Secondary metabolites from species of the biocontrol agent

Trichoderma
Jose Luis Reino Raul F. Guerrero
Rosario Herna ndez-Gala n Isidro G. Collado
Received: 25 July 2006 / Accepted: 21 September 2006 / Published online: 13 March 2007
Springer Science+Business Media B.V. 2007
Abstract Trichoderma species are free-living
fungi that are highly interactive in root, soil and
foliar environments and have been used success-
fully in eld trials to control many crop patho-
gens. Structural and biological studies of the
metabolites isolated from Trichoderma species
are reviewed. This review, encompassing all the
literature in this eld up to the present and in
which 269 references are cited, also includes a
detailed study of the biological activity of the
metabolites, especially the role of these metabo-
lites in biological control mechanisms. Some
aspects of the biosynthesis of these metabolites
and related compounds are likewise discussed.
Keywords Trichoderma Biological control
Phytopathogen Metabolites Toxins
Introduction
Biological control provides an alternative to the
use of synthetic pesticides with the advantages of
greater public acceptance and reduced environ-
mental impact. While the natural suppression of
plant diseases has been recognized but inade-
quately understood for at least a century, the
deliberate use of biological agents for disease
control is a recent relative of the biological
control of insects and weeds. Many of the soils
that naturally suppress plant diseases are rich in
organic matter that supports the growth of ben-
ecial microorganisms. The use of these micro-
organisms as biological control agents seeks to
restore the benecial balance of natural ecosys-
tems which is often lost in the crop situation
(Cutler and Cutler 1999). Soil-borne fungi survive
in a highly competitive environment. Antagonism
between species of naturally competing fungi has
been observed in virtually every fungal ecosystem
(Wicklow 1998; Ghisalberti 2002). Trichoderma
species are free-living fungi which are highly
interactive in root, soil and foliar environments.
Considered to be eager colonizers and particu-
larly invasive fungi, they work against fungal
phytopathogens either indirectly by competing
for nutrients and space, modifying environmental
conditions or promoting plant growth and plant
defensive mechanisms and antibiosis; or directly
through mechanisms such as mycoparasitism.
This dominance is achieved biosynthesizing a
wide array of secondary metabolites, transform-
ing a great variety of natural and xenobiotic
compounds and producing varied degradative
enzymes such as chitinase (Gloer 1997). It
J. L. Reino R. F. Guerrero R. Herna ndez-Gala n
I. G. Collado (&)
Departamento de Qumica Orga nica, Facultad de
Ciencias, Universidad de Ca diz, Apdo. 40, 11510
Puerto Real, Ca diz, Spain
e-mail: isidro.gonzalez@uca.es
Phytochem Rev (2008) 7:89123
DOI 10.1007/s11101-006-9032-2
1 3
appears clear that Trichodermas growth
inhibiting properties of other fungi are probably
due to the combined action of cell-wall degrading
enzymes together with the capacity of Trichoder-
ma to produce different secondary metabolites.
Furthermore, it has been shown that Trichoderma
spp. induces local and systemic defense responses
in cucumber and other agricultural crops, such as
cotton, tobacco, lettuce and bell pepper (Harman
et al. 2004; Yedidia et al. 2003).
Trichoderma species are valuable sources of
commercial enzymes used in recycling cellulosic
waste. Several strains of Trichoderma are com-
mercially available to control plant disease in
environmentally friendly agriculture. Examples
include the control of Nectria galligena in apples,
Sclerotium rolfsii in tobacco, bean and iris,
Rhizoctonia solanii in radish, strawberry, cucum-
ber, potato and tomato, Chondrosterum purpur-
eum in stone-fruit and other crops, and Botrytis
cinerea in apple (Cutler and Cutler 1999).
A number of commercial formulations to
prevent several diseases in crops as well as in
forest trees with economic importance have been
developed (Cardoza et al. 2005). Therefore in
Spain, a formulation marketed under the name
TUSAL

made from T. harzianum and T. viride

cultures to prevent the growth of pathogen soil-
borne fungi responsible for leaf-falling disease in
several crops, has been prepared by the phytopa-
thology research group of the University of
Salamanca and Newbiotechnic S.A. Corporation.
Papavizas (1985) comprehensively reviewed the
potential of Trichoderma as biocontrol agents.
Furthermore, because of their biological diversity,
they are a readily exploitable source of a broad
range of metabolites.
Research on these topics has generated a broad
knowledge base gathered from a massive number
of publications dealing with the biology, biochem-
istry and applications of these fungi (Kubicek and
Harman 1998). In this paper we summarize the
most important secondary metabolite types iso-
lated from Trichoderma spp. emphasizing their
biological activities, especially the role that these
metabolites play in biological control mecha-
nisms. Some aspects relating to the biosynthesis
of these metabolites and related compounds are
also discussed. It must be stressed that some of
the groups of products mentioned here are
the most important fungal metabolite families
known.
Anthraquinones
Anthraquinones are well-known metabolites of
Trichoderma species. In 1967 a wild strain of
T. viride isolated from soil produced pachybasin
(1), chrysophanol (2) and emodin (3) (Fig. 1)
(Slater et al. 1967). Subsequently, T. polysporum
grown in contact with the basidiomycete fungus
Fomes annosus, afforded the same three com-
pounds (Donnelly and Sheridan 1986). In 1999
compounds 1 and 2 were extracted from dry
mycelium and culture ltrates of a T. aureoviride
isolate (De Stefano and Nicoletti). Additionally,
Betina et al. (1986) showed that a brown
conidiating mutant generated from exposure of
a parental T. viride strain to UV radiation
produced 1,3,6,8-tetrahydroxyanthraquinone (4)
and 1-acetyl-2,4,5,7-tetrahydroxyanthraquinone
(5) (Fig. 1). Probably the mutation rendered
inoperative some enzyme involved in the pro-
duction of normal anthraquinones allowing alter-
native pathways to be expressed (Ghisalberti
2002).
Trichodermaol (6) (Fig. 1) is an anthraqui-
none-derivative isolated from the combined cul-
ture of a strain of Trichoderma species and
Fusarium oxysporum or F. solani. Spectroscopic
methods determined 6 to be a 1,2,3,4,4a,9a-
hexahydromonoanthraquinone (Adachi et al.
1983).
Although dimeric xanthone 7 (Fig. 1) does not
belong to the anthraquinone family, we include it
here because its monomeric unit seems to arise
from the same octaketide intermediate in their
biosynthesis (Fig. 2) (Manyu 1980; Sivasithampa-
ram and Ghisalberti 1998).
While the biological activity of anthraquinones
is typically related to pigmentation, other func-
tions have been reported as well. Biological
testing of a mixture of compounds 1, 2 and 3;
pure compounds and their O-acetyl and O-methyl
derivatives were carried out against two growing
strains of F. annosus. A decrease in the linear
growth rate of the fungal strains was observed
90 Phytochem Rev (2008) 7:89123
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when treated with the O-acetyl derivatives
(Donnelly and Sheridan 1986). Emodin (3) pos-
sesses both monoamine oxidase (Fujimoto et al.
1998) and tyrosine kinase (Jayasuriya et al. 1992;
Kumar et al. 1998) inhibiting activity. This com-
pound acts also as an antimicrobial, antineoplasic
O
O
OH R1
R2
O
O
OH
OH
OH
O H
R
OH O
O
O H
OH
H
H
1 R
1
= R
2
= H
2 R
1
= OH, R
2
= H
3 R
1
= R
2
= OH
4 R= H
5 R=COCH
3
6
O
OH O OH
O H
O
O
O H
OH OH
O
O
7
Fig. 1 Anthraquinones
and xanthone derivatives
SACP
O O O
O O O O
O
S-ketoSyn
O
SACP
O
O O
O
O SACP
O O O
O
O
O
O
O
OH OH
O H
O
OH O OH
HO
O
O
OH O OH
O H
O
O
O H
OH OH
O
O
3
7
Fig. 2 Biosynthesis of anthraquinone and xanthone polyketides
Phytochem Rev (2008) 7:89123 91
1 3
and cathartic agent (Wu et al. 2006; Huang et al.
2006; Ali et al. 2004) and exhibits a remarkable
bacteriostatic effect on Gram-positive bacteria,
especially towards S. aureus (Chukwujekwu et al.
