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Pigments of fungi (macromycetes)
Zhong-Yu Zhou and Ji-Kai Liu*
Received 12th April 2010
DOI: 10.1039/c004593d
Covering: June 2003 to December 2009. Previous review: Nat. Prod. Rep., 2003, 20, 615
This review surveys the chemical, biological and mycological literature dealing with the isolation,
structure elucidation, biological activities, and synthesis of pigments manufactured by those fungi that
produce conspicuous fruiting bodies (macromycetes).
1 Introduction
2 Compounds from the shikimate–chorismate pathway
2.1 Compounds derived from arylpyruvic acids
2.1.1 Terphenylquinones
2.1.2 Pulvinic acids and related butenolides
2.2 Compounds derived from phenylalanine and tyrosine
2.3 Compounds derived from cinnamic acids
2.4 Compounds derived from 4-hydroxybenzoic acid
3 Pigments from the acetate–malonate pathway
3.1 Pentaketides
3.2 Hexaketides
3.3 Heptaketides
3.4 Octaketides
3.4.1 Anthraquinones and anthraquinone carboxylic acids
3.4.2 Coupled pre-anthraquinones
3.4.3 Pyranonaphthoquinones
3.5 Other polyketides and compounds of fatty acid origin
4 Compounds from the mevalonate pathway
5 Pigments containing nitrogen
5.1 Nitrogen heterocycles
5.1.1 Indoles
5.1.2 Quinolines
5.2 Compounds derived from anthranilic acid
5.3 Polyenes with tetramic acid or amino acid end groups
5.4 Other pigments containing nitrogen
6 Acknowledgements
7 References
1 Introduction
This review, like its predecessors,
1–5
surveys the chemical, bio-
logical and mycological literature dealing with the isolation,
structure elucidation, biological activities, and synthesis of
pigments manufactured by those fungi that produce conspicuous
fruiting bodies (macromycetes). Also included, as before, are
some pigments from slime moulds (myxomycetes) and, in certain
circumstances, pigments produced by fungi grown in mycelial
culture and some colourless metabolites where they are signifi-
cant. This review covers the literature from June 2003 to
State Key Laboratory of Phytochemistry and Plant Resources in West
China, Kunming Institute of Botany, Chinese Academy of Sciences,
Kunming, 650204, China. E-mail: jkliu@mail.kib.ac.cn; Fax: +86-871-
5150227; Tel: +86-871-5216327
Zhong-Yu Zhou
Zhong-Yu Zhou was born in
Hunan province, P. R. China, in
1982, and has carried out post-
graduate and doctoral research
at Kunming Institute of Botany,
Chinese Academy of Sciences,
since 2005, under the supervision
of Professor Ji-Kai Liu. She is
currently studying the isolation,
structure elucidation, bioactiv-
ities and chemical modification
of natural products.
Ji-Kai Liu
Ji-Kai Liu has been a professor
at Kunming Institute of Botany
since 1997. He acquired his
Ph.D. degree at Lanzhou
University in 1988. From 1993
to 1994 he worked as a research
fellow of Alexander von Hum-
boldt at the University of the
Saarland in Germany. Then he
worked as a research scientist at
the Pharma Research Center of
Bayer AG in Germany. His field
of interest concerns natural
bioactive compounds from
higher fungi. He has published
over 180 peer-reviewed articles
in international journals. He is the author of the book Myco-
chemistry and also one of the inventers for ten patents.
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December 2009, and compounds are grouped according to their
perceived biosynthesis.
2 Compounds from the shikimate–chorismate
pathway
2.1 Compounds derived from arylpyruvic acids
2.1.1 Terphenylquinones. Terphenyls are aromatic hydro-
carbons consisting of a chain of three benzene rings. There
are three isomers in which the terminal rings are o-, m-, or
p-substituents of the central ring. Most of the natural
terphenyls are p-terphenyl derivatives. Very few m-terphenyl
derivatives occur naturally, and o-terphenyls have not been
found in Nature. p-Terphenyl compounds, which have so far
only been present in lichens and fungi, are a large class of
fungal pigments. The isolation, structure elucidation, biolog-
ical activities, transformation, and total synthesis of terphenyl
derivatives from natural sources since 1877 has been exten-
sively reviewed.
6
The isolation of polyporic acid 1,
7,8
atromentin 2,
9
and thele-
phoric acid 3
10
early in the 1870s marked the start of the chemical
investigation of fungal pigments. Atromentin 2is the central
terphenylquinone intermediate for a prominent and widely
Scheme 1 Atromentin biosynthesis. L-Tyrosine is deaminated to 4-hydroxyphenylpyruvic acid by the PLP-dependent transaminase AtrD, which
transfers the amino group onto 2-oxoglutaric acid (2-OG). Condensation of two molecules of 4-hydroxyphenylpyruvic acid to atromentin is catalyzed by
the quinone synthetase AtrA.
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occurring class of basidiomycete pigments. Biochemical charac-
terization of a multi-domain biosynthetic enzyme for basidio-
mycete secondary metabolism – namely the tri-domain enzyme
atromentin synthetase AtrA from Tapinella panuoides, which
adenylates and dimerizes 4-hydroxyphenylpyruvic acid
into atromentin 2(Scheme 1) – has been reported. Also, the
L-tyrosine:2-oxoglutarate aminotransferase AtrD, which
provides the substrate for this dimerization step (Scheme 1), has
been characterized. The genes atrA and atrD were cloned and
found to be clustered within one genetic locus.
11
Sarcodonins a4,b5, and g6, episarcodonin 7, and epis-
arcodonins a8and b9have been isolated from the EtOAc
Scheme 3 Reagents and conditions:i,Na
2
S
2
O
4
, EtOAc–aq. MeOH, rt; ii, n-BuLi, 69, THF, from 78 to 0 C; iii, lead tetraacetate, benzene, 80 C; iv,
10% HCl–MeOH, CH
2
Cl
2
, rt; v, H
2
, Pd(OH)
2
, THF–MeOH, rt (81%).
Scheme 2 Reagents and conditions:i,Na
2
S
2
O
4
, aq. EtOAc, rt; ii, MOMCl, NaH, DMF, 0 C (80%); iii, 68 (2.3 mol equiv), Pd(OAc)
2
(0.05 mol equiv),
Ph
3
P (0.15 mol equiv), Na
2
CO
3
, aq. 1-propanol, 100 C, 4 h; iv, HCl, CH
2
Cl
2
–MeOH, rt; v, O
2
, DMF, rt (90%); vi, BnBr, K
2
CO
3
,n-Bu
4
NI, DMF, 80 C
(72%); vii, Na
2
S
2
O
4
, EtOAc–aq. MeOH, rt; viii, n-BuLi, 69, THF, from 78 to 0 C; ix, H
2
, Pd(OH)
2
, THF–MeOH, rt (86%).
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extract of the fruiting bodies of Sarcodon leucopus.
12
From the
EtOH extract of the fruiting bodies of the same fungus, a mixture
of two violet pigments, sarcoviolin a10 and episarcoviolin a11,
were obtained.
12
Sarcodonins a4and g6, episarcodonin 7,
a mixture of 10 and 11 (sarcoviolins), and sarcodonin 12 were
found to be cytotoxic at a concentration of 5 10
5
M against
NCI-H460 (lung), MCF7 (breast), and SF-268 (CNS) cells. In
particular, 6,7and 12 showed the highest cytotoxicity towards
SF-268 cells, with 93, 95 and 96% of cells killed, respectively.
Sarcoviolins significantly reduced the growth of all cell lines at
10
4
M (MCF7 totally blocked). A mixture of sarcodonins was
tested for anti-HIV activity and showed EC
50
5mgml
1
(the
concentration at which the viral antigen p24 or progeny virus in
infected cell cultures is reduced by 50%).
12
Episarcodonin 7, episarcodonin a8, and episarcodonin b9were
characterized as the N-oxide epimers of 4,5, and 12, respectively,
by a molecular mechanics study, carried out using the molecular
dynamics methodology and assuming the obtained energy
minima as the preferred conformations in solution. Examination
of stereomodels of 4and 8showed that an intramolecular
hydrogen bond between the hydroxyl proton and the oxygen atom
of the N-oxide function (OH/ON) played an important role in
the N-epimerisation of 4to 8. A possible mechanism to explain the
role of the bridge proton in the N-epimerisation of 4to 8resembles
the Cope b-elimination of N-oxides, followed by a stereoselective
retro-Cope of the unstable intermediate, to give the isomer 8as the
final stable product.
12
Sarcodonin d13 and two known p-terphenyl metabolites 14
and 15 were isolated from the fruiting bodies of Sarcodon
scabrosus.
