmatocystin and variecoxanthone from the
marine-derived fungus Aspergillus versicolor. Compounds 145 and 146, showed selective antibacterial
activity against S. aureus, while stergmatocystin exhibited moderate cytotoxicity against human
cancer cell lines [15]. Averantin was also isolated from the marine-derived fungus Aspergillus sp.
SCSIO F063 together with its seven related chlorinated anthraquinones as (1′S)-7-chloroaverantin,
(1′S)-6-O-methyl-7-chloroaverantin, (1′S)-1′-O-methyl-7-chloroaverantin,
(1′S)-6,1′-O,O-dimethyl-7-chloroaverantin, (1′S)-7-chloroaverantin-1′-butyl ether,
7-chloroaverythrin, and 6-O-methyl-7-chloroaverythrin (149–155, Figure 13, Table 1). Five known
analogues, identified as 1′-O-methylaverantin, 6-O-methylaverantin, averantin-1′-butyl ether, and
averythrin (7) were also isolated when the fungus was grown on sea salt-containing potato dextrose
broth. When sodium bromide was added to the culture medium also two new brominated
anthraquinones as (1′S)-6,1′-O,O-dimethyl-7-bromoaverantin and
(1′S)-6-O-methyl-7-bromoaverantinone (156 and 157, Figure 13, Table 1) and a nonhalogenated
anthraquinone, identified as (1′S)-6,1′-O,O-dimethylaverantin (158, Figure 13, Table 1) were
extracted from fungal mycelia. Among all the compounds isolated only 6-O-methyl-7-chloroaveratin
Figure 12.
Bioactive anthraquinones and analogues produced by Fusarium solani, Ascochyta lentis,A.
versicolor and Aspergillus sp. SCSIO F063.
Funiculosone (
163
, Figure 13, Table 1), a new substituted dihydroxanthene-1,9-dione, was isolated
together with its two known analogues mangrovamide J and ravenelin (
164
–
165
, Figure 13, Table 1)
from the culture filtrates of Talaromyces funiculosus (Trichocomaceae) an endolichenic fungus obtained
from lichen thallus of Diorygma hieroglyphicum in India [
82
]. When assayed against E. coli and S. aureus,
all the compounds displayed antibacterial activity with an IC
50
range 23–104
µ
g/mL. Compound
163
also showed anticandidal activity against Candida albicans with an IC50 35 µg/mL [82].
A new hexasubstituted anthraquinone, named neoanthraquinone (
166
, Figure 13, Table 1) was
isolated from Neofusicoccum luteum, the causal agent of Botryosphaeria dieback in Australia. N. luteum
produced also a new disubstituted furo-
α
-pyrone and a trisubstituted oxepi-2(7H)-one, named
luteopyroxin and luteoxepinone respectively, together with the known (
±
)-nigrosporione, tyrosol,
(R)-(
−
)-mellein and (3R,4S)-(
−
)- and (3R,4R)-(
−
)-4-hydroxymellein. Compound
166
caused severe
shriveling and withering when assayed on grapevine leaves, while the other metabolites showed
different degrees of toxicity [83].

Toxins 2020,12, 714 19 of 30
Toxins 2020, 12, x FOR PEER REVIEW 20 of 31
(155) displayed inhibition activity against three human tumor cell lines, SF-268, MCF-7, and
NCI-H460, with IC50 values of 7.11, 6.64, and 7.42 μM, respectively [47].
Figure 13. Bioactive anthraquinones and analogues produced by Aspergillus sp. SCSIO F063,
Alternaria tenuissima, Talaromyces funiculosus, Neofusicoccum luteum and Rubia tinctorum.
Figure 13.
Bioactive anthraquinones and analogues produced by Aspergillus sp. SCSIO F063, Alternaria
tenuissima,Talaromyces funiculosus, Neofusicoccum luteum and Rubia tinctorum.
Table 1. Anthraquinones and analogues produced by phytopathogenic and endophytic fungi.