2006). Another compound exhibiting antibacte-
rial activity is trichodermaol (6), proving active at
50 lg/ml on Bacillus subtilis and Streptococcus
aureus (Adachi et al. 1983). Chrysophanol (2)
exhibited antifungal activity against Candida
albicans, Cryptococcus neoformans, Trichophyton
mentagrophytes and Aspergillus fumigatus at a
MIC (minimum inhibitory concentration) of 25
250 lg/ml (Agarwal et al. 2000). Compounds 4
and 5 function as uncouplers on mitochondrial
oxidative phosphorylation (Betina and Kubela
1987) but they showed limited antimicrobial
activity (Gottasova et al. 1998).
Daucanes
Daucane sesquiterpenes, also known as caro-
tanes, are usually conned to the plant families
Umbelliferae and Compositae, but are rare as
fungal metabolites. During the course of a
screening program for antifungal compounds, a
strain of T. virens was found to produce a novel
bioactive carotane-type metabolite (8) (Fig. 3)
exhibiting antifungal activity against various yeast
and dermatophytes and having a remarkable
effect on Candida albicans (Watanabe et al.
1990).
Lee et al. (1995a) isolated an oleic ester
derivative of 8 named L-735,334 (9) (Fig. 3),
from T. virens grown in several culture broths.
Both metabolites, 8 and 9, are modulators of the
high conductance calcium-activated potassium
channel (Ondeyka et al. 1995; Lee et al. 1995a).
Four new metabolites with carotane skeletons,
trichocaranes AD (1013) (Fig. 3), were isolated
from T. virens, their relative structures being
elucidated by spectral analysis. These compounds
signicantly inhibited the growth of etiolated
wheat coleoptiles (Macias et al. 2000).
Simple pyrones
The pyrone 6-pentyl-2H-pyran-2-one (14) (Fig. 4)
is the representative metabolite common to the
Trichoderma genus. This compound is a avoring
agent responsible for the coconut aroma associated
with this fungus. Compound 14 was rst identied
by Collins and Halim (1972) in the culture broth of
T. viride. Since then, it has been obtained from
T. harzianum(Claydon et al. 1987) and T. koningii
(Simon et al. 1988). This metabolite was used in
plate tests against Rhizoctonia solani andFusarium
oxysporum f. sp. Lycopersici. The addition of
0.3 mg/ml of 14 to agar medium caused a 69.6%
H
O H
O H
R
14
15
11
3
5
7
1
9
12
13
8 R= H
9 R= OCO(CH
2
)
7
CH=CH(CH
2
)
7
CH
3
H
O H
O H
O
10
H
O H
O H
R2
R1
11 R1 = H, R2 = OH
12 R1=R2= OH
H
O H
O H
OH
13
Fig. 3 Daucanes
O O O O
14 15
O O O O
16 17
O
O
O
18
Fig. 4 Pyrone metabolites
92 Phytochem Rev (2008) 7:89123
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growth reduction in R. solani and a 31.7% reduc-
tion in F. oxysporum after 2 days. When used in
spore germination tests, 0.45 mg/ml was found to
completely inhibit the germination of Fusarium
spores. A strong relationship was found between
the production of this pyrone by T. harzianumand
the antagonistic ability of this fungus in vitro
(Scarselletti and Faull 1994; Worasatit et al.
1994). The control of Botrytis cinerea rots in stored
kiwi fruits has also been investigated by Poole et al.
(1998). Thus, application of 14 at rates from 0.4 to
4 mg, neat or diluted in oil, water or acetone,
consistently reduced the incidence of B. cinerea
storage rots to low levels in both inoculated and
naturally infected fruit.
Four analogues of pyrone 14 (1518) (Fig. 4)
have been isolated from Trichoderma species.
Two strains of T. harzianum were both found to
produce the volatile metabolite 6-(1-pentenyl)-
2H-pyran-2-one (15), exhibiting activity against
Penicillium spp., Aspergillus fumigatus, Candida
albicans and Cryptococcus neoformans (Claydon
et al. 1987; Parker et al. 1997). The hydro-deriv-
atives massoilactone (16) and d-decanolactone
(17) were patented by Hill et al. (1995) for their
ability to control a range of plant afictions
including, for example, those produced by Botrytis
or Phytophtora species. These compounds inhibit
the growth of Aspergillus niger, Candida albicans,
and Staphylococcus aureus at 31.5125 lg/ml and
62.5250 lg/ml, respectively, using the agar dilu-
tion method and 96-well microbioassay system
with a liquid culture system (Kishimoto et al.
2005). Recently, viridepyronone (18) was isolated
from a cultural ltrate of a strain of T. viride. This
compound showed antagonistic activity in vitro
against Sclerotium rolfsii at a MIC of 196 lg/ml
(>90% inhibition) (Evidente et al. 2003).
Koninginins
A series of complex pyranes named koninginins
AE (1923) and G (24) (Fig. 5) were discovered
in some species of Trichoderma. The culture
broth of a strain of T. koningii isolated from the
roots and soil line of an ornamental Diffenbachia
species yielded koninginin A (19) and B (20)
(Cutler et al. 1989; 1991a). Both compounds were
subsequently obtained from liquid cultures of two
strains of T. harzianum isolated from wheat roots
(Almassi et al. 1991). Total synthesis of com-
pounds 19 and 20 allowed for, in 1995 and 2001
respectively, the correction of the relative cong-
urations of koninginin A (19a) and B (20a) and
the assignment of the absolute conguration of 19
as lS, 4R, 5S, 6S, 9S, 10S (Xu and Zhu 1995; Liu
and Wang 2001). This stereochemistry was con-
rmed in 2002 by X-ray analysis (Mori et al.
2002). In 1995 koninginin C (21) was isolated
from T. koningii fermented on a shredded wheat
medium, but no stereochemical analyses were
performed (Parker et al. 1995a).
Koninginin D (22) was obtained as the major
metabolite in the culture of a T. koningii strain
isolated from soil (Dunlop et al. 1989). The E
derivative of this series (23) was produced in
liquid cultures of T. harzianum (Ghisalberti and
Rowland 1993) and T. koningii (Parker et al.
1995b). Total syntheses of koninginin D (22) and
E (23) have been performed (Liu and Wang
2001). Finally, koninginin G (24) was isolated
from T. aureoviride (Cutler et al. 1999). Mean-
while, the derivatives 25 and 26 (Fig. 5) were
obtained from T. harzianum (Ghisalberti and
Rowland 1993). Compound 25 features an inter-
esting seco-koninginin skeleton indicating that it
is most likely a precursor in the biosynthetic
pathway to koninginins.
Koninginins AC (1921), E (23) and G (24)
were assayed in a growth inhibition study of
etiolated wheat coleoptiles and showed different
activities. Thus, while 19 showed weak inhibition
at 10
3
M, 24 exhibited 56% inhibition, 23 65%
inhibition and koninginin B (20) and C (21)
inhibited growth by 100% at the same concen-
tration (Cutler et al. 1989, 1991a, Parker et al.
1995a, b). Further assays showed antibiotic
activity for 19, 20, 2224 towards the take-all
fungus Gaeumannomyces graminis var. tritici
(Almassi et al. 1991; Ghisalberti and Rowland
1993). Koninginin D (22) also affected the
growth of other soil-borne plant pathogens such
as Rhizoctonia solani, Phytophthora cinnamomi,
Pythium middletonii, Fusarium oxysporum and
Bipolaris sorokiniana. For this bioassay the
T. koningii strain, which is the producer of 22,
was grown on dialysis membrane overlay of 1/5
Phytochem Rev (2008) 7:89123 93
1 3
strength Potato Dextrose Agar for 4 days at
15C after which the membrane and hyphae
were removed. Agar was then inoculated with
the pathogen and the colony area was measured
for 3 days (Dunlop et al. 1989). Upon comparing
values for blank and treated plates, total inhibi-
tion was observed for G. graminis var. tritici,
R. solani and B. sorokiniana. Strong inhibition
was also showed in the case of the remaining
tested pathogens.