13
Sarcodan 16 and three known terphenyls co-occur
in the Chinese mushroom S. laevigatum.
14
Hydnellins A 17 and
B18, and sarcodonin d13 have been found in methanol
extracts of the fruiting bodies of the inedible mushroom Hyd-
nellum suaveolens.
15
Sarcodonin d13 was also found in
H. geogerirum.
The p-terphenyl derivatives named curtisians A–V 19–40,
known to be free-radical scavengers, together with previously
reported kynapcin-12 41, were found in the methanolic extract of
fruiting bodies of Paxillus curtisii.
16–20
Curtisians A–D 19–22
were first described by Yoo from Korean P. curtisii early in
2000,
20
of which the structure of 21 was only partially deter-
mined, since the location of four substituents on the p-terphenyl
was unclear. Nonetheless, Gill had not covered these curtisians in
the previous review of this area.
1
To determine the absolute
configuration of curtisians E–H 23–26, a mixture of curtisians
E–H was saponified with potassium hydroxide in methanol,
followed by methylation and acetylation to afford 3-acetoxy-n-
butyric acid methyl ester.
17
It was analyzed by GC–MS on
a chiral column with authentic samples (each 3R- and 3S-ace-
toxy-n-butyric acid methyl ester) derived from 3R- and
3S-hydroxy-n-butyric acid to give the chromatograms. Conse-
quently, the absolute configuration at C3a,3b of the side-chain of
curtisians E–H was established to be S.
17
The Thelephoraceae family has been shown to be a rich
source of p-terphenyl compounds. Thelephantins D–H 42–46
from the inedible mushroom Thelephora aurantiotincta,
21
the-
lephantins I–N 47–52 from the inedible mushroom Hydnellum
caeruleum,
22
terrestrins A–G 53–59 from the inedible mushroom
Thelephora terrestris,
23
vialinins A 53 (same as terrestrin A)
24
and B 60 from an edible mushroom T. vialis,
25,26
and aur-
antiotinin A 61 from T. aurantiotincta,
27
along with related
known compounds, have been reported. The structure of ter-
restrin A 53 was confirmed by X-ray crystallographic analysis.
Vialinins A 53 and B 60 strongly inhibited tumour necrosis
factor (TNF-a) production in rat basophilic leukemia (RBL-
2H3) cells (IC
50
values of 0.09 nM and 0.02 nM, respec-
tively).
25,28
p-Terphenyls are attractive for their antioxidant
activities. Therefore, 2,2-diphenyl-1-picryhydrazyl (DPPH)
radical scavenging activities of ten natural p-terphenyl deriva-
tives from three edible mushrooms (Thelephora ganbajun,
T. aurantiotincta and Boletopsis grisea) indigenous to China
were investigated and compared with BHA and a-tocopherol.
29
Vialinin A 53 showed strong DPPH free-radical-scavenging
activity (EC
50
14.0 mM), almost equal to that of butylated
hydroxytoluene (BHT, EC
50
value of 10.0 mM). The proposed
DPPH radical-scavenging mechanism of vialinin A was also
reported from its conversion into product 62 during the DPPH
radical-scavenging reaction.
26
Thelephantin G, whose structure was revised from 45 to 63 by
total synthesis (Schemes 2 and 3), strongly inhibited TNF-
aproduction in RBL-2H3 cells (IC
50
value of 3.5 mM), while
a mixture of 45 and its regioisomer 64 showed no such
activity.
30
The key steps of total synthesis of thelephantin G
involved a double Suzuki–Miyaura coupling and an esterifica-
tion reaction. By a similar strategy, the synthesis of ganbajunins
D65 and E 66 was also accomplished (Scheme 4).
30
The total
Scheme 4 Reagents and conditions:i,Na
2
S
2
O
4
, aq. EtOAc, rt; ii, n-BuLi, PhCH
2
COCl, THF, from 78 to 0 C (73%); iii, H
2
, Pd(OH)
2
, EtOAc–
CH
2
Cl
2
, rt (80%) (see Scheme 2 for earlier steps).
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synthesis of vialinin A 53 was achieved from sesamol in 11 steps
with 28% overall yield.
31
The key reactions included a double
Suzuki coupling of an electron-rich aryl triflate with phenyl-
boronic acid and an oxidative deprotection of bis-MOM ether
(Scheme 5).
31
In addition, the proposed structure of ganbajunin
C67 was also synthesized by a similar strategy (Scheme 6).
However, the spectral data of synthetic 67 were not in accor-
dance with those of reported ganbajunin C, which suggested the
need to reinvestigate the structure of natural ganbajunin C.
31
The same research group also reported the total synthesis of
vialinin B 60 in 11 steps with 18% overall yield from a known
sesamol derivative (Scheme 7).
32
Kehokorins A–C 75–77 are yellow pigments occurring in field-
collected fruiting bodies of the myxomycete Trichia favoginea
var. persimilis.
34
Kehokorins D 78 and E 79 have been isolated
from field-collected fruiting bodies of T. favoginea.
35
Kehokorin
Aisaa-L-rhamnopyranoside of kehokorin B, and kehokorins A,
D and E showed cytotoxic activity against HeLa cells with IC
50
values of 1.5, 6.1 and 4.5 mgml
1
, respectively.
34,35
Induction of cellular phase 2 detoxifying enzymes is associated
with cancer preventive potential, while quinone reductase (QR)
has been used as a prototype for anticarcinogenic phase
2 enzymes. Polyozellin 82 from Polyozellus multiplex was found to
induce phase 2 enzymes in mouse hepatoma cells and differenti-
ation in HL-60 human promyelocytic leukemia cells. In contrast,
thelephoric acid 3, which was isolated from the same mushroom
and is similar to polyozellin in its chemical structure except for the
absence of two acetyl groups, was not effective in QR induction,
Scheme 5 Reagents and conditions: i, see ref. 33 (65%); ii, NaH, MOMBr, DMF, 0 C (87%); iii, n-BuLi, THF, 0 C, and then (i-PrO)
3
B, 0 C followed
by addition of H
2
O
2
, AcOH, 0 C to rt (87%); iv, Tf
2
O, pyridine, 0 C (89%); v, 4-(tert-butyldimethylsilyloxy)phenylboronic acid, (Ph
3
P)
4
Pd, K
3
PO
4
,
KBr, dioxane, 100 C (96%); vi, DDQ, p-TsOH, benzene, 80 C (95%); vii, 10% HCl–MeOH, CH
2
Cl
2
, rt (95%); viii, Na
2
S
2
O
4
, EtOAc, aq. MeOH, rt; ix,
PhCH
2
COCl, n-BuLi, THF, from 78 to 0 C (86%); ix, 10% HCl–MeOH, CH
2
Cl
2
, rt (95%); x, Pb(OAc)
4
, benzene, 80 C (90%); xi, 10% HCl–MeOH,
CH
2
Cl
2
, rt (92%).
Scheme 6 Reagents and conditions: i, NaS
2
O
4
, aq. EtOAc, rt; ii, BOMBr, NaH, DMF, 0 C (92%); iii, 4-(tert-butyldimethylsilyloxy)phenylboronic acid,
Pd(OAc)
2
,Ph
3
P, Na
2
CO
3
, aq. Propanol, 100 C (83%); iv, PhCH
2
COCl, n-BuLi, THF, 0 C (79%); v, Pd(OH)
2
,H
2
, EtOAc, methanol, rt (82%).
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suggesting a crucial role of the acetyl groups attached to the
benzofuran dimer in the activation of phase 2 enzyme expres-
sion.
36
It was also reported that polyozellin inhibited nitric oxide
production by down-regulating lipopolysaccharide (LPS)-
induced activity of NF-kB and stress-activated protein kinase
(SAPK)/c-Jun N-terminal kinase (JNK) in RAW 264.7 cells.
37
The neuroprotective mechanism of p-terphenyl leucomentins
from the mushroom Paxillus panuoides was reported.
38
Leucomentins showed potent inhibition of lipid peroxidation and
H
2
O
2
neurotoxicity, but were free from any role as reactive oxygen
species (ROS) scavengers. Iron-mediated oxidative damag e has been
implicated in these processes, as a provider of ROS via iron. Leu-
comentins could chelate iron when DNA was present with iron and
H
2
O
2
, and so inhibited DNA single-strand breakage. These results
suggest that the neuroprotective action of leucomentins is dependent
on their ability to chelate iron.
38
Also, p-terphenyl curtisians from
the mushroom Paxillus curtisii protected cultured neuronal cells
against glutamate neurotoxicity via iron chelation.