Anthraquinone Fungus Biological Activity Reference
Dothistromin (1, Figure 2)Dothistroma pini Phytotoxic [13]
Bisdeoxydothistromin (2, Figure 2)“1No activity [14]
Bisdeoxydehydrodothistromin (
3
, Figure 2)
“ “ “
6-Deoxyversicolorin C (4, Figure 2) “ “ “
Averufin (5, Figure 2) “ “ “
Nidurufin (6, Figure 2) “ “ “
Averythrin (7, Figure 2)Dothistroma pini
Aspergillus versicolor ““
[15]
Macrosporin (8, Figure 2)
Alternaria porri,
Alternaria solani,
Alternaria cucumerina,
Diaporthe angelicae,
Stemphyfium botryosum
Phytotoxic [16,17,20]
6-Methylxanthopurpurin 3 methyl eter
(9, Figure 2)
Alternaria bataticola
Alternaria solani “ “
Alternasolanol A (10, Figure 2)D. angelicae ” [17]
Alternasolanol J (11, Figure 2) “ “ “

Toxins 2020,12, 714 20 of 30
Table 1. Cont.
Anthraquinone Fungus Biological Activity Reference
Stemphylin (12, Figure 2)S. botryosum Phytotoxic and weak
antitumor [20]
Dactylariol (13, Figure 2) “ Phytotoxic and in vitro
anticancer “
Stemphyperylenol (14, Figure 2)Stemphylium botryosum Weak phytotoxic [21]
Alterporriol (15, Figure 3) “ No activity “
Stemphylenol A (16, Figure 3) “ “ “
Stemphylenol B (17, Figure 3) “ “ “
Rugulosin (18, Figure 3)Cryphonectria parasitica
Hormonema dematioides
Phytotoxic
Insecticidal [22,24]
Skyrin (19, Figure 3)”Phytotoxic ”
Crysophanol (20, Figure 3) “ “ “
Emodin (21, Figure 3)
C. parasitica,
Pyrenophora
tritici-repentis,
Gliocladium sp. T31,
Aspercgillus glaucus,
H. dematioides,
Aspergillus fumigatus,
Phoma foevata
Phytotoxic
Mycotoxic
Anticancer and
inhibition in vitro
DNA-dependent RNA
polymerase
[22,24,25,29,45,59,70]
2-Chloroemodin (22, Figure 3)Aspergillus fumigatus No activity [25]
Physcion (23, Figure 3)“
Microsporum sp. Anticancer “
[26]
Catenarin (24, Figure 3)
Drechslera teres,
Drechslera graminea,
Drechslera tritici-repentis,
Drechslera phlei,
Drechslera dictyoides,
Drechslera avenae
Aspergillus cristatus
Antibiotic against Gram+
Phytotoxic
Anticancer and
inhibition in vitro
DNA-dependent RNA
polymerase
[28,29,70]
Helminthosporin (25, Figure 3)D. avenae,
Bipolaris sorokiniana No activity [28.29]
Cynodontin (26, Figure 3) “ No activity “
Cytoskyrin A (27, Figure 3)Cytospora sp. CR200 BIA [30,31]
Cytoskyrin B (28, Figure 3) “ BIA “
Luteoskyrin (29, Figure 3) “ No activity “
Dendryol A (30, Figure 4)Dendryphiella sp. Phytotoxic [35]
Dendryol B (31, Figure 4) “ “ “
Dendryol C (32, Figure 4) “ “ “
Dendryol D (33, Figure 4) “ “ “
Rubellin A (34, Figure 4)Ramularia collo-cygni Increased photodynamic
oxygen activation [37,38]
Rubellin B (35, Figure 4)
Phytotoxic, antibiotic,
antiproliferative,
and cytotoxic
[38,39]
Rubellin C (36, Figure 4) “ “ “
Rubellin D (37, Figure 4) “ “ “
Rubellin E (38, Figure 4) “ “ “
Rubellin F (39, Figure 4)“No activity “
Uridinetubellins I (40, Figure 4)Ramularia uredinicola
Ramularia collo-cygni
The photodynamic
action toward three
mammalian cell lines
[40]
Uridinetubellins II, (41, Figure 4) “ “ “
Caeruleoramularin (42, Figure 4) “ No activity “
1-Hydroxy-3-methyl-anthraquinone
(43, Figure 4)Trichoderma harzianum No activity [41]

Toxins 2020,12, 714 21 of 30
Table 1. Cont.