O
OH
OH
H
O
H
H
O
OH
OH
H
O
H
H
19 19a
O
O
OH
H
OH
O
O
OH
H
OH
20 20a
O
OH
O
OH
O
O
OH
H
OH
H
OH
21 22
O
O
OH
H
OH
H
O
OH
OH
H
H
OH
OH
23 24
OH OH
H
O H
O
O
O
OH
H
OH
H
OH
25 26
Fig. 5 Koninginins AE,
G and derivatives
94 Phytochem Rev (2008) 7:89123
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Trichodermamides
Two modied dipeptides named trichoderma-
mides A (27) and B (28) (Fig. 6) were isolated
from cultures of T. virens isolated from marine
environments. The structure of 28 was established
by X-ray diffraction analysis while the structure
assignment of 27 and the determination of the
absolute stereochemistry was accomplished by
means of spectral and chemical methods. Com-
pound 28 displayed signicant in vitro cytotoxic-
ity against HCT-116 human colon carcinoma with
an IC
50
(inhibitor concentration yielding 50%
inhibition) of 0.32 lg/ml while 27 was found to
have a weak cytotoxic effect on three cancer cell
lines P388, A-549, and HL-60 (Garo et al. 2003;
Liu et al. 2005a).
Recently, isolation of compounds 27 and 28 has
been described from the fungi Spicaria elegans
and Aspergillus unilateralis, co-occurring with the
aspergillazines AE (2933) (Fig. 6), which fea-
ture similar structures (Liu et al. 2005a; Capon
et al. 2005).
Viridins
The steroidal antibiotics of the viridin series
(3441) (Fig. 7) show selective antifungal activity
and specic inhibitory action at specic steps in
the cell signaling process. These compounds
possess an unusual furan ring fused between C-4
and C-6 of the steroid framework, some with an
aromatic ring C (Hanson 1995).
O
NH
N
O
OH
O
O
OH
H
OH
OMe
MeO O
NH
N
O
O
O
OH
H
Cl
OH
OMe
MeO
27 28
O
NH
N H
O
O
O
S
OMe
MeO
OH
H
OH
H
O
NH
O
S
NH
2
H
OH
OH
O
OH
OMe
MeO
29 30 and 31 C-2 epimers
O
NH
O
O
NH
2
H
OH
OH
O
OH
OMe
MeO
32 and 33 C-2 epimers
Fig. 6 Trichodermamides
Phytochem Rev (2008) 7:89123 95
1 3
Viridin (34) was rst described in 1945 as an
antifungal metabolite of the fungus Glioclaudium
virens (Trichoderma virens) (Brian and McGowan
1945). This compound has been detected in other
Trichoderma species such as T. koningii (Berest-
eskii et al. 1976), T. viride (Golder and Watson
1980) and T. virens (Singh et al. 2005). An efcient
total synthesis from a simple acyclic triyne has
recently been published (Aderson et al. 2004).
Compound(34) prevents the germinationof spores
of Botrytis allii, Colletotrichum lini and Fusarium
caeruleum (MIC of 0.0030.006 lg/ml), Penicil-
liumexpansum, Aspergillus niger and Stachybotrys
atra (6 lg/ml) (Brian and McGowan 1945; Ghisal-
berti 2002). The related C-3 alcohol viridiol (35)
was obtained from T. viride and other Glioclaudi-
um species. It has been shown to be an antifungal
and phytotoxic metabolite (Moffat et al. 1969;
Howell and Stipanovic, 1994). A recent search for
inhibitors of enzymes involved in aatoxin biosyn-
thesis led to the isolation of a metabolite produced
by a T. hamatum strain (Sakuno et al. 2000). The
compound, assigned structure (35a), showed a
striking resemblance to 35. Further NMR studies
led to the conclusion that the two compounds were
identical sharing the viridiol (35) structure (Wipf
and Kerekes 2003).
Demethoxyviridin (36) and demethoxyviridiol
(37) were isolated as fungicidal metabolites from
an unknown fungal strain (Aldridge et al. 1975).
Compound 37 was also obtained as a phytotoxic
metabolite from the fungus Nodulisporium hin-
nuleum (Cole et al. 1975). The fungicidal metab-
olites wortmannin (38) (Brian et al. 1957) and
11-desacetoxywortmannin (39) (Haeiger and
Hauser 1973) were rst obtained from Penicillium
species. Chemical and biological properties have
recently been reviewed for 38 (Wipf and Halter
2005). Wortmannolone (40) and virone (41) were
obtained from a culture of Glioclaudium virens
(Trichoderma virens), which had been grown at
32C (Blight and Grove 1986).
Compounds 3437, 40 and 41 have been shown
to be inhibitors of the phosphatidylinositol
3-kinase (Dodge et al. 1995). Such compounds
can be used to treat PI 3-kinase-dependent
conditions, particularly neoplasms, in humans.
The metabolism of inositol phospholipids is
believed to be an essential part of the receptor-
mediated signal transduction pathways in
response to various hormones and growth factors
(Ghisalberti 2002).
Viridiofungins
The structural element of citric acid, 42 (Fig. 8), is
present in several biologically active fungal
O
OH
O O
R
O
O
OH
O H
O
O
R
O
OH
O H
MeO
O O
34 R= OCH
3
36 R= H
35 R= OCH
3
37 R= H
35a
O
O
H
O
O
O
MeO
R
H
O
O H
O
O
H
O
O
O
O
H
O
38 R= OAc
39 R= H
40 41
Fig. 7 Viridin family of
steroidal antibiotics
96 Phytochem Rev (2008) 7:89123
1 3
metabolites such as viridiofungins AC, A
14
, B
2
and Z
2
(4351), obtained from the solid fermen-
tation of T. viride (Harris et al. 1993; Mandala
et al. 1997); the cytotoxic compound trachyspic
acid (52), isolated from Talaromyces trachysper-
mus (Shiozawa et al. 1995); citrafungin A (53),
obtained as an antifungal metabolite from the
mycelium MF6339 (Singh et al. 2004); or the
squealene synthase inhibitors L-731,120 (54)
(Harris et al. 1995) and zaragozic acid A (55)
(Wilson et al. 1992). Alkylation in the 2-position
of 42 with a lipophilic tail with a varying number
of carbon atoms and different further functional
groups is also a shared feature of all these natural
products. Meanwhile, viridiofungins (4350)
(Fig. 8) are distinguished by the presence of an
aromatic amino acid moiety in their structures.
Mass spectrometry and NMR studies allowed
the assignment of the two-dimensional structure
of compounds 4345, as well as that of the
trimethyl ester derivative of viridiofungin A
(Me
3
-43) (Harris et al. 1993). The rst synthesis
of Me
3
-43 was achieved by Esumi et al. (1998)
allowing for the designation of the relative and
absolute conguration of 43. A modied syn-
thesis of 43 by acidic hydrolysis of the tri-tert-
butyl ester derivative (t-Bu)
3
-43 was reported in
2005 (Morokuma et al. 2005).
The viridiofungins (4351) are potent broad-
spectrum fungicidal compounds with MFC (min-
imum fungicidal concentration) of 120 lg/ml
versus the Candida, Cryptococcus and Aspergillus
species (Harris et al. 1993). Further analyses have
shown that these compounds act as inhibitors of
the farnesyl transferase and the farnesylation of
the oncogenic Ras protein, indicating their
potential to treat cancer (Meinz et al. 1993).
Compounds 4345 also inhibited in vitro the
squalene synthase of Saccharomyces cerevisiae
and Candida albicans (Onishi et al. 1997) and the
serine palmitoyltranferase of C. albicans (Man-
dala et al. 1997). Cytotoxic effects in nanomolar
concentrations were observed towards HeLa cells
(Mandala et al. 1997).
R
O H COOH
HOOC
COOH
2
HOOC
O H
COOH
O R1
R2 R3
R4
42 43 R1= Tyrosine; R2, R3 = O; R4= Me
44 R1= Phenylalanine; R2, R3= O; R4= Me
45 R1= Tryptophan; R2, R3= O; R4= Me
46 R1= Tyrosine; R2= OH; R3= H; R4= Me
47 R1= Tyrosine; R2= R3= H; R4= Me
48 R1= Tyrosine; R2, R3= O; R4= H
49 R1= Tyrosine; R2, R3= O; R4= n-Pr
50 R1= Phenylalanine; R2=R3= H; R4= Me
51 R1= OH; R2=R3= H; R4= Me
O O
O
(CH
2
)
8
CH
3
COOH
HOOC
HOOC
O
O
O
(CH
2
)
7
CH
3
O
H
HOOC
COOH
COOH COOH
O H
52 53
(CH
2
)
5
O H
HOOC
COOH
COOH
O
O
O
O
OH
Ph
OAc
OH
COOH
HOOC
HOOC
54 55
Fig. 8 Viridiofungins and
alkyl citrate derivatives
Phytochem Rev (2008) 7:89123 97
1 3
Nitrogen heterocyclic compounds
The penta-substituted pyridine ring system with a
2,3-dimethoxy-4-pyridinol pattern is present in
natural fungal molecules (Fig. 9) such as harzi-
anopyridone (56), isolated from T. harzianum in
1989 (Dickinson et al. 1989); piercidin A (57),
obtained from Streptomyces mobaraensis and
S. pactum (Takahashi et al. 1965; Jansen and
Ho e 1983); atpenins (5860), produced by Pen-
icillium sp. (Omura et al. 1988; Oshino et al.