39
2.1.2 Pulvinic acids and related butenolides. Pulverolide 90
and pulveraven A 91 were found in the acetone extracts of the
Scheme 7 Reagents and conditions: i, NaH, MOMBr, DMF, 0 C (90%); ii, 83, Pd(OAc)
2
,K
3
PO
4
,Ph
3
P, aq. THF, 65 C (78%); iii, 84, Pd(OAc)
2
,
K
3
PO
4
,85, aq. THF, 65 C (91%); iv, mCPBA, KF, CH
2
Cl
2
,0C (78%); v, Cu
2
O, pyridine, 110 C (88%); vi, HCl, CH
2
Cl
2
, MeOH, rt, quant; vii, Z-Cl,
pyridine, CH
2
Cl
2
,0C (89%); viii, Pb(OAc)
4
, benzene, 80 C (73%); ix, aq. AcOH, 60 C; x, LHMDS, THF, 78 C, then PhCH
2
COCl, 0 C (71%); xi,
H
2
, Pd(OH)
2
, EtOAc, rt (89%).
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fresh fruiting bodies of Pulveroboletus ravenelii.
40
The structure
of pulverolide has now been corrected to 92 by total synthesis.
41
A possible biosynthetic pathway of pulverolide from vulpinic
acid 93 was proposed, as shown in Scheme 8.
Two major pigments, norbadione A 94 and sclerocitrin 95,
have been isolated from Scleroderma citrinum (Common Earth-
ball), while small amounts of badione A 96 and xerocomic acid
97 could be detected by HLPC.
42
In the same paper, compounds
94,95,97 and chalcitrin 98 were also reported from Chalciporus
piperatus (Peppery Bolete). The biosynthesis of chalcitrin 98
from the oxidation of xerocomic acid 97 was shown in
Scheme 9.
42
Norbadione A was shown to display important
antioxidant properties,
43,44
and its total synthesis has been per-
formed.
45
The key steps were a Diels–Alder cycloaddition
employed in the preparation of an appropriately substituted
naphtholactone intermediate and a double Suzuki–Miyaura
coupling, allowing the completion of the carbon framework of
norbadione A 94 (Scheme 10).
45
Methyl-30,50-dichloro-4,40-di-O-methylatromentate 100 has
been reported from the fruiting bodies of Scleroderma sp. The
structure of 100 was elucidated by spectroscopic methods and
X-ray analysis, and 100 displayed moderate antimicrobial
activity against Bacillus subtilis.
46
Four phenolic pigments,
(3,4-dihydroxyphenyl)-2-(4-hydroxyphenyl)-2-(2-pyrrolidon-5-yl)-
4-cyclopentene-1,3-dione 101,(4Z)-5-hydroxy-2-(3,4-dihydroxy-
phenyl)-5-(4-hydroxyphenyl)-2,4-pentadien-4-olide 102,
involutone 103, and involutin 104, have been isolated from the
fruiting bodies of Paxillus involutus.
47,48
Xerocomic acid 97, atromentic acid 105, and variegatic acid
106 were isolated from the fruiting bodies of Suillus bovinus.
49
Compounds 97 and 106 have also been found in the fruiting
bodies of Boletus calopus.
49
These compounds showed cyto-
chrome P450 (CYP) inhibitory effects with ferrylheme-reducing
properties.
49
Cultures and fruiting bodies of S. bovinus also
produce methyl bovinate 107, which contains an extra carbonyl
group that bridges ring A of methyl variegatate with the hydroxy
group at the central butenolide ring. This unprecedented struc-
ture was deduced from the spectroscopic data and confirmed by
total synthesis from bromoacetal 108 in 7 steps with 11% overall
yield (Scheme 11).
50
Scheme 8 Possible biosynthetic pathway of pulverolide 90 from vulpinic acid 93.
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Isoravenelone 109, ravenelone 110, and a large amount of
vulpinic acid 93, are butenolides isolated from a methanolicextract
of the Japanese fungus Pulveroboletus ravenelii (Boletales).
51
Pulvinic acid and related derivatives containing a g-alkylide-
nebutenolide ring system are yellow pigments that are common
in fungi and lichens, and have attracted a great deal of interest
among synthetic organic chemists due to their diverse bioactiv-
ities and drug-like structure. Numerous robust and straightfor-
ward syntheses of pulvinic acid and its derivatives have been
accomplished.
52–58
Various isomerically pure (Z)-pulvinones 111
have been synthesized in 75–91% yield by tandem Claisen
condensation–transesterification between arylacetate enolates
and arylmethylene-substituted 2,2-dimethyl-1,3-dioxolan-4-
ones.
59
In addition, structure–activity relationships between
monoaromatic derivatives of pulvinic acid and antioxidant
properties were studied for the first time.
60
2.2 Compounds derived from phenylalanine and tyrosine
()-Xylariamide A 112, isolated from a culture of Xylaria sp.,
had its absolute stereochemistry determined by the total
synthesis of its enantiomer, (+)-xylariamide A 113 (Scheme 12).
61
Later, the synthesis of ()-xylariamide A was also achieved by
a similar methodology (Scheme 13).
62
(–)-Xylariamide A dis-
played some toxicity in a brine shrimp lethality assay.
61
2.3 Compounds derived from cinnamic acids
Orirubenones A–G 114–120 have been isolated from the mush-
room Tricholoma orirubens.
63,64
Compounds 114–116 exhibited
hyaluronan-degradation inhibitory activity, with IC
50
values of 15,
21 and 57 mM, respectively,while 117–120 showed no such activity.
These results suggest that the catechol moiety in orirubenones is
indispensable for hyaluronan-degradation inhibitory activity.
63,64
Bioassay-guided isolation of the fruiting bodies of the mushroom
Pholiota squarrosa and the mycelium of Phellinus pini have led to
two fungal phenylpropanoid-derived polyketides, squarrosidine
121 and pinillidine 122, with an unprecedented 3,30-fused bis-
(styrylpyrones) structure and potent xanthine oxidase (XO)
inhibitory activities.
65
The biosynthesis of 121 was rationalized by
the nucleophilic vinylogous addition of 124 to an oxidation
product of a methylated bisnoryangonin derivative. In the
formation of 122, the additional methyl group could be derived from
subsequent methylation of the methylene bridge, whereas an ethyl
substituent at the pyrone ring would be less likely (Scheme 14).
65
Phelligridins A–J 125–134 and phelligridimer A 135 were new
pigments reported by the same group from the Chinese medicinal
fungus Phellinus igniarius.
66–70
Other related compounds from
this fungus included davallialactone 136, inoscavin A 137, his-
polon 138, and (E)-4-(3,4-dihydroxyphenyl)but-3-en-2-one
139.
66–70
Phelligridins show diverse bioactivities – phelligridins D
128,E129,G131, and J 134 exhibit in vitro cytotoxic activity
against several human cancer cell lines,
66,68,69
while phelligridins
Scheme 9 Proposed biosynthesis of chalcitrin 98 from the oxidation of xerocomic acid 97.
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Scheme 10 Reagents and conditions: i, toluene, reflux, 15 h; ii, conc. HCl, EtOH, reflux, 5 h (67%); iii, BnOLi, THF, 40 C to rt (77%); iv, Na
2
S
2
O
4
, rt,
15 min; v, p-TsOH, toluene, acetone, reflux, 22 h (57%); vi, Tf
2
O, pyridine, CH
2
Cl
2
,40 C to rt, 3 h, quant.; vii, bis(pinacolato)diboron, Pd(OAc)
2
,2-
(dicyclohexylphosphino)biphenyl, i-Pr
2
NEt, dioxane, 4 h, rt (59%); viii, pyrrolidine, THF, rt, 15 min; ix, 99, PdCl
2
(PPh
3
)
2
, THF, 2 M Na
2
CO
3
, reflux,
3.5 h (58%); x, AcOH, reflux, 2 h (74%); xi, Me
3
SiI (15 equiv), CDCl
3
,55C, 11 days (28%).
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G–I 131–133 and phelligridimer A 135 showed antioxidant
activity, inhibiting rat liver microsomal lipid peroxidation with
IC
50
values of 3.9, 4.8, 3.7 and 10.2 mM, respectively.
68,69
Phel-
ligridins H 132 and I 133 inhibited protein tyrosine phosphatase
1B (PTP1B) (IC
50
values of 3.1 and 3.0 mM, respectively).
69
Hispidin 140 in mushrooms is known to be biosynthesized by
two different mechanisms: (i) the condensation of 4-hydroxy-
6-methyl-2-pyrone which is formed by the reaction of three
molecules of acetyl-SCoA and one molecule of 3,4-
dihydroxybenzoyl-SCoA (or 3,4-dihydroxybenzaldehyde)
(Scheme 15),
66,71
(ii) from phenylalanine via a cinnamyl deriva-
tive that is combined with either acetate or malonate through
the polyketide pathway (Scheme 16).