Anthraquinone Fungus Biological Activity Reference
1,8-Dihydroxy-3-methyl-anthraquinone
(44, Figure 4)“ “ “
Averantin (45, Figure 5)Aspergillus versicolor Antibiotic,
Cytotoxic [42,45,48]
Methyl-averantin (46, Figure 5) “ Cytotoxic “
Averufin (47, Figure 5) “ No activity “
Nidurufin (48, Figure 5) “ Antibiotic and cytotoxic “
Versiconol (49, Figure 5) “ No activity “
Isorhodoptilometrin-1-methyl ether
(50, Figure 5)“Antibiotic and mild
anticancer [43]
Pachybasin (51, Figure 5)
P. foevata,
Coniothyrium sp.,
Ascochyta lentis
Weak antibiotic
Antibiotic [45,71,78]
Phomarin (52, Figure 5) “ Antifungal activity
Antibiotic [45,71,78]
Anhydropseudophlegmacin-9,10-quinone
-30-amino-80-O-methyl ether (53, Figure 5)Phoma herbarum Phytotoxic [46]
Tetrahydroaltersolanol C (54, Figure 5)Alternaria sp. Antiviral [47]
Tetrahydroaltersolanol D (55, Figure 5) “ No activity “
Tetrahydroaltersolanol E (56, Figure 5) “ “ “
Tetrahydroaltersolanol F (57, Figure 5) “ “ “
Dihydroaltersolanol A (58, Figure 6) “ “ “
Alterporriol N (59, Figure 6) “ “ “
Alterporriol O (60, Figure 6) “ “ “
Alterporriol P (61, Figure 5) “ Cytotoxic “
Alterporriol Q (62, Figure 6) “ Antiviral “
Alterporriol R (63, Figure 6) “ No activity “
Holoroquinone (64, Figure 7)Halorosellinia sp. Antitumor [48]
Torrubiellin A (65, Figure 7)
Torrubiella sp. BCC 28517
Moderate antimalarial,
antifungal, antibacterial,
cytotoxic
[49]
Torrubiellin A (66, Figure 7) “ Antimalarial, antifungal,
antibacterial, cytotoxic “
Acremoxanthone C (67, Figure 7)Hypocreales sp. MSX
17022 Moderate cytotoxic [50]
Acremoxanthone D (68, Figure 7) “
Moderate cytotoxic,
and moderate 20S
proteosome inhibition
“
Penicillanthranin A (69, Figure 7)Penicillium citrinum
PSU-F51
Moderate antibacterial
and mild cytotoxic [51]
Penicillanthranin B (70, Figure 7) “ No activity “
Auxarthrol C (71, Figure 7)Stemphylium sp. 33231 “ [52]
Macrosporin
2-O-(60-acetyl)-α-d-glucopyranoside
(72, Figure 7)
“ “ “
2-O-Acetylaltersolanol B (73, Figure 8) “ “ “
2-O-Acetylaltersolanol L (74, Figure 8) “ “
Alterporriols T (75 Figure 8) “ “ “
Alterporriols U (76 Figure 8) “ “ “
Alterporriols V (77 Figure 8) “ “ “
Alterporriols W (78 Figure 8) “ Weak antibacterial
and moderate zootoxic “
6,8,10-Tri-O-methyl averantin (79, Figure 8)
Penicillium purpurogenum
Endophytic fungus
ZSUH-36
Zootoxic and
antifungal [53,54]

Toxins 2020,12, 714 22 of 30
Table 1. Cont.
Anthraquinone Fungus Biological Activity Reference
6,8-Di-O-methyl averufnin (80, Figure 8)
Penicillium purpurogenum
Endophytic fungus
ZSUH-36
Aspergillus versicolor
No activity [53,54,56]
6,8-Di-O-methyl averufanin (81, Figure 8)“
Antibiotic and zootoxic [53,54,56]
Aversin (82, Figure 9)“ Antifungal [53,55,56]
1,3-Dihydroxy-6,8-dimethoxy
-9,10-anthraquinone (83, Figure 9)
Penicillium purpurogenum
No activity [53]
6,8-Di-O-methylnidurufin (84, Figure 9)
Penicillium purpurogenum
Endophytic fungus
ZSUH-36
Aspergillus versicolor
Antifungal
and phytotoxic [53,54,56]
6,8-Di-O-methyl versiconol (85, Figure 9)
Penicillium purpurogenum
Endophytic fungus
ZSUH-36
Antifungal and
phytotoxic [53,55]
5-Methyoxysterigmatocystin (86, Figure 9) “ Zootoxic [53]
Sterigmatocystin (87, Figure 9)
Penicillium purpurogenum
No activity [55]
Questin (88, Figure 9)
Aspergillus sp.
YL-6,
Polygonum cuspidatum
Allelopathy [57,58]
Isorhodoptilometrin (89, Figure 9)
Aspergillus sp.