1990; Kumagai et al. 1990) and WF-16775 A2
(61), isolated from Chaetasbolisia erysiophoides
(Otsuka et al. 1992).
Racemic form of harzianopyridone (56)
showed signicant antifungal activity against
Botrytis cinerea, Rhizoctonia solani (Dickinson
et al. 1989) Gaeumannomyces graminis var. tritici
N
H
O
O
OH
MeO
MeO
N
OH
OH
MeO
MeO
56 57
N
H
OH
O
R O
MeO
MeO
N
H
CH
2
Cl
O
OH O
MeO
MeO
R Cl
58 R= Cl
59 R= H
60 R= H
61 R= Cl
Fig. 9 Pyridine ring-
containing fungal
metabolites
N
R2
O H
OH
O
O
R1
COOH
N
R
OH
O
O H
O
62 R1= Me, R2= Me
63 R1= H, R2= Me
64 R1= Me, R2= Et
65 R= -CH=CH-COOH
66 R= -COOH
N
O
O
OH
H
R2
OH
N
OH
O
O
R1
H
OH
H
H
67 R1= Me, R2= H
68 R1= R2= Me
Fig. 10 Pirrolidinediones
98 Phytochem Rev (2008) 7:89123
1 3
and Pythium ultimum (Vinale et al. 2006). Mean-
while, laevorotatory form isolated by Cutler and
Jacyno (1991) showed weak antifungal and anti-
bacterial activity but signicant phytotoxicity in
the etiolated wheat coleoptile bioassay (100%
inhibition at 10
3
M). The same work also showed
the capability of this form of 56 to produce
necrosis in bean, tobacco and corn in a concen-
tration-dependent manner. These observations
suggest that the two enantiomers of harziano-
pyridone (56) may possess different activities
(Sivasithamparam and Ghisalberti 1998). Biosyn-
thetically, this compound was shown to come
from a tetraketide with the possible involvement
of aspartic acid (Dickinson et al. 1989; Sivasi-
thamparam and Ghisalberti 1998).
The pirrolidindione ring system also appears in
several fungal metabolites (Fig. 10). Harzianic
acid (62) was obtained by fermentation of a strain
of T. harzianum isolated from a water sample
collected in Japan (Sawa et al. 1994). Recently,
Kawada et al. (2004) have found the acids
harzianic (62), demethylharzianic (63) and homo-
harzianic (64) from the culture of the fungal strain
F-1531, which was isolated from a soil sample
collected in Japan. All of these three compounds
were shown to be protein phosphatase type 2A
(PP2A) inhibitors. Biogenesis of 6264 seems to
be related with the condensation of a pentaketide
with amino acids (Sivasithamparam and Ghisal-
berti 1998).
Physarorubinic acids A (65) and B (66) and the
unusual tetramic acids polycephalin B (67) and C
(68), all compounds exhibiting strong absorption
in the UVvisible spectra, were isolated from
plasmodia of the slime mold P. polycephalum
(Nowak and Steffan 1997, 1998).
Additionally two oxazol derivatives, named
melanoxadin (69) and melanoxazal (70) (Fig. 11),
were isolated from the fermentation broth of the
strain ATF-451 of Trichoderma. Both compounds
inhibited melanin formation in the larval hemol-
ymph of the silkworm Bombyx mori. Melanoxa-
zal (70) also showed strong inhibitory activity
against mushroom tyrosinase (Hashimoto et al.
1995; Takahashi et al. 1996).
Trichodenones and cyclopentenone derivatives
Several series of naturally occurring cyclopente-
nones have been described from fungal sources.
Trichodenones AC (7173) (Fig. 12), were
obtained from the culture broth of a strain of
T. harzianum which was isolated from the
sponge Halichondria okadai collected in Japan
(Amagata et al. 1998). These compounds exhibit
signicant cytotoxicity against cultured P388
cells with ED
50
(median effective dose) of
0.211.45 lg/ml.
A different cyclopentenone identied as
5-hydroxy-3-methoxy-5-vinylcyclopent-2-en-1-one
(74) (Fig. 12) was isolated from the cultures of
T. album in 1977 (Strunz et al. 1977).
O
N
OH
OH
O
N
O H
CHO
69 70
Fig. 11 Oxazol derivatives
O
OH
O
OH
Cl
OH
71 72
O
Cl
OH
O
OH
OMe
73 74
O
OR
1
OH
OR
2
O
OR
1
OH
OR
2
75 R1= R2= H
76 R1= Ac, R2= H
77 R1= H, R2= Ac
78 R1= R2= H
79 R1= Ac, R2= H
80 R1= H, R2= Ac
Fig. 12 Trichodenones and other cyclopentenones
Phytochem Rev (2008) 7:89123 99
1 3
Another group with the same ring system are
the pentenomycins (7578) (Fig. 12). Pentenomy-
cin I (75) and II (76) were rst isolated from
Streptomyces eurythermus in 1973 (Umino et al.
1973), while pentenomycin III (77) was isolated
three years later from Strepovertcillium eurocidi-
cum (Shomura et al. 1976). Epipentenomycin I
(78), however, was isolated in 1989 (Bernillon
et al. 1989) from carpophores of Perziza sp., much
later than its rst synthesis in racemic form in
1980 (Smith and Pilla 1980; Sono et al. 1980).
Pentenomycins have exhibited antibiotic effects
against both Gram-positive and Gram-negative
bacteria (Umino et al. 1974).
The biological activities of the natural cyclo-
pentenones have attracted several synthetic stud-
ies. A total synthesis carried out in 2000 allowed
for the establishment of the (4R,1R)- and (1R)-
congurations for 72 and 73, respectively (Usami
et al. 2000). The same work also deduced that the
major molecule with the R conguration coexists
with its enantiomer in natural trichodenone A
(71). Total synthesis of pentenomycins (Elliott
et al. 1983; Hetmanski et al. 1984; Sugahara and
Ogasawara 1999; Seepersaud and Al-Albed 2000;
Gallos et al. 2001), their racemates (Smith and
Pilla 1980; Sono et al. 1980; Smith et al. 1982;
Pohmakotr and Popuang 1991) and their ana-
logues epipentenomycin II (79) and III (80) (Sono
et al. 1980; Elliott et al. 1983) have been achieved.
Azaphilones
The azaphilones form a structurally diverse fam-
ily of natural products containing a highly oxy-
genated bicyclic core and a chiral quaternary
center (Fig. 13). Two azaphilone-type com-
pounds, harziphilone (81) and eephilone (82),
were isolated from the butanolmethanol (1:1)
extract of the fermentation broth of T. harzianum
by bioassay-guided fractionation. Compound 81
belongs to the class of hydrogenated azaphilones,
while 82 seems to be structurally related to
azaphilones with a 3-hydroxy butanoyl moiety.
Harziphilone (81) and eephilone (82) have
demonstrated inhibitory activity against the bind-
ing of REV-proteins to RRE RNA with IC
50
values of 2.0 lM and 7.6 lM, respectively.
Furthermore, 81 demonstrated cytotoxicity at
38 lM against the murine tumor cell line M-109
(Qian-Cutrone et al. 1996).
O
O H
O H
O
N
O
O
O
O
OH O
OH
H
H
81 82
O
O
O
O
O
H
O H
O
(CH
2
)
6
CH
3
O
O
O
CH
3
(CH
2
)
6
O
83 84
O
O
O
O
O
N
Cl
O
AcO
Et
O
COOH
85 86
Fig. 13 Azaphilones
100 Phytochem Rev (2008) 7:89123
1 3
Recently, two commercial strains of T. harzia-
num have been found to produce T22azaphilone
(83). This compound showed marked in vitro
inhibition of Rhizoctonia solani, Pythium ultimum
and Gaeumannomyces graminis var. tritici (Vinale
et al. 2006). Other examples of fungal metabolites
of the azaphilone family are the sphingosine
kinase inhibitor S-15183a (84), which was isolated
from Zopella inermis in 2001 (Kono et al. 2001);
trichoectin (85) from submerged cultures of the
ascomycete Trichopezizella nidulus (Thines et al.