71,72
The co-occurrence
of hispolon 138, hispidin 140, 3,4-dihydroxybenzoic acid, 3,4-
dihydroxybenzaldehyde, and 4-hydroxybenzaldehyde in
P. igniarius led to the postulated biosynthetic formation of
phelligridins A and C–J (Schemes 17–20 and 24)
66,68,69
and
phelligridimer A (Scheme 21).
70
Scheme 11 Reagents and conditions: i, BuLi, THF, 78 C; ii, ClCO
2
Menthyl (70%); iii, acetone, cat. HCl (98%); iv, pyrandione, AcOH, NH
4
OAc
(69%); v, MeONa, MeOH (47%); vi, Ac
2
O, DMSO (82%); vii, 2% KOH, MeOH, separation on a SiO
2
column (>99%); viii, BBr
3
(69%).
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Scheme 14 Biosynthetic model for the formation of bis(styrylpyrones) 121 and 122.
Scheme 13 Reagents and conditions:i,D-tyrosine, BSA, DMF, 60 C, 16
h (54%); ii, Oxone, KCl, CH
3
CN–H
2
O, rt, 72 h (78%).
Scheme 12 Reagents and conditions: i, 3-chloro-L-tyrosine, BSA, DMF,
55 C, 24 h.
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Scheme 15 One mechanism for the biosynthesis of hispidin 140.
Scheme 16 An alternative mechanism for the biosynthesis of hispidin 140.
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Twelve new hispidin derivative pigments, methylinoscavins A–
D141–144,
73–75
inoscavins B–E 145–148,
73–76
methyl-
davallialactone 149,
75
and interfungins A–C 150–152,
71
together
with known phelligridins D 128 and F 130, davallialactone 136,
and inoscavin A 137, have been isolated from the fruiting bodies
of Inonotus xeranticus.
71,73–76
The mycelial culture of the same
species provided hispidin 140, 3,14-bihispidinyl 153,
hypholomine B 154, and 1,1-distyrylpyrylethane 155.
77
This class
of compounds showed free-radical scavenging activity against
the superoxide radical cation, the ABTS radical anion, and the
DPPH radical. Compounds 128,144,147,150, and 151 might be
biosynthesized by the oxidative coupling of 140 and 156,140 and
157,140 and 156,138 and 140, and 139 and 140, respectively.
71,73
Phelligridin F 130, davallialactone 136 and inoscavin A 137 may
Scheme 17 Proposed biosynthesis of phelligridins D 128,E129 and G 131 (see Scheme 15 for earlier steps).
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be derived from 150, and inoscavins B 145 and C 146 may be
biosynthesized from 151.
71
All the condensation processes
proposed are shown in Schemes 22–25.
Chemical investigation of the medicinal mushroom Inonotus
obliquus has led to the isolation of inonoblins A 133 (same as
phelligridin I),
24
B158 and C 159 and known phelligridins D 128,
E129 and G 131.
78
Compounds 128,129,131,133,158 and 159
exhibited scavenging activities against the ABTS radical cation
and DPPH radical, and showed moderate superoxide radical
anion scavenging activity.
78
Meshimakobnols A 128 (same as
Scheme 18 Proposed biosynthesis of phelligridins A 125,C127,D128 and J 134.
Scheme 19 Proposed biosynthesis of phelligridin H 132 (see Scheme 18 for earlier steps).
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Scheme 20 Proposed biosynthesis of phelligridin I 133 (see Scheme 18 for earlier steps).
Scheme 21 Proposed biosynthesis of phelligridimer A 135 from hispidin.
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Scheme 22 Proposed biosynthesis of phelligridin D 128.
Scheme 23 Proposed biosynthesis of methylinoscavin D 144 and inoscavins D 147.
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phelligridin D)
24
and B 127 (same as phelligridin C),
24,79
phelli-
gridin G 131, and phellifuropyranone A 148 (same as inoscavin
E)
24,80
have been identified from fruiting bodies of Japanese wild
Phellinus linteus (‘meshimakobu’ in Japanese). Meshimakobnols
A128 and B 127, and phellifuropyranone A 148 exhibited an
antiproliferative effect against mouse melanoma cells and human
lung cancer cells in vitro.
79,80
Another research group in Korea
have isolated phelligridimer A 135, davallialactone 136, inosca-
vin A 137, hispidin 140, methyldavallialactone 149, interfungins
A150, hypholomine B 154, and ellagic acid 160 from the fruiting
bodies of P. linteus. Among them, 136,154 and 160 exhibited
potent rat lens aldose reductase and human recombinant aldose
reductase inhibitory activity, with IC
50
values of 0.33, 0.82 & 0.63
mM and 0.56, 1.28 & 1.37 mM, respectively.
81
Phellinins A
1
161
and A
2
162, hispidin 140 and 1,1-distyrylpyrylethane 155 have
been found in the cultured broth of Phellinus sp. KACC93057P.
82
These compounds significantly scavenged free-radicals such as
1,1-diphenyl-2-picrylhydrazyl, 2,20-azinobis-(3-ethylbenzothia-
zoline-6-sulfonic acid) and superoxide.
2.4 Compounds derived from 4-hydroxybenzoic acid
Three new grifolin derivatives 163–165, and four known phenolic
compounds 166–169 have been afforded from MeOH extract of
the Korean wild mushroom Boletus pseudocalopus. The
structures of 163–169 were elucidated as 4-(1-methoxyethyl)-5-
methyl-2-[(2E,6E)-3,7,11-trimethyldodec-2,6,10-trienyl]benzene-
1,3-diol, 4-(1-ethoxyethyl)-5-methyl-2-[(2E,6E)-3,7,11-trimethyldo-
dec-2,6,10-trienyl]benzene-1,3-diol, 3,4-dihydro-4,5-diemethyl-
8-[(2E,6E)-3,7,11-trimethyldodec-2,6,10-trienyl]-2H-[1]benzopyran-
2,7-diol, grifolin, neogrifolin, 2-(4,8-dimethylnona-3,7-dienyl)-
3,4-dihydro-2,7-dimethyl-2H-[1]benzopyran-3,5-diol, and 2-
((2E,6E)-4,8-dimethylnona-3,7-dienyl)-2,7-dimethyl-2H-[1]ben-
zopyran-5-ol, respectively.
83
In the original paper, all compounds
163–169 were described as coloured substances. However, their
colour might not be inherent, but instead be due to impurities.
A variety of dimeric meroterpenoid pigments have been
reported from Albatrellus species, which included (i) a purple
pigment, named grifolinone B 170, from the methanolic extract
of the inedible mushroom A. caeruleoporus,
84
(ii) grifolinone B
170, albatrellin 171 and 16-hydroxyalbatrellin 172 from fruiting
bodies of A. flettii,
85
(iii) grifolinone B 170, albatrellin 171, and
grifolinone C 173 from the fruiting bodies of the basidiomycete
A. confluens.
86
Grifolinone B displayed inhibitory activity against
lipopolysaccharide (LPS)-induced production of nitric oxide
(NO) in RAW 264.7 cells with an IC
50
value of 22.9 mM.
84
Albatrellin 171 exhibited cytotoxic activity against HepG2
human lung carcinoma cells with IC
50
value of 1.55 mgml
1
(the positive controls were DDP, which had an IC
50
value of
0.28 mgml
1
, and 173, which had no activity under the same
conditions).
86
The structure of albatrellin 171 suggests its formation from
two components, one derived from grifolin 166 and the other
from cristatic acid 174. Albatrellin 171 and its analogues 175–178
were synthesized by a biomimetic route in vitro. Coupling of 179
Scheme 24 Proposed biosynthesis of phelligridin F 130, davallialactone 136, inoscavin A 137 and interfungin A 150.
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Scheme 25 Proposed biosynthesis of inoscavins B 145 and C 146, and interfungin B 151.
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and 180 in dichloromethane gave 171, which could be isolated in
30% yield (Scheme 26).
85
Compound 175 was very unstable and
underwent easy decarboxylation to albatrellin, even when kept in
the refrigerator. All biomimetically synthesized products,
including the simplest derivative 178, were blue and displayed
UV spectra similar to those of the albatrellins. On the basis of
this observation, Steglich suggested that the colour originated
from electronic interactions between the benzoquinone and the
conjugated furan chromophore rather than from a charge
transfer interaction of the quinone with the remote resorcinol
group.
87
Tridentoquinone 181, the main pigment of Suillus tridentinus,
was accompanied by its dimer tridentorubin 182 and deoxy-
tridentoquinone 183. The absolute configuration of 181 was
established as 140Rby a single-crystal X-ray diffraction analysis of
the corresponding ()-camphanoate. The structure of 182 was
elucidated by 2D NMR techniques including an INADEQUATE
experiment.