YL-6,
Gliocladium sp. T31
Alleopathy [57,59]
Fallacinol (90, Figure 9)Polygonum cuspidatum No activity [58]
Citreorosein (91, Figure 9)Polygonum cuspidatum
Gliocladium sp. T31 “ [58,59]
Questinol (92, Figure 9)Gliocladium sp. T31 “ [58]
Engyodontochone A (93, Figure 9)Engyodontium album Antibiotic [60]
Engyodontochone B (94, Figure 10) “ No activity “
Engyodontochone C (95, Figure 10) “ Antibiotic “
Engyodontochone D (96, Figure 10) “ “ “
Engyodontochone E (97, Figure 10) “ “ “
Engyodontochone F (98, Figure 10) “ “ “
Betacolin-like compound (99, Figure 9) “ Antibiotic “
JBIR-99 (100, Figure 10) “ No activity “
1,2,8-Trihydroxyanthraquinone
(101, Figure 10)Nigrospora sp. “ [61]
1,3,8-Trihydroxyanthraquinone
(102, Figure 10)“ Antifungal “
1,3,6-trihydroxy-8-methylanthraquinone
(103, Figure 10)“ “ “
Rheoemodin (104, Figure 10 “ Antimicrobial “
Aloesaponarin II (105, Figure 10) “ Antifungal “
Isozyganein (106, Figure 10) “ Antioxidant “
1-Acetyl-4,5-dihydroxy-anthraquinone
(107, Figure 10)“ No activity
Aspetritone A (108, Figure 10)Aspergillus tritici Strong antibiotic
and cytotoxic activity [63]
Aspetritone B (109, Figure 10) “ No activity “
Bostrocyn (110, Figure 10) “ “ “
Compound 111 (Figure 10) “ “ “
Compound 112 (Figure 10) “ “ “
Compound 113 (Figure 10) “ “ “

Toxins 2020,12, 714 23 of 30
Table 1. Cont.
Anthraquinone Fungus Biological Activity Reference
Compound 114 (Figure 11) “ “ “
1-O-methyl-6-O-(
α
-d-ribofuranosyl)-emodin
(115, Figure 11)Gaeumannomyces sp.
Anti-inflammatory
Reduction of NO
production by LPS-
[64]
1-O-Methylemodin (116, Figure 11)Gaeumannomyces sp.
Phialophora alba
Anti-inflammatory
Reduction of NO
production by LPS
Growth inhibition of
Phellinus tremulae
Inhibition of
the secretion of IL-625
Protein tyrosine
phosphatase 1B
inhibition
[64–68]
5-Chloro-6,8-dihydroxy-1-methoxy-3
-methylanthraquinone (117, Figure 11)Phialophora alba No activity [65]
7-Chloro-6,8-dihydroxy-1-methoxy-3
-methylanthraquinone (118, Figure 11)“ “ “
5-Chloro-6,8,10-trihydroxy-1-methoxy-3
-methyl-9(10H) anthracenone
(119, Figure 11)
“ “ “
5-chloro-8,10-dihydroxy-l,6-dimethoxy-3
-metbyl-9(10H)-anthracenone
(120, Figure 11)
“ “ “
Rubrumol (121, Figure 11)Eurotium rubrum Activity when tested on
Topo I [69]
Rubrocristin (122, Figure 11)
“
Aspergillus
glaucus
No Activity “
2-Methyleurotinone (123, Figure 11)Eurotium rubrum “ “
Conyothyrinone A (124, Figure 11)Eurotium rubrum
Coniothyrium sp. Antifungal activity [69–71]
Erythroglaucin (125, Figure 11)Aspergillus glaucus No activity [70]
Physcion-9-anthrone (126, Figure 11) “ “ “
Viocristin (127 Figure 11) “ Antibacterial activity
Anticancer activity “
Isoviocristin (128, Figure 11) “ Antibacterial activity “
Conyothyrinone B (129, Figure 11)Coniothyrium sp. Antimicrobial activity [71]
Conyothyrinone C (130, Figure 11) “ “ “
Conyothyrinone D (131, Figure 11) “ “ “
1,7-Dihydroxy-3-methyl-9,10-anthraquinone
(132, Figure 11)“
Antimicrobial activity
and strong antibacterial
activity
“
1-Hydroxy-3-hydroxymethyl-9,10
-anthraquinone (133, Figure 11)“ Antimicrobial “
(–)-20R-1-hydroxyisorhodoptilometrin
(134, Figure 11)
Penicillium sp.