1998) and the antibiotic isochromophilone IX
(86), obtained from the cultured mycelia of a
fungus of the Penicillium species (Michael et al.
2003). The potent biological activities of this class
of compounds may be related to the reaction of
the 4H-pyran nucleus with amines to produce the
corresponding vinylogous 4-pyridones (Zhu et al.
2004).
Harzialactones and derivatives
Two new hydroxy-lactones named harzialactones
A (87) and B (88), and the known R-mevalono-
lactone (88a) (Fig. 14) were isolated from the
OUPS-N115 strain of T. harzianum, originally
separated from the sponge Halichondria okadai
(Amagata et al. 1998).
Total synthesis of compound 87 and their
isomers (3S,5R), (3R,5S) and (3S,5S) allowed for
the unambiguous assignation of the absolute ste-
reochemistry (3R,5R) to harzialactone A (Merey-
ala et al. 2000). Additionally biological assays have
shown that metabolism of cholesterol in aged skin
is activated by applying 88a. This characteristic
indicates potential use as a skin cosmetic with anti-
aging effects (Yamashita 2000).
Butenolides
Bioactive secondary metabolites with a buteno-
lide ring system have been identied in some
fungi (Fig. 15). Harzianolide (89) has been iso-
lated from three different strains of T. harzianum
(Almassi et al. 1991; Claydon et al. 1991; Ordent-
lich et al. 1992). Meanwhile, Almassi et al. also
found the dehydro-derivative 90. Biosynthesis of
these compounds probably involves two Favorskii
rearrangements from a C-14-diepoxide resulting
in the extrusion of the two carbons that form the
lactone (Sivasithamparam and Ghisalberti 1998).
Recently, T39butenolide (91) was isolated from a
commercially available T. harzianum strain
(Vinale et al. 2006).
All of these compounds, 8991, have shown
antagonism towards the growth of the take-all
fungus Gaeumannomyces graminis var. tritici
(Almassi et al. 1991; Vinale et al. 2006). In
particular, harzianolide (89) completely inhibited
G. graminis var. tritici at 200 lg and T39buteno-
lide (91) at 100 lg. Furthermore, 89 and 91
inhibited the growth of Rhizoctonia solani and
Pythium ultimum (Vinale et al. 2006).
In 1997, 5-hydroxyvertinolide (92) a different
butenolide of the vertinolide series was isolated
from the fungus T. longibrachiatum Rifai aggr.
which is antagonistic to the fungus Mycena
citricolor, the agent responsible for American
leaf spot disease of coffee (Andrade et al. 1992).
Other examples of fungal butenolides are the
O
CH
2
Ph
O H
O
O
O H R
O
87 88 R= -CH=CH
2
88a R= Me
Fig. 14 Harzialactones and derivatives
O
R1
O
R2
O
O
89 R1=H, R2=OH
91 R1, R2= O
90
O
O
O H
OH O
O
O
R
92
93 R= -(CH
2
)
5
CH(OH)CH
3
94 R= -(CH
2
)
4
CH(OH)CH
2
CH
3
Fig. 15 Butenolides
Phytochem Rev (2008) 7:89123 101
1 3
phytotoxic compounds seiridin (93) and
isoseiridin (94) isolated from Seiridium cardinale,
the pathogen of cypress canker disease (Evidente
et al. 1986; Sparapano et al. 1986). The biological
activity of these compounds and derivatives was
reported in 1995 (Sparapano and Evidente 1995).
Trichothecenes
Fusarium genus is the main producer of tricho-
thecene metabolites, although these are also
produced by other fungal species (Grove, 1988,
1993, 1996). These closely related sesquiterpe-
noids possess a 12,13 epoxide ring and a variable
number of hydroxyl or acetoxy groups (Fig. 16).
Some commonly found trichothecenes only differ
by one acetyl group, for example, acetylated
deoxynivalenol (95), nivalenol (96), HT-2 (97)
and T2 toxin (98). The epoxide ring is considered
to be and essential contributor to their toxicity
(Roush and Russo-Rodriguez 1987). Most of
them also have a C-9,10 double bond, also
important playing an important role in their
activity (Ehrlich and Daigle 1987). Trichothec-
enes present a wide range of biological activities
and are considered mycotoxins for human and
animal health. They are found to cause symptoms
such as vomiting, food refusal, diarrhea, intestinal
hemorrhage, and impairment of the immune
response (Hussein and Brasel 2001).
Trichothecenes are divided into four categories
according to functional groups (DMello et al.
1997). Type A has a functional group other than a
keto group at C-8. This is the largest group and
includes toxins like T-2 toxin (98). Type B
trichothecenes have a keto group at C-8 and
include the most widespread trichothecene de-
oxynivalenol (99). The third category (Type C)
has a second epoxide ring at C-7,8 or C-9,10 and
toxins from the fourth group (Type D) contain a
macrocyclic ring between C-4 and C-15 with two
ester-linkages.
Trichodermin (100) was rst isolated in 1964
from a proposed T. viride strain (Godtfredsen and
Vangedal 1964). Subsequently, this compound
has been obtained from T. polysporum and
T. sporulosum (Adams and Hanson 1972) and
O
O
O
OR
1
H H
OR
1
OR
1
R2
10
9
8
7 5
13
12 4
3
O
O
O
OH
H H
H
OAc
OR
O
95 R1= Ac, R2= H
96 R1= H, R2= OH
99 R1= R2= H
97 R= H
98 R= Ac
O
O
H H
OR
O
O
H H
O
O OH
O
100 R= Ac
101 R= H 102
Fig. 16 Trichothecenes
102 Phytochem Rev (2008) 7:89123
1 3
T. reesei (Watts et al. 1988). The deacetyl deriv-
ative trichodermol (101) was obtained by hydro-
lysis of 100 (Godtfredsen and Vangedal 1964),
and later isolated as a natural product from
T. polysporum and T. sporulosum (Adams and
Hanson 1972). Both structures were fully eluci-
dated and revised by NMR and X-ray crystallog-
raphy in the mid-60s (Godtfredsen and Vangedal
1965; Abrahamsson and Nilsson 1966). Tricho-
dermin (100) was shown to be an inhibitor of the
elongation and termination steps in the protein
synthesis (Westerberg et al. 1976). This com-
pound also showed cytotoxic activity towards
several cell lines (Choi et al. 1996). Trichodermol
(101) has been claimed as an antimalarial agent
(Takashima and Wataya 1999).
T-2 toxin (98) was produced from a T. ligno-
rum strain isolated from moldy corn (Bamburg
and Strong 1969). It is a potent mycotoxin with an
important bearing on human health (McKean
et al. 2006). In addition, a culture of T. harzianum
was found in 1994 to produce harzianum A (102)
(Corley et al. 1994). This compound showed
cytotoxicity to HT1080 and HeLa cell lines with
IC
50
values of 0.65 and 5.07 lg/ml, respectively
(Lee et al. 2005).
A recent study based on metabolite proles,
micromorphology, macromorphology and DNA
sequences criteria, has revised the T. viride and
T. harzianum strains from which 100 and 102
were originally isolated to be T. brevicompactum.
Moreover, certain doubts surround the isolation
of T-2 toxin (98) from Trichoderma species
(Nielsen et al. 2005).
Isocyano metabolites
Isocyano metabolites from the Trichoderma spe-
cies have a characteristic ve-member ring with
various levels of oxidation in the form of alkenyl,
hydroxy, and/or epoxide functions. Although
approximately 1020 isonitriles were detected
their isolation and separation has proven to be
extremely difcult. Two types of skeleton can be
found for these compounds: dermadin-type (103)
(Fig. 17) and trichoviridin-type (104) (Fig. 18),
with a b-propionic acid or ethyl residue respec-
tively (Chang 2000).
The rst reports on isocyano cyclopentenes in
Trichoderma species were published 40 years ago
(Pyke and Dietz 1966; Meyer 1966). Authors
reported biological and chemical properties for a
substance with code name U-21,963 fromT. viride.