88
The biosynthesis of 181 and 182 has been studied by
feeding experiments of 4-hydroxy-[1-
13
C]benzoic acid 184 or 3,4-
dihydroxy-[1-
13
C]benzoic acid 185 to the fruiting bodies of Suillus
tridentinus.
88
Tridentoquinone 181 was monolabeled at C-1,
suggesting the formation of the ansa ring by oxidative cyclisation
of 2-geranylgeranyl-6-hydroxy-1,4-benzoquinone 186 (Scheme
27), which was confirmed by the isolation of the expected inter-
mediate 183 from the same mushroom. Tridentorubin 182 may be
biosynthesized by addition of precursor 186 to tridentoquinone
181 (Scheme 27). This hypothesis is supported by the in vitro
synthesis of an analogous compound (187) from 181 and 1,4-
benzoquinone 188 (Scheme 28).
88
The biosynthesis of suillin 189,
boviquinone-4 190 and bovilactone-4,4 191 was also studied by
feeding experiments of 184 or 185 to the fruiting bodies of
S. suillus and S. tridentinus. Unlike 181 and 182, the biosynthesis
of which starts with geranylgeranylation of 3,4-dihydroxybenzoic
acid 185 at C-5, the initial step in the biosynthesis of suillin 189,
boviquinone-4 190 and bovilactone-4,4 191 in Suillus species is
the geranylgeranylation of 3,4-dihydroxybenzoic acid at the 2-
position. Feeding experiments with advanced precursors have
identified 190 and deacetylsuillin 192 as building blocks for the
dilactone and catechol moieties of 191, respectively. The results of
the feeding experiments are depicted in Scheme 29.
89
A major pigment, rhizopogone 193, and a minor pigment,
2-acetoxyrhizopogone 194, were identified from the fruiting
bodies of the basidiomycete Rhizopogon pumilionus.
90
The
absolute configuration of 193 was determined as 130Sby
comparison of its CD spectrum with that of secotridentoquinone
195. The structure of 193 suggests a similar biosynthetic pathway
to that for tridentoquinone 181, originating from 2-geranylger-
anyl-6-hydroxy-1,4-benzoquinone 186 (Scheme 30).
90
Ochroleucin A
1
196 and ochroleucin B 197 were isolated from
the fruiting bodies of Russula ochroleuca.
91
Yellow ochroleucin
A
1
196 is very labile and rearranges rapidly into a stable red
isomer, ochroleucin A
2
198, which is responsible for the red
colour produced when the stalk base of R. ochroleuca is treated
with aqueous KOH. The absolute configurations of 196 and 197
Scheme 26 Reagents and conditions: i, NO(SO
3
K)
2
; ii, CO
2
, 120 C; iii, CH
2
Cl
2
,20C, 2 weeks.
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Scheme 28 Reagents and conditions: i, THF, rt (10–16%).
Scheme 29 Proposed sequences for the formation of 189–191 and labeling patterns after feeding of [1-
13
C]-labeled 184 or 185 to S. bovinus and
S. variegates.
Scheme 27 Labeling patterns of the meroterpenoids 181 and 182 after feeding of 4-hydroxy-[1-
13
C]benzoic acid (184) or 3,4-dihydroxy-[1-
13
C]benzoic
acid (185) to the fruiting bodies of Suillus tridentinus.
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have been determined by quantum chemical calculation of their
CD spectra.
91
3 Pigments from the acetate–malonate pathway
3.1 Pentaketides
Three new homologous 3-alkyl-1,4-benzoquinones 200–202,
with chain lengths of C
21
to C
23
, respectively, were isolated from
the fruiting bodies of Daldinia concentrica.
92
2-Chloro-5-
methoxy-3-methylcyclohexa-2,5-diene-1,4-dione 203, xylaria-
quinone A 204 and 2-hydroxy-5-methoxy-3-methylcyclohexa-
2,5-diene-1,4-dione 205 have been isolated from the culture of an
endophytic fungus, Xylaria sp.
93
The structures of 203 and 205
were confirmed by X-ray crystallographic analysis. Pigments 203
Scheme 30 Proposed biosynthesis of rhizopogone 193 and tridentoquinone 181.
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and 204 exhibited antimalarial activity against Plasmodium
falciparum (IC
50
values of 1.84 and 6.68 mM, respectively) and
cytotoxicity against African green monkey kidney fibroblasts
(Vero cells) with IC
50
values of 1.35 and >184 mM, respec-
tively.
93
Austrogracilins A 206 and B 207 have been easily obtained
pure by preparative reverse-phase HPLC of the methanol extract
of air-dried fruiting bodies of Austroboletus gracilis.
94
Xylarenol
208 was found in the xylariaceous fungus PSU-A80, which was
isolated from the leaves of Garcinia atroviridis.
95
Four azaphi-
lones, named sassafrins A–D 209–212, were isolated from the
methanol extract of the stromata of the fungus Creosphaeria
sassafras.
96
Sassafrin D 212 possessed an unprecedented skel-
eton, and its biosynthetic pathway from 210 is depicted in
Scheme 31. All four compounds 209–212 showed broad-spec-
trum antimicrobial activity.
96
Azaphilone pigments are produced in abundance in Hypo-
xylon and its relatives, and are known to be chemotaxonomi-
cally significant for Hypoxylon and allied genera.
97–99
These
azaphilones include rutilins A 213 and B 214, entonaemin A
215, and rubiginosins A 216 and B 217 from Hypoxylon ruti-
lum,
100
cohaerins A–F 218–223 from H. cohaerens (¼Annulo-
hypoxylon cohaerens),
97,98
daldinins C–F 224–226 from
H. fuscum,
101
multiformins A–D 227–230 from H. multiforme
(¼Annulohypoxylon multiforme),
102
and entonaemin A 215,
rubiginosins A 216,B217 and C 231, and daldinin C 224 from
H. rubiginosum.
103
A biosynthetic aldol condensation of
entonaemin A 215 with dihydromitorubrinol acetate to
synthesize 213 is proposed in Scheme 32.
100
Cohaerins C–F
displayed moderate inhibitory activity of nitric oxide produc-
tion in RAW cells, and nonselective antimicrobial effects,
98
while multiformins A–D showed potent and apparently nonse-
lective antimicrobial activity.
102
Asakawa’s group in Japan have used HPLC profiling as
a routine procedure in chemotaxonomic studies of Hypo-
xylon and allied genera. According to their chemotaxonomic
results, the metabolites that are frequently encountered in
Annulohypoxylon are cohearins, multiformins, 4,5,40,50-tetra-
Scheme 31 Proposed biosynthetic pathway to sassafrin D 212.
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hydroxy-1,10-binaphthyl (BNT) 232, daldinone A 233, and
truncatone 234, whereas the genus Hypoxylon is instead
characterized by the occurrence of, e.g., mitorubrins, ento-
naemins, rubiginosins and daldinin-type azaphilones, and by
the lack of truncatone, cohaerins and multiformins.
98
This
confirmed the acceptance of the new genus Annulohypox-
ylon,
104
which had previously been treated as Hypoxylon
sect. Annulata.
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Chloroazaphilone is a common structure found in a number of
fungal pigments. A practical synthesis of a model chlor-
oazaphilone 235 (Scheme 33), and reaction of 235 with various
primary amines to afford the corresponding vinylogous g-pyr-
idones, has been fully investigated.
105
3.2 Hexaketides
Cribrariones A–C 238–240 are naphthoquinone pigments iso-
lated from myxomycetes Cribraria purpurea,C. cancellata, and
C. meylanii, respectively.
106–108
Unfortunately, the absolute
stereochemistry of C-11 in cribrarione A could not be determined
by the Mosher method, since MTPA esterification easily led to
dehydration of 11-hydroxyl group to give a furan.
107
Shintani has
reported cribrarione C 240 as a natural product for the first
time,
108
although it had previously been synthesized from gallic
acid by Natori and Kumada.
109
Compound 238 showed antimi-
crobial activity against Bacillus subtilis, whereas compound 239
was inactive against B. subtilis.
106,107
Compound 240
exhibited mild TNF-related apoptosis inducing ligand
(TRAIL)-resistance overcoming activity against TRAIL-
resistant human gastric adenocarcinorma (AGS) cells, but it was
inactive against Staphylococcus aureus at 50 mgml
1
.
108
6,7-Dimethoxydihydrolindbladione 241, dihydrolindbladione
242 and 6-methoxydihydrolindbladione 243 were reported from
a myxomycete Lindbladia tubulina, while lindbladione 244 has
been found in a myxomycete, Cribraria intricata.