OUCMDZ-4736 Anti-hepatitis B virus [72,73]
Methyl 3,4,8-trihydroxy-6-methyl-9-oxo-9H
-xanthene-1-carboxylate. (135, Figure 11)“ No activity [72]
Methyl
6,8-dihydroxy-3-methyl-9-oxo-9H
-xanthene-1-carboxylate (136, Figure 11)
“ “ “
Danthron (137, Figure 11)Paraconiothyrium sp. Antibacterial, antifungal
and anticancer [74]
Bostrycoidin (138, Figure 12)Fusarium solani Antimicrobial
and anticancer [77]
Lentiquinones A (139, Figure 12)Ascochyta lentis Phytotoxic
and antimicrobial [78]

Toxins 2020,12, 714 24 of 30
Table 1. Cont.
Anthraquinone Fungus Biological Activity Reference
Lentiquinones B (140, Figure 12)““ “
Lentiquinones C (141, Figure 12) “ “ “
Lentisone (142, Figure 12) “ “ “
ω-Hydroxypachybasin (143, Figure 12 “ “ “
1,7-Dihydroxy-3-methylanthracene
-9,10-dione (144, Figure 12)“ “ “
Anthraquinone dimer (145, Figure 12)Aspergillus versicolor Selective antibacterial [15]
Anthraquinone dimer (146, Figure 12) “ “ “
10-O-Methylaverantin (147, Figure 12) “ No activity “
Averantin (148, Figure 12)
“
Aspergillus sp. SCSIO
F063
“ “
[80]
(10S)-7-Chloroaverantin (149, Figure 13)Aspergillus sp. SCSIO
F063 “ [80]
(10S)-6-O-Methyl-7-chloroaverantin
(150 Figure 13)“ “
(10S)-10-O-Methyl-7-chloroaverantin
(151, Figure 13)“ “ “
(10S)-6,10-O,O-Dimethyl-7-chloroaverantin
(152, Figure 13)“ “ “
(10S)-7-Chloroaverantin-10-butyl ether
(153, Figure 13)“ “ “
7-Chloroaverythrin (154, Figure 13) “ “ “
6-O-Methyl-7-chloroaverythrin
(155, Figure 13)“ Anticancer “
(10S)-6,10-O,O-Dimethyl-7-bromoaverantin
(156, Figure 13)“ No activity “
and (1
0
S)-6-O-Methyl-7-bromoaverantinone
(157, Figure 13)“ “ “
(10S)-6,10-O,O-Dimethylaverantin
(158, Figure 13)“ “ “
Anthrininone A (159, Figure 13)Alternaria tenuissima
Inhibition activity
against indoleamine
2,3-dioxygenase
and stimulate
intracellular calcium
levels
[81]
Anthrininone B (160, Figure 13) “
Inhibition activity
against indoleamine
2,3-dioxygenase
and against different
protein tyrosine
phosphatases
“
Anthrininone C (161, Figure 13) “ “ “
6-O-Methylalaternin (162, Figure 12 “ “ “
Funiculosone (163, Figure 13)Talaromyces funiculosus Antimicrobial [82]
Mangrovamide J (164 Figure 13) “ “ “
Ravenelin (165, Figure 13) “ “ “
Neoanthraquinone (166, Figure 13)Neofusicoccum luteum Phytotoxic [83]
Alizarin (167, Figure 13)Rubia tinctorum Dye [84]
1This menas that the table cells contain the same concept.

Toxins 2020,12, 714 25 of 30
3. Industrial Application of Anthraquinones
Since 1869 with the determination of the structure of alizarin (
167
, Figure 13, Table 1), a yellow
anthraquinone, the main industrial application of this anthraquinone was its use as a dye in textile
manufacturing [
85
]. Compound
167
was isolated for the first time from Rubia tinctorum [
84
]. Thus, over
a span of 20 years many analogues with different functionalities were also prepared by synthesis to
obtain different dyes such as red, blue, and green mordant. Successively, the first acidic anthraquinone
dye used to color wool without pretreatment with mordants was reported. At the beginning of 1900
the sulfonation and nitration of anthraquinone opened up a new era for anthraquinone based dyes.
A new phase in this development occurred with the introduction of synthetic fibers, such as
polyester, polyamide, and polyacrylonitrile fibers, with the substitution of anthraquinones with other
dyes. The use of acid anthraquinone dyes increased with the discovery of the first fiber-reactive dyes.
At the same time, the utilization of natural substances instead of synthetic ones, increased worldwide.