Subsequently, this compound was named
dermadin (105) (Fig. 17) and its antibiotic activity
was patented in 1971 (Coats et al. 1971). Derm-
adin (105) was also isolated from T. koningii in
1975 (Tamura et al. 1975) and its methyl ester
derivative (106) obtained from T. hamatum
(Brewer et al. 1979). All data available for 105
seems to t with that reported for isonitrinic acid
E, which was isolated from T. hamatum in 1982
(Fujiwara et al. 1982). In this work isonitrinic acid
F (107) was also described. The diol-isomers 108
and 109 and the spirolactones 110 and 111 were
HOOC
NC
103
ROOC
NC
O
NC
HOOC
105 R= H
106 R= CH
3
107
O H
NC O H
HOOC
O H
NC O H
HOOC
108 109
O
O
NC
O
O
NC
OH
110 111
Fig. 17 Dermadin-type cyclopentylisocyanides
Phytochem Rev (2008) 7:89123 103
1 3
obtained from fermentations of the T. hamatum
HLX 1379 strain (Baldwin et al. 1985; Boyd et al.
1991).
The isonitrile trichoviridin (112) (Fig. 18) was
rst isolated in 1975 by Tamura et al. and one
year later by Nobuhara et al. (1976) from
T. koningii. Antibiotic properties of this com-
pound and its isolation from T. viride were the
subject of a patent in 1970 (Yamano et al. 1970).
X-ray crystallographic analyses were performed
by Ollis et al. (1980). Isonitrins A (113), B (114),
C and D (115) were obtained from T. hamatum
in 1982 (Fujiwara et al. 1982). Data for isonitrin
C appear to be identical to those corresponding
to 112. The structures of 113 and 114 were
established by X-ray studies while that of 115
was deduced by spectral methods. Syntheses of
racemic trichoviridin (112), deoxytrichoviridin
(isonitrin B) (114) and isonitrin A (113) were
achieved by Baldwin et al. in 1996, 1989 and
1991, respectively.
Metabolites 116 and 117 are two further
examples of hydroxy-cyclopentylisocyanides
(Boyd et al. 1991; Baldwin et al. 1985). The rst
was detected and isolated as a rhodium complex
following two-dimensional chromatography and
the use of [Rh{(g
5
-C
5
Me
5
)(SCN)
2
}
2
] as reagent.
An isomer of 116, designated as MR 304A (118),
was isolated by Lee et al. (1995b) from a strain of
T. harzianum. The relative stereochemistry was
based on NOE experiments and on the magni-
tudes of the coupling constants. This compound
inhibited melanin formation in Streptomyces
bikiniensis and B16 melanoma cells and inhibited
mushroom tyrosinase activity but did not exhibit
antimicrobial activity. Continued studies on
another T. harzianum strain resulted in isolation
of MR566B (119) and the report of the rst
chlorine-substituted cyclopentyl isonitrile,
MR566A (120). The IC
50
values of 120 and 119
against mushroom tyrosine were 1.72 and 47 lM,
respectively. They also inhibited melanin biosyn-
thesis in B16 melanoma cells with MIC values of
0.1 and 2.2 lM, respectively (Lee et al. 1997a, b).
In addition, strains of T. koningii afforded a
serie of cyclopentenes named homothallin I (121)
(Pratt et al. 1972; Edenborough and Herbert
1988), homothallin II (122), and the amine-,
formamide-, and N,N-dimethylamine-derivatives
from 122 (123125) (Edenborough and Herbert
1988; Mukhopadhyay et al. 1996). Production of
homothallin II (122) by a UV-induced mutant
strain of T. harzianum has been also reported
(Faull et al. 1994).
Cyclopentylisocyanide metabolites have been
found to have physiological activity in three
distinct elds: (I) induction of bacteriostasis
in vivo and in vitro of functionally important
rumen bacteria and the reversal of this activity
by nickelous ion (Brewer et al. 1982, 1986, 1990);
(II) induction of oospores of the A2 mating type
of Phytophthora spp. and other effects on fungal
morphology (Pratt et al. 1972; Reeves and Jack-
son 1972; Brasier 1975); (III) inhibition of the
enzyme tyrosinase and its implication for melanin
biosynthesis in mammals (Lee et al. 1997a, b).
NC
O
NC
O H
OH
O
O
H
O
NC
104 112 113
O
NC
O H
OH
NC
OH
O OH
O H
OH
OH
NC
114 115 116
O
O H
O H
NC O H
O H
OH
NC
OH
O H
OH
NC
OH
OH
117 118 119
O H
OH
NC
Cl
O H
O
NC R O
O H
120 121 122 R= NC
123 R= NH
2
124 R= NHCHO
125 R= N(CH
3
)
2
Fig. 18 Trichoviridin-type cyclopentylisocyanides
104 Phytochem Rev (2008) 7:89123
1 3
Setin-like metabolites
The dual culture of T. harzianum and Catharan-
thus roseus callus produced an antimicrobial
compound named trichosetin (126) (Fig. 19), with
remarkable activity against the Gram-positive
bacteria Staphylococcus aureus and Bacillus sub-
tilis (Marfori et al. 2002). Compound 126 shows
an alkylated decalin skeleton bearing a tetramic
acid moiety. In seedling growth assays, 126
inhibited root and shoot growth of the plant
species Oryza sativa, Vigna radiata, Medicago
sativa, Capsicum frutescens and Lycopersicum
esculentum. Tests were performed analyzing
damage on cell membranes (Marfori et al. 2003).
Equisetin (127), a homolog of 126, was
obtained from several Fusarium species. This
compound is a potent inhibitor of the HIV-1
integrase enzyme and has been claimed as an
antibiotic against Gram-positive bacteria (Bur-
meister et al. 1974). Phytotoxic assays suggest
that 127 may be a pathogenic factor of Fusarium
species on seed and seedling health of cotton and
other plants (Wheeler et al. 1999). Another setin-
like fungal metabolite is phomasetin (128) which
was isolated from a Phoma species and also shows
in vitro inhibition of the HIV-1 integrase enzyme
(Singh et al. 1998).
In addition, cissetin (129) was isolated from
fungus OSI 50185 and is active against several
Gram-positive organisms but it is most known for
the atypical cis ring fusion in the octalin portion
of the molecule. Cissetin (129) was 48 times
more active than 126 and 127 against penicillin-
resistant Streptococcus pneumoniae (Boros et al.
2003).
Bisorbicillinoids
The bisorbicillinoids are a growing family of
novel natural products with interesting and
diverse biological activities. Fungal species of
the Trichoderma genus are the main producers of
this kind of compounds. Bisorbicillinoids
(Figs. 21, 22) are thought to be derived from
sorbicillin (130) (Fig. 20), itself a naturally occur-
ring substance (Andrade et al. 1992; Abe et al.
1998b), or a closely related derivative such as
sorbicillinol (131) (Abe et al. 2000a). Other
vertinoid sorbicillin-derivatives such as demeth-
ylsorbicillin (132), oxosorbicillinol (133) (Abe
et al. 2000b) and epoxysorbicillinol (134)
(Fig. 20) (Sperry et al. 1998), have also been
obtained from several Trichoderma species.
N
H
H
OH
O
O
O H
R
126 R= H
127 R= Me
N
H
H
OH
O
O
O H
N
H
H
OH
O
O
O H
128 129
Fig. 19 Setin-like antibiotics
O H
O
OH
OH
O
O
OH
130 131
OH
O H
O
O
O H
OH
O
OH
132 133
OH
O
O
O
OH
134
Fig. 20 Sorbicillin derivatives
Phytochem Rev (2008) 7:89123 105
1 3
Trichodimerol (135) (Fig. 21) has been isolated
from three different sources: T. longibrachiatum
(Andrade et al. 1992), Penicillium chrysogenun
(Warr et al. 1996), and the USF-2690 strain of
Trichoderma (Abe et al. 1998a). This compound
exhibits signicant inhibitory activity against
lipopolysaccharide-induced production of tumor
necrosis factor a (TNF-a) in human monocytes
and thus represents a new lead for a potential
treatment of septic shock (Mazzucco and Warr
1996). Two new derivatives of 135, the demethyl
derivative 136 (Abe et al. 1998a) and bisorbibe-
tanone (137) (Abe et al. 1999), were obtained
from the Trichoderma USF-2690 strain. Subse-
quent fermentations of this strain also afforded
bisorbicillinol (138) (Abe et al. 1998a), bisorbi-
butenolide (139) and bisorbicillinolide (140) (Abe
et al. 1998b). All of these compounds exhibited
antioxidant properties.