110
3.3 Heptaketides
Hypocrellin D 245 and three related perylenequinone derivatives
were isolated from the fruiting bodies of Shiraia bambusicola
collected from China.
111
Structurally, 245 is a 6a,7a-seco product
of hypocrellin A 246, and it significantly inhibited the growth of
tumour cell lines Bel-7721, A-549 and Anip-973 with IC
50
values
of 1.8, 8.8, 38.4 mgml
1
, respectively.
Naturally occurring perylenequinonoid pigments (PQPs), such
as hypocrellins A 246 and B 247 from Shiraia bambusicola and
Hypocrella bambuase,
112–114
cercosporin 248 from Cercospora
kikuchii,
115–117
and elsinochromes A–C 249–251 from Elsinoe
species,
118,119
have long been known as excellent nonporphyrin
photosensitizers. Upon exposure to light, perylenequinones
Scheme 32 Proposed biosynthetic pathway to rutilin A 213.
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initiate the generation of reactive oxygen species, including the
superoxide radical anion (O
2
) and singlet oxygen (
1
O
2
), that kill
cells. Thus, the perylenequinones are promising photodynamic
therapy (PDT) agents for cancer and viral infections. The
development of perylenequinonoid PDT agents with lower
aggregation tendency, longer absorption wavelengths, higher
quantum yields, greater stability, and greater selectivity against
cancer cells is of current interest.
120–122
3.4 Octaketides
3.4.1 Anthraquinones and anthraquinone carboxylic acids.
Shiraiarin 252 was reported for the first time from the submerged
fermentation of Shiraia bambusicola.
123
The effects of fermentation
conditions upon the production of shiraiarin by a submerged
culture of S. bambusicola were also reported,
123
and lactose as the
carbon source, NaNO
3
as the nitrogen source, and a pH >8 during
the stationary phasewere favorable forthe production of shiraiarin.
2-Hydroxy-6-methyl-8-methoxy-9-oxo-9H-xanthene-1-
carboxylic acid 253, 2-hydroxy-6-hydroxymethyl-8-methoxy-9-
oxo-9H-xanthene-1-carboxylic acid 254, 7-hydroxy-3-
(hydroxyl-methyl)-1-methoxy-9H-xanthen-9-one 255 and
2,5-dihydroxy-8-methoxy-6-methyl-9-oxo-9H-xanthene-1-carbox-
ylic acid 256 were four new xanthones found in the microfungus
Xylaria sp. isolated from the Australian rainforest tree Glochidion
Scheme 33 Reagents and conditions: i, DMF, POCl
3
,60C (87%); ii, CH(OMe)
3
,p-TsOH, MeOH, 4
A MS, 50 C (95%); iii, 236,n-BuLi, THF, 78 C
to 20 C, then 237 (42%); iv, n-BuLi, THF, MeI, 78 Cto10 C (75%); v, 1 N HCl, acetone (92%); vi, Ac
2
O, Et
3
N, CH
2
Cl
2
, DMAP (cat.) (96%); vii,
Hg(OAc)
2
,CH
3
CN–H
2
O (4 : 1 v/v) (95%); viii, AlCl
3
,CH
2
Cl
2
, reflux (86%); ix, SO
2
Cl
2
,CH
2
Cl
2
(72%); x, HOAc, HClO
4
, rt, 1 h; xi, HOAc, Pb(OAc)
4
,rt
(51%) (over two steps).
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ferdinandi.
124,125
Methylation of 253 using diazomethane affor-
ded the crystalline compound 2,8-dimethoxy-6-methyl-9-oxo-
9H-xanthene-1-carboxylic acid methyl ester 257, whose structure
was determined by single-crystal X-ray analysis.
125
3.4.2 Coupled pre-anthraquinones. The axial stereochemistry
of dimeric pre-anthraquinones has been deduced from CD
spectroscopy using ‘exciton coupling’ between the two extended
naphthalene chromophores.
126
A compound exhibiting a nega-
tive Cotton effect at longer wavelength and a positive one at
shorter wavelength (an ‘A-type’ curve according to Steglich) is
Scheme 34 Possible biosynthetic relationships between members of the ‘atrovirin B
2
cascade’.
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consonant with ‘negative chirality’ (an anticlockwise twist
between the aromatic chromophores), while a compound
showing the mirror-image Cotton effect (a ‘B-type’ curve)
corresponds to ‘positive chirality’ (a clockwise aromatic helical
twist). According to the Prelog–Helmchen rules, a P-axial
stereochemistry for icterinoidin B
1
258 and atrovirin B
2
259, and
an M-axial chirality for icterinoidin A
1
260 were determined.
Furthermore, the P-axial stereochemistry of 258 was confirmed
by Steglich’s kinetic resolution method, while the absolute
central stereochemistry of 258–261 was assigned by application
of the ‘syn–anti rule’, which exploits the empirical relationship
between the respective CD and
1
H NMR spectra of individual
pre-anthraquinones.
126
A possible biosynthetic relationship
between members of the atrovirin B
2
cascade from Dermocybe
icterinoides and D. austroveneta represents the absolute config-
uration as P(and 3R,30R, where appropriate), and is shown in
Scheme 34.
126
The absolute stereostructures of phlegmacins A
1
262 and B
1
263 were determined as (M,3R,30R) and (P,3R,30R) configura-
tions, respectively, by biosynthetic studies, quantum chemical
CD calculations, and NOE experiments. Feeding synthetic (R)-
and (S)-[methoxy-
13
C]torosachrysone to Cortinarius odorifer,
only the former 264 was incorporated into 262 and 263. Each of
the stereoisomers, 262 and 263, exhibited a
13
C-enrichment of
about 3.5% for each methoxy group. By contrast, the mixture
of 262 and 263 obtained after feeding (S)-[methoxy-
13
C]tor-
osachrysone showed no enhancement of the methoxy signals in
the
13
C NMR spectrum. This indicated that both 262 and 263
were R-configured at C-3 and C-30and differed only in their
absolute configurations at the chiral axes.
127
The 10,100-coupled dimers of the dihydroanthracenones are
referred to as the tricolorins. The atropisomeric austrocolorins
A
1
265 and B
1
266 from Australian toadstool Dermocybe sp.
WAT 26641, are new members of this tricolorin class.
128
Their
absolute central and axial configurations were deduced from
respective
1
H NMR and CD spectra, and confirmed by chemical
degradation and chiral HPLC analysis. The ascomycete Xylaria
euglossa produces phlegmacin A 8,80-di-O-methyl ether 267 and
two related pigments.
129
The absolute configuration of 267 was
assigned as P,30Sby comparing the CD and
1
H NMR spectra of
267 with those of phlegmacins A
1
262 and B
1
263. It is note-
worthy that 267 is the first report of a phlegmacin-type pigment
from an ascomycete.
129
Rufo-olivacin B 268 and rufo-olivacin 269 are two red
pigments produced by the fruiting bodies of the Chinese toad-
stool Cortinarius rufo-olivaceus.
130
Their structures were charac-
terized by means of analysis of spectroscopic methods, including
2D-NMR experiments and HR-ESI-MS. Unfortunately, the
axial configuration of 268 remains unknown.
130
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3.4.3 Pyranonaphthoquinones. The cardinalins are a series of
pyranonaphthoquinone-type pigments isolated from a New
Zealand toadstool, Dermocybe cardinalis,
131,132
while ven-
tiloquinone L 270, the monomer of cardinalin 3 271, was iden-
tified in the root bark of Ventilago goughii.
133
Several syntheses of
270 and 271 have been reported.
134–138
An overview of the synthesis of the fungal metabolites (S)-
dermolactone 272,(R)-semixanthomegnin 273,(R)-mellein 274,
(S)-mellein 275,(R)-ochratoxin a276,()-(1R,3S)-thysanone
277, and the enantiopure ventiloquinones L 270,E278 and G 279
from a common chiral intermediate, was presented by Gill.
139
Further methodology potentially leading towards extended
quinones such as (3S,30S)-xylindein 280 was also outlined in the
same paper.
139
3.5 Other polyketides and compounds of fatty acid origin
The myxomycete Fuligo cinerea produces a glycosidic dibenzo-
furan metabolite, fulicineroside 281, which was highly active
against Gram-positive bacteria and crown gall tumours.
140
Concentricolide 282 has been found in the fruiting bodies of
Daldinia concentrica, and its structure was confirmed by X-ray
crystallographic analysis.
141
Concentricolide 282 inhibited HIV-
1-induced cytopathic effects (EC
50
0.31 mg ml
1
), and it was also
effective in the blockage (EC
50
0.83 mg ml
1
) of syncytium
formation between HIV-1 infected cells and normal cells.