This satisfy the request of environmentally friendly sustainable technologies. As reported in Section 1
fungi are a significant source of pigments as several genera can produce pigments in good amounts
identified as anthraquinones or analogues. The production of anthraquinones by fungal fermentation
had been developed for rapid and easy growth to produce pigments useful in various industrial
applications [
86
]. The natural anthraquinones, as well as other natural pigments, have noteworthy
less toxic effects than the synthetic dyes and are easily degradable avoiding the high environmental
pollution. Thus, these anthraquinone based dyes are used in medical, textile coloring, food coloring,
and cosmetic industries [84,86].
On this basis also plants have been largely used as a source of natural colored anthraquinones.
In fact, screening of dyeing plants was carried out for their widespread use in previous centuries.
Colorimetric analysis showed that the principal color was yellow-orange shades and could be
attributed to flavonoids while the red colors were due to anthraquinones. Colors from plants that
contain anthocyanins varied from blue-violet through to red. The nature of the support fibers (wool or
cotton) plays an important role in the perceived colors [87].
At the same time several anthraquinone based dyes were synthesized for industrial applications as
nitro derivatives useful also as dye intermediates. The reactions used were nitration methods
for the preparation of 1- and 2-nitroanthraquinones and 1,5-, 1,8-, 1,6-, 1,7-, 1,8-, 2,6-, and
2,7-dinitroanthraquinone. These were also used to obtain their reduced analogues such as
1-amino-anthraquinone and 1,5-diaminoanthraquinones, both useful to produce vat dyes. Other
methods were the preparation of 1-SO
3
H and 1-MeNH derivatives of anthraquinones useful for
manufacturing of dyes for wool, acetate rayon, and polyamide fibers. Another method enables
the preparation of leuco-1,4,5,8-tetrahydroxyanthraquinone useful for synthesis of acid and disperse
dyes [88].
Recently water-repellent, self-cleaning and stain resistant textiles were obtained by developing
anthraquinone reactive dyes which were covalently grafted onto cotton fabric surfaces obtaining bright
colors with good wash-fastness properties and giving rise to breathable superhydrophobic textiles
with self-cleaning properties [89].
The large number of textile dyes required a method for their classification which was based
on the functional groups attached to the typical anthraquinone carbon skeleton. Thus, there are:
anthraquinone, azo, phthalocyanine, sulfur, indigo, nitro, nitroso anthraquinone derivatives etc. taking
into account their chemical structures. Another classification was based on the method of applying
these dyes on an industrial scale, grouped as disperse, direct, acid, reactive, basic, vat dyes etc. [90].
The intensity of research focused on natural compounds has been growing over the past few
decades. Anthraquinones have been most studied in China producing several publications which
report different advanced extraction methods, analytical techniques, and industrial applications. These
publications also describe the most used plants for anthraquinone content as Polygonaceae, Rubiaceae,
and Fabaceae and report the best known anthraquinones: rhein aloe emodin, emodin, physcion,
chrysophanol which are responsible for their numerous biological properties. Furthermore, the use of

Toxins 2020,12, 714 26 of 30
natural anthraquinones for industrial applications, has been described as an alternative to synthetic
dyes to avoid some unwanted side effects [9].
However, the environmental contamination by wastewater containing dyes is today a severe
problem to solve. The application of advanced oxidation processes (AOPs) to industrial wastewater
has increased as well as an integrated approach for their biological and chemical treatment. The toxicity
of the detergents and the dye have been determined in terms of effective concentration EC
50
using
mixed cultures of activated sludge as well as a pure culture of luminescent bacteria Vibrio fischeri
NRRLB-11177. However, the dye was not degraded without AOP pretreatment, therefore the degree of
its removal (decolorization) by the AOPs is an important preliminary stage of bio-sorption on activated
sludge [91].
4. Conclusions
The sources, structures, and the biological activities of fungal bioactive anthraquinones were
reported starting from 1966 to the present day. In the introduction the previous review published on
this topic was also cited which did not however treat the topic extensively. The anthraquinones were
chronologically described and in some cases their isolation and biological activity was investigated in
depth. Furthermore, their industrial application in different fields, essentially as natural dyes, was
also reported focusing on the comparison between natural and synthetic anthraquinone based dyes,
their chemical derivatization and classification, and the advanced methods used in the treatment of
the relative industrial wastewaters to avoid severe negative environmental pollution.
Author Contributions:
The authors equally contributed to this work. All authors have read and agreed to
the published version of the manuscript.
Funding: This research received no external funding.
Acknowledgments: A.E. is associate to the Istituto di Chimica Biomolecolare, CNR, Pozzuoli, Italy.
Conflicts of Interest: The authors declare no conflict of interest.
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