Furthermore, fermentation of T. longibrachia-
tum has allowed for the attainment of bisvertino-
lone (141) (Andrade et al. 1992; Abe et al.
1998a), and its reduced form bisvertinol (142)
(Andrade et al. 1992), bislongiquinolide (bisorb-
ibutenolide) (139) (Andrade et al. 1997), tricho-
dermolide (143) and sorbiquinol (144) (Andrade
et al. 1996) (Fig. 22). Compound 141 presents
antifungal properties developed via inhibition of
b-(1,6)-glucan biosynthesis (Kontani et al. 1994).
Two different dimeric compounds were iso-
lated from Trichoderma sp. Trichotetronine (145)
and its dihydro congener 146 (Fig. 22), possess a
tetronic acid moiety and their relative and abso-
lute stereochemistry were established using a
variety of data including extensive NMR and
CD spectral studies (Shirota et al. 1997).
Recently, two new bisorbicillinoids named
dihydrobisvertinolone (147) and tetrahydrobis-
O
O
OH
O H
OH
OH
O
O
R
O
O
O
O
O H
OH
OH
OH
O
135 R= Me
136 R= H
137
O
O
OH
OH
O
O H
O H
O
O
O
O
OH
OH
OH
O
O
138 139
O O
OH
OH
O
O
O
OH
140
Fig. 21 Bisorbicillinoids 1
106 Phytochem Rev (2008) 7:89123
1 3
vertinolone (148) (Fig. 22) have been isolated
from a marine-derived fungus Penicillium species.
Their structures were established on the basis of
spectroscopic methods and their cytotoxic effects
on P388 and A-549 cell lines were preliminarily
examined (Liu et al. 2005b)
Several studies were performed in order to
clarify the biosynthetic origin of this class of
compounds (Abe et al. 2001, 2002a, b). In support
of the proposed biosynthetic pathways, two
research groups independently and concurrently
completed the total biomimetic syntheses of
bisorbicillinol (138) and trichodimerol (135)
(Fig. 23) (Nicolaou et al. 1999, 2000; Barnes-
Seeman and Corey 1999).
Diketopiperazines
Gliotoxin (149) (Fig. 24) was the rst member
of this class of compounds to be identied.
O
O H
OH
H
O
OH
O
O H
O OH
2'
3'
2''
3''
O
O H
OH
H
OH
OH
O
OH O
141
147 2,3-dihydro
148 2,3,2,3-tetrahydro
142
O
O
O
O
O
H
H
O H
O
O
OH
H
O
OH
O H
143 144
O
OH
O
O
O
O H
O
OH
C H
3
24
25
145
146 24,25-dihydro
Fig. 22 Bisorbicillinoids 2
Phytochem Rev (2008) 7:89123 107
1 3
Production of 149 by T. viride has been known
since 1944 (Brian 1944). Subsequent isolations
(Wright 1954) and biosynthetic analyses (Kirby
and Robins 1980) have been performed from
this strain. In 1975 Hussain et al. also isolated
this compound from T. hamatum. Gliotoxin
(149) displays a wide range of biological effects
including antiviral, antibacterial and immuno-
suppressive properties (Hebbar and Lumsden
1998). Gliovirin (150) (Fig. 24) was isolated
from the fungus Glioclaudium virens (Tricho-
derma virens) (Stipanovic and Howell 1982).
Recently, analysis of the evolution of the
concentration of this toxin in a compost used
as carrier for three Trichoderma species (T. har-
zianum, T. hamatum and T. koningii) was
performed (Haggag and Abo-Sedera 2005). In
addition, an isolate of T. longibrachiatum, cul-
tured in medium containing sucrose, dry yeast
and salts, produced the analogues (151a, b)
(Fig. 24) which showed inhibitory activity to
Staphylococcus aureus (MIC 13 lg/ml) (Nakano
et al. 1990). Strains producing 149 were antag-
onistic to Rhizoctonia solani (Jones and Pettit
1987), whereas those producing gliovirin (150)
were effective against Pythium ultimum (Howell
and Stipanovic 1983).
Ergosterol derivatives
Sterol production in Trichoderma species was rst
detected by Kamal et al. (1971) in the fermenta-
tion of a T. pseudokoningii strain. Lanosterol
(152), ergosterol (153) and pyrocalciferol (154)
were obtained (Fig. 25). Ergosterol (153), the
most commonly occurring fungal sterol, was also
isolated in 1975 from T. hamantum (Hussain et al.
1975). More recently, two highly oxygenated
ergosterol-derivatives, named ergokonin A (155)
and B (156) (Fig. 25) were isolated from T. kon-
ingii (Reichenbach et al. 1990; Augustiniak et al.
1991). Subsequently, ergokonin A (155) was also
isolated from T. viride (Kumeda et al. 1994) and
T. longibrachiatum (Vicente et al. 2001). The
inhibition of yeast and mycelial fungi using
ergokonins was the subject of a patent, 155 being
approximately ten times more potent than 156
(Reichenbach et al. 1990). In addition, ergokonin
A (155) has proven active against Candida and
Aspergillus species but is ineffective against
Cryptococcus, Fusarium and Saccharomyces
(Vicente et al. 2001). Interestingly, a third anti-
fungal analogue, ergokonin C (157), was isolated
from a Tolyplocadium inatum mutant (Graefe
et al. 1991).
O
O
OH
O H
OH
OH
O
O
R
O
O
OH
OH
O
O H
O H
O
O
OH
O
AcO
O
O
OH
O H
O
OH
O
O H
A
KOH then HCl (aq)
or conc/HCl
dienophile diene
1. NaOMe, MeOH
B
Diels-Alder reaction
2. NaH2PO4-H2O
3. HCl, MeOH
138
135
Fig. 23 Biomimetic total syntheses of 138 by Nicolaou et al. (Path A) and of 135 by BarnesSeeman and Corey (Path B)
108 Phytochem Rev (2008) 7:89123
1 3
Peptaibols
The peptaibols are a large and growing family of
linear natural products biosynthesized by many
fungi. Fungal species of the Trichoderma genus
are the main producers of this class of compounds
which contain 720 amino acids and characteris-
tically have an acylated N-terminal group, a
C-terminal amino alcohol, and a high content of
2-amino-isobutyric acid (Aib). Unusual amino
and imino acids found in peptaibols include
isovaline, b-alanine, hydroxyproline and pipecolic
acid. The rst compound of this class was isolated
from T. viride and named alamethicin F30 (158)
(Fig. 26) (Brewer et al. 1987; Meyer and Reusser
1967). The interest in these compounds arose
from their effectiveness as antimicrobial agents
towards Gram-positive organisms. Other
N
N
O
O
S
S
H
OH
OH
149
O
N
NH
O H
S
S
O OH
H
O
O
H
H
OMe
OMe O
N
NH
O H
S
S
O OH
OH
O R
OMe
OMe
150 151a R= Cl
151b R=Br
Fig. 24 Diketopiperazines
O H
H
O H
R
H H
152
153 R= -Me
154 R= -Me
RO
HO
2
C
O
OH
155 R= COCH(NH
2
)CH(OSO
3
H)CHMe
2
156 R= H
157 R= COC(NH
2
)Me
2
Fig. 25 Sterols
Phytochem Rev (2008) 7:89123 109
1 3
examples of peptaibols are included in Table 1
with their respective references.
The trichogins A from T. longibrachiatum
(Auvin-Guette et al. 1992) and the trichodecenins
(159) from T. viride (Fujita et al. 1994) are
examples of lipopeptaibols. The trichopolyns,
e.g. 160 (Fig. 26), from T. polysporum have an
R-2-methyldecanoyl group esterifying the N-ter-
minal amino acid, a 2-amino-6-hydroxy-4-methyl-
8-oxodecanoic acid residue at position 2 and the
unusual C-terminal group (Fujita et al. 1981;
Mihara et al. 1994).
Cyclonerodiol derivatives
Sesquiterpenic compounds bearing a 4-methyl-3-
pentenyl chain and derivatives have been
obtained from culture broth of Trichoderma
species. Cyclonerodiol (161) (Fig. 27) has been
known since the 70s. Firstly reported from a strain
of Trichothesium (Nozoe et al. 1970) and Gib-
berella fujikuroi (Pitel et al. 1971), it was isolated
from T. koningii (Cutler et al. 1991b; Huang et al.