141
Synthesis of racemic concentricolide was accomplished recently
(Scheme 35).
142
Aurovertins B 283,C284 and E 285 were identified from the
culture of Albatrellus confluens,
143,144
while aurovertins D 286,F–
H287–289 have been isolated from the entomopathogenic
fungus Metarhizium anisopliae.
145
Aurovertins are of polyketide
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origin and are characterized by a 2,6-dioxabicyclo[3.2.1]octane
ring system with a conjugated a-pyrone moiety. 283 can bind to
F1-ATPase and thus inhibits ATP synthesis and hydrolysis in
mitochondorial enzyme systems.
146
Cyathusals A–C 290–292, cyathuscavins A–C 293–295, and
the known pulvinatal 296 have been isolated from the fermented
mushroom Cyathus stercoreus.
147,148
These compounds showed
antioxidant activity, and 293–295 protected supercoiled plasmid
DNA from Fe
2+
/H
2
O
2
-induced breakage, which would be due
to their abilities to scavenge free-radicals derived from the
phenolic moiety and to chelate metal ions by means of the o-
dihydroxy group of the structures. The metal ion chelating ability
of the catechol moiety in 293–295 might combine the with free-
radical scavenging ability to afford DNA protection from Fen-
ton-mediated breakage.
147,148
Fuligoic acid 297 is a yellow pigment with a chlorinated poly-
ene–pyrone acid structure isolated from field-collected fruiting
bodies of the myxomycete Fuligo septica. The structure of 297 was
established by spectroscopic methods, and the absolute configu-
ration of C-5 was assigned as Sby comparingthe CD data with that
of a related compound, kawain.
149
Laetiporic acid 298,
150
later re-
named laetiporic acid A,
151
occurred as a mixture of cis and trans
isomers at C-7 in a 6 : 4 ratio. This was the major orangepigment in
the fruiting bodies and liquid cultures of Laetiporus sulfureus.A
Scheme 35 Reagents and conditions:i,PBr
3
/Br
2
, 70–90 C (57%); ii, PhSH,
Et
3
N, Et
2
O(98%);iii,NCS,CCl
4
, reflux (82%); iv, Li
2
CO
3
, LiBr, THF,
reflux (35%); v, m-CPBA, DCM, 0 C (82%); vi, 3-vinylfuran, hydroquinone
(0.1 equiv), rt, toluene, 72 h; vii, CaCO
3
, toluene, reflux, 19 h.
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derivative, 2-dehydro-3-deoxylaetiporic acid A 299, was also
found in this fungus.
151
Since fruiting bodies of L. sulfureus are
edible, laetiporic acids might have potential as food colourants.
Calolstomal 300, a polyene pigment, is responsible for the
red-orange colour of the stalked puffball Calostoma cinnabar-
inum.
152
Its structure has been identified by
1
H and
13
C NMR
spectra of the corresponding methyl ester 301 (due to the low
solubility of 300), 301 having been reported before as an inter-
mediate in the total synthesis of a Xanthomonas pigment.
152
Fungi of the order Boletales, to which C. cinnabarinum belongs,
are chemotaxonomically well characterized by the occurrence of
hydroxylated pulvinic acids and biosynthetically related shiki-
mate-derived pigments. Nevertheless, none of the typical Bole-
tales pigments were detected in C. cinnabarinum.
152
4 Compounds from the mevalonate pathway
When the fruiting bodies of Lactarius deliciosus are injured, the
latex is firstly carrot-coloured, but then slowly (within minutes)
darkens, and eventually turns green, these colour changes having
been reported to be due to guaiane sesquiterpenes.
153
Isolation of
the fruiting bodies of L. deliciosus led to four azulene pigments,
7-acetyl-4-methylazulene-1-carbaldehyde 302, 7-(1,2-dihydroxy-
1-methylethyl)-4-methylazulene-1-carbaldehyde 303, 7-acetyl-4-
methylazulene-1-carboxylic acid 304, 4-methyl-7-(1-methyl-
ethenyl)azulene-1-carbaldehyde 305.
154,155
7-(1-Hydroxy-1-
methylethyl)-4-methylazulene-1-carbaldehyde 306, 4-methyl-7-
(1-methylethyl)azulene-1-carboxylic acid 307, 1-[(15E)-buten-17-
one]-4-methyl-7-isopropylazulene 308, and 4-methyl-7-(1-meth-
ylethyl)azulene-1-carbaldehyde 309 have been found in the
fruiting bodies of L. hatsudake.
156,157
However, 307 had previ-
ously been obtained by organic synthesis,
158,159
while 308 might
be a work-up product of 309 following aldolization with acetone.
Two rare aromatic steroids, (17b,20R,22E,24R)-19-nor-
ergosta-1,3,5,7,9,14,22-heptaene 310 and (17b,20R,22E,24R)-1-
methyl-19-norergosta-1,3,5,7,9,14,22-heptaene 311, have been
isolated from the fruiting bodies of Daldinia concentrica,of
which 311 bears an unusual methyl group at position C-1.
160
The
identification of aromatic steroid hydrocarbons bearing a methyl
group at positions 1, 2, 3, 4 or 6 in sediments and petroleum has
been puzzling, since possible steroidal precursors have not yet
been reported from living organisms. Thus, compounds 310 and
311 could be the long-sought biological precursor steroids for
organic matter in Earth’s subsurface. Their existence provides
a link between biological marker compounds (or ‘fossil mole-
cules’) and their origin.
160
5 Pigments containing nitrogen
Nitrogen-containing compounds of macromycetes, including
nitrogenous pigments, have been comprehensively reviewed by
our group.
161
5.1 Nitrogen heterocycles
5.1.1 Indoles. Two unusual 1-hydroxyindole pigments,
named birnbaumins A 312 and B 313, have been isolated from the
Yellow Parasol or Flower Pot Parasol (Leucocoprinus birnbau-
mii).
162
Their structures were established by ESI MS/MS, NMR
including
1
H and
15
N HMBC spectra, and chemical methods
including permethylation with diazomethane and reduction with
zinc in glacial acetic acid. A postulated pathway for the biosyn-
thesis of the birnbaumins which starts from L-tryptophan,
citrulline, glycine, and nitrite is depicted in Scheme 36.
162
Various bisindole alkaoids have been isolated from myxomy-
cetes. These include dihydroarcyriarubin C 314, arcyriarubin C
315 and arcyriaflavin C 316 from Arcyria ferruginea,
163
arcyria-
flavins B 317 and C 316 from Tubifera casparyi,
163
ciner-
eapyrroles A 318 and B 319 from Arcyria cinerea,
164
three new
bisindole alkaloids 320–322, 6-hydroxystaurosporinone 323 and
5,6-dihydroxyarcyriaflavin A 324 from Lycogala epiden-
drum,
164,165
arcyriarubin B 6-O-sulfate 325 and arcyroxocin B 326
from Arcyria denudata,
166
dihydroarcyriacyanin A 327 from
Arcyria obvelata,
166
and several related known bisindole alkaoids
from these fungi. Both cis- and trans-dihydroarcyriarubin C
were synthesized to determine the stereochemistry of dihy-
droarcyriarubin C 314. Comparison of their NMR characteris-
tics allowed the trans stereochemistry of the natural product to
be confirmed.
167
Arcyriaflavin C 316 displayed cell cycle inhibi-
tion activity of the G1 and G2/M stages at 10 and 100 ng ml
1
,
respectively,
163
while arcyriaflavin B 317 showed cytotoxicity
(IC
50
2.28 mgml
1
) against vincristine (VCR)-resistant KB
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cells.
164
6-Hydroxystaurosporinone 323 exhibited protein tyro-
sine kinase inhibition activities.
165
Two compounds, cis- and trans-tryptophan 4-amino-
cinnamamides (328 and 329), were isolated from field-collected
fruiting bodies of myxomycete Fuligo aurea.
168
Tryptophan 4-
aminobenzmide 330 was detected in fruiting bodies of
myxomycete F. candida.
169
1-(1-b-Glucopyranosyl)-3-(methox-
ymethyl)-1H-indole 331, 1-(1-b-glucopyranosyl)-1H-indole-3-
carbaldehyde 332,N-1-b-glucopyranosyl-3-(carboxymethyl)-
1H-indole 333 and N-1-b-glucopyranosyl-3-(2-methoxy-2-
oxoethyl)-1H-indole 334 have been found in fruiting bodies of
Cortinarius brunneus. Compound 333 is the N-glucoside of the
plant-growth regulator 1H-indole-3-acetic acid (IAA), but, in
contrast, it did not exhibit auxin-like activity in an Arabidopsis
thaliana tap root elongation assay.
170
5.1.2 Quinolines. A group of pyrroloquinoline alkaloid
pigments were isolated from Mycena species by German chem-
ists.
171–173
These pyrroloquinoline alkaloid pigments included
mycenarubins A 335 and B 336 from fruiting bodies of
M. rosea,
172
sanguinones A 337 and B 338, sanguinolentaquinone
339, and decarboxydehydrosanguinone A 340 from M. sangui-
nolenta,
173
mycenarubins A 335, and D–F 343–345, sanguino-
lentaquinone 339, haematopodin 341, and haematopodin B 342
from M. haematopus.
171
Surprisingly, the name of mycenarubin
C was skipped and not used. The absolute configurations of
mycenarubins A and B were determined as shown in the
formulae 335 and 336 by comparison of their CD spectra with
that of a synthetic model compound 346, which (lacking only the
side chain of 335) was prepared from the known 6,7-bis(benzy-
loxy)indole 347 (Scheme 37).
172
The absolute configurations were
Scheme 36 Proposal for the formation of the N-hydroxyoxamidine terminus in the biosynthesis of birnbaumins A 312 and B 313 (the sequence of the
C–N and C–C bond formation may be reversed).
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determined as 4S,12Sfor 337 and 338,4Rfor 342, and 4Sfor
343–345 by comparison of their CD spectra with that of myce-
narubin A 335 or haematopodin 341.
171,173
Mycenarubin B 336 is
the first example of a dimeric pyrroloquinoline alkaloid occur-
ring in Nature.
172
Decarboxydehydrosanguinone A 340 was
identified as an oxidative decarboxylation artifact of sanguinone
A337.
173
Metabolic profiling of the red pigments of intact and
injured fruiting bodies of M. haematopus by HPLC indicated that
the degradation product haematopodin 341 originated from
haematopodin B 342, which is the native main pigment of
M. haematopus.
171
A hypothetical biosynthesis leading from 344
to 342 and 339 is shown in Scheme 38.
171
Unlike the previously known pyrroloquinoline alkaloids,
mycenarubins A 335,B336 and D–F 343–345 have carboxylic
groups at C-4, which indicates that mycenarubins might be
biosynthetically derived from L-tryptophan and S-adenosylme-
thionine. Previously, pyrroloquinoline alkaloids were isolated
from marine sponges.
174
However, makaluvamin A 348 from a
culture of the myxomycete Didymium bahiense,
175
and the pres-
ence of a series of such alkaloids from Mycena species,
171–173,176,177
confirmed that pyrroloquinoline alkaloids were not restricted to
marine sources but appeared also to be common in some fungi.
A green pigment, makaluvamine I 351, and a red pigment,
damirone C 352, were isolated from myxomycete Didymium iri-
dis,
178
both compounds having previously been reported from
a marine sponge, Zyzzya fuliginosa.
179
Two quinoline pigments
353 and 354, and one isocarbostyryl alkaloid 355, have been
Scheme 37 Reagents and conditions: i, serine, AcOH, Ac
2
O, 75 C, 2 h (73%); ii, acylase I, cat. CoCl
2
, pH 7.0, 37 C, 3 h (59%); iii, Pd/C, H
2
, 1 h; ix, cat.
NEt
3
,O
2
, 10 min (23%).
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isolated from the fruiting bodies of the agaricoid fungus Corti-
narius subtortus. Compound 353 showed inhibitory activity
against the growth of phytopathogenic fungus Colletotrichum
coccodes. Compounds 353–355 exhibited moderate antioxidant
activity of DPPH free-radical scavenging.
180
5.2 Compounds derived from anthranilic acid
Fruiting bodies of a myxomycete Fuligo candida contained
a yellow pigment 356, which was considered to be derived from
condensation of a cycloanthranilic acid, an acetone, and an
indole-3-carbaldehyde.
169
5.3 Polyenes with tetramic acid or amino acid end groups
Three new yellow pigments, physarigins A–C 357–359, have been
reported from a cultured plasmodium of the myxomycete
Physarum rigidum.
181
These yellow pigments are relatively
unstable and not easily dissolved in organic solvents, and the
HPLC analysis of physarigins A 357 and C 359 revealed that
physarigin A was produced from physarigin C. Physarigins A–C
are structurally similar to physarochrome A 360, which is
produced by P. polycephalum and considered to act as a photo-
receptor in the physiology of this organism.
182
Pachydermin 361, whose structure was deduced from its
degradation product, 5-(3-chloro-4-hydroxybenzylidene)tetramic
acid 362, has been isolated from the fruiting bodies of New
Zealand fungus Chamonixia pachydermis.
183
A ene-triyne
Scheme 38 Hypothetical biosynthesis of 339 and 342 from 344.
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antibiotic 363 from the culture of Baeospora myosura is an amide
of the C9 ene-triyne carboxylic acid 364 with p-aminobenzoic
acid.
184
363 showed potent antibiotic activity against Gram-
positive bacteria, while it was less active against Gram-negative
bacteria and a yeast. MICs of 363 against several strains of
Staphylococcus aureus were as low as 0.001 mgml
1
. The potent
antibacterial activity of 363 was attributed to its highly reactive
property of the conjugated ene-triyne, since analogues of 363
that did not contain the ene-triyne moiety were inactive against
all microorganisms.
184
5.4 Other pigments containing nitrogen
Brunneins A–C 365–367 and 3-(7-hydroxy-9H-b-carboline-1-
yl)propanoic acid 368 from Cortinarius brunneus,
185
harmane 369
and norharmane 370 from fruiting bodies of Hygrophorus ebur-
neus,
186
brunnein A 365 from fruiting bodies of H. hyacinthi-
nus,
186
and flazin 371 from Suillus granulatus,
187
are b-carboline
alkaloid pigments. Brunnein A 365 showed very low cholines-
terase inhibitory effects and no cytotoxicity,
185
while flazin 371
exhibited anti-HIV activity (EC
50
¼2.36 mM, therapeutic index
¼12.1). A series of flazin analogues were synthesized for
a structure–activity relationship study, and among them, flazi-
namide 372 showed the most potent anti-HIV activity (EC
50
¼
0.38 mM, therapeutic index ¼312.0).
188,189
A unique set of thiomethylated canthin-6-one derivatives, 373–
378, were detected in Boletus curtisii, which were accompanied by
canthin-6-one 379 and two carbolines 380 and 381. Pigments 377
and 378, named curtisin and 9-deoxycurtisin, respectively, are
responsible for the bright yellow colour of this mushroom, while
compounds 373 and 379 are colourless. The absolute configu-
ration of the sulfoxides in curtisin was assigned as Sby quantum
chemical calculations.
190
These results were partially covered in
a previous review.
3
Pycnoporin 382, cinnabarin 383, tramesanguin 384 and cinna-
barinic acid 385 are phenoxazone alkaloids isolated from the
Australian fungus Pycnoporus cinnabarinus.
191
Compound 383
showed antitumour activity against murine leukaemia cell line
(P388) with IC
50
of 13 mM at 1 mg ml
1
.
191
Cordyformamide 386,
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structurally close to xanthocillins X 387,Y
1
388 and Y
2
389,which
are known to occur in Penicillium notatum,wasisolatedfrom
a culture broth of the insect pathogenic fungus Cordyceps brun-
nearubra BCC 1395.
192
Cordyformamide 386 is a plausible biosyn-
thetic precursor of 389, and it showed activity against the malarial
parasite Plasmodium falciparum K1 with an IC
50
of 18 mM.
192
Sterenins A–D 390–393, from a solid-state culture of Stereum
sp. SANK 21205, are potent 11b-hydroxysteroid dehydrogenase
type 1 (11b-HSD1) inhibitors with IC
50
values of 0.24, 6.6, 0.23
and 2.6 mM, respectively.
193
The first total synthesis of 390,392
and 393 has also been reported.
194
Clitocybins A 394
195
and D
395
196
were isolated from the culture broth of Clitocybe aur-
antiaca, while clitocybins B 396 and C 397 were synthesized
from modification of 394 for studies of their effect on H
2
O
2
-
induced apoptotic cell death and cellular senescence.
197
Xylo-
pyridine A 398 and pyrocoll 399 have been found in the
mangrove endophytic fungus Xylaria sp. (#2508) collected from
the South China Sea coast.
198
Xylopyridine A 398 showed
DNA-binding affinity, presumably via an intercalation mecha-
nism in fluorescence quenching and spectrophotometric titra-
tion experiments.
6 Acknowledgements
We wish to acknowledge the National Basic Research Program
of China (973 Program, 2009CB522300), the National Natural
Science Foundation of China (30830113), and MOST
(2009ZX09501-029; 2009ZX09501-013).
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