1995a) and from T. harzianum (Ghisalberti and
Rowland 1993). Two derivatives of 161, cyclon-
erodiol oxide (162) and epicyclonerodiol oxide
(163), were isolated from T. polysporum (Fujita
et al. 1984). In addition, a compound with santa-
lane-like structure named lignoren (164), was
recently isolated from T. lignorum by chromato-
graphic methods (Berg et al. 2004).
Cyclonerodiol (161) shows certain biological
activity. It inhibits growth of etiolated wheat
coleoptiles 61% at 0.001 M (Cutler et al. 1991b)
and also inhibits the sodium channel in voltage-
clamped frog skeletal muscle bers (Sauviat et al.
1992). Additionally, lignoren (164) displays mod-
erate antimicrobial activity towards Bacillus sub-
tilis, Mycobacterium smegmatis, Pseudomonas
aeruginosa, Sporoblomyces salmonicolor and
Rhodotorula rubra, but no activity was found
against Candida albicans, Penicillium notatum or
Fusarium culmorum (Berg et al. 2004).
Statins
Statins are a diverse group of drugs, which share
the ability to inhibit HMG CoA reductase and
thereby the conversion of acetoacetyl CoA to
mevalonate, the rate-limiting step in cholesterol
biosynthesis. By inhibiting mevalonate produc-
tion, statins inhibit the pathway leading to the
generation of farnesylpyrophosphate and gera-
nylgeranyl pyrophosphate, two pyrophosphates
Ac-Aib-Pro-Aib-Ala-Aib-Ala-Gln-Aib-Val-Aib-Gly-Leu-Aib-Pro-Val-Aib-Aib-Glu-Gln-Phe-OH
158
Me(CH
2
)
4
CH=CH(CH
2
)
3
CO-Gly-Gly-Leu-Aib-Gly-Ile-Leucinol
159
methyldecanoyl-Pro- N
H
Ala-Aib-Aib-Ile-Ala-Aib-Aib
O
O
N H
N
OH
CH
3
H
(R)-2-
160
Fig. 26 Peptaibols
structures
110 Phytochem Rev (2008) 7:89123
1 3
which are critical for the induction of a variety of
signal transduction pathways, which promote a
cascade of events leading to endothelial dysfunc-
tion, inammation, proliferation, apoptosis and
other effects important for atherogenesis (Jako-
bisiak and Golab 2003).
Compactin (165) (Fig. 28), also named mevast-
atin, has been isolated from different sources
including several fungi such as Penicillium brev-
icompactum (Brown et al. 1976), T. longibrachi-
atum and T. pseudokoningii (Endo et al. 1986).
This compound has attracted considerable global
attention due to its biological activity as a
cholesterol-lowering agent (Endo 1985; Goldstein
et al. 1979). The key structural feature of 165 is
the chiral b-hydroxy-d-lactone moiety which, in
its open acid form, closely mimics mevalonic acid,
a crucial intermediate in the biosynthesis of
cholesterol as previously described (Rosen et al.
1983; Stokker et al. 1985). Monacolin K (166),
also named lovastatin, which is obtained from
different fungal species such as Monascus,
Verticillium or Aspergillus; and simvastatin
(167), a synthetic derivative of 166, are leading
the worldwide lipid-lowering drug market (Jones
1990).
Heptelidic acid and derivatives
The sesquiterpene heptelidic acid (168) (Fig. 29),
also named koningic acid, was found in the
Table 1 Examples of peptaibols
T. viride
Suzukacillin A Krause et al. (2006)
Trichotoxin A40 Brueckner et al. (1985)
Trichovirins II Jaworski et al. (1999)
Trichorovins Fujita et al. (1994)
Trichodecenins I, II Fujita et al. (1994)
Trichocellins Fujita et al. (1994)
T. polysporum
Polysporins AD New et al. (1996)
Trichosporin BV Iida et al. (1993)
T. reesei
Paracelsin Breuckner et al. (1984)
T. saturnisporum
Paracelsin E Ritieni et al. (1995)
Saturnisporins SA II, SA
IV
Rebuffat et al. (1993)
T. koningii
Trichokonins VVIII Huang et al. (1995b)
Trikoningin KA, KB Auvin-Guette et al. (1993)
T. longibrachiatum
Trichobrachin A IIV, B I
IV
Mohamed-Benkada et al.
(2006)
Tricholongins B I, B II Rebuffat et al. (1991)
Longibrachin LGBII,
LGBIII
Leclerc et al. (2001)
Trichogin A IV Auvin-Guette et al. (1992)
T. harzianum
Trichorzianines A, B El Hajji et al. (1987),
Rebuffat et al. (1989)
Trichokindins IVII Iida et al. (1994)
Harzianins HC Rebuffat et al. (1995)
Trichorozins IIV Iida et al. (1995)
T. atroviride
Atroviridins AC Oh et al. (2000)
Trichoderma sp.
Trichofumin AD Berg et al. (2003)
O H
OH
O
R
OH
H
161 162 R= -CMe
2
OH
163 R= -CMe
2
OH
O
164
Fig. 27 Cyclonerodiol derivatives
O
O
O
H
H
O OH
R1
R2
165 R1= R2= H
166 R1= -Me, R2= H
167 R1= R2= -Me
Fig. 28 Statins
Phytochem Rev (2008) 7:89123 111
1 3
culture ltrate of three different strains of fungi
isolated from soil samples. These strains were
identied as Gliocladium virens, Chaetomium
globosum, and Trichoderma viride (Itoh et al.
1980). The antimicrobial spectrum of the antibi-
otic 168 showed its specic activity against
anaerobic bacteria, especially against Bacteroides
fragilis (Itoh et al. 1980). Isolation from Tricho-
derma koningii and subsequent bioactivity assays
revealed its potent ability to alter ATP generation
through inhibition of the D-glycealdehyde-3-phos-
phate dehydrogenase (GAPDH) (Endo et al.
1985; Sakai et al. 1988; Kato et al. 1992). This
compound has also been shown to have in vitro
activity towards the human malaria parasite
Plasmodium falciparum (Tanaka et al. 1998).
Heptelidic acid chlorohydrin (169) (Fig. 29),
obtained from an Acremonium strain, showed
in vitro cytotoxicity against some types of human
tumor cells with IC50 values of 0.130.74 lg/ml
(Kawashima et al. 1994).
Pentalenolactone (170) (Fig. 29), an antibiotic
produced by several strains of Streptomycetes, is
mechanistically related to 168 in terms of its
biological activities. It is an inactivator of
GAPDH and active against a wide range of
microorganisms, including Gram-positive and
Gram-negative bacteria, pathogenic and sapro-
phytic fungi and protozoa. It also inhibits repli-
cation of DNA viruses such as HSV-1 and HSV-2,
the causal agents of herpes simplex (Cane and
Sohng 1994)
Acoranes
Acoranes are a family of spiro-sesquiterpenic
compounds obtained from different sources. Tric-
hoacorenol (171) (Fig. 30) was isolated from T.
koningii (Huang et al. 1995a). It was hailed as a
newcompound, but in fact it is identical to coccinol
which was previously isolated from Fusidium
coccineum. The acorane-type 15-hydroxyacore-
none (172) (Fig. 30) was isolated from the culture
broth of T. harzianum (Tezuka et al. 1997). This
compound is a known metabolite of the medicinal
mushroom Ganoderma lucidum (Fr.) Karst.
Other examples of acoranes are acorenone
(173), obtained from essential oils of several plant
species and culture broth of fungi; and its isomers
acorenone-B (174), 4-epiacorenone (175) and
4-epiacorenone-B (176) (Fig. 30). Compound
174 shows strong anti-resistance activity against
multi-drug resistant microorganisms such as
Staphylococcus aureus SA2.
O
O
O
H
H
COOH
O
H
H
COOH
O H
Cl
168 169
O
O
O
H
COOH
170
Fig. 29 Heptelidic acid and closely related compounds
O H
O
R1
R2
171 172 R1= -Me, R2= OH
173 R1= -Me, R2= H
175 R1= -Me, R2= H
O
R
174 R= -Me
176 R= -Me
Fig. 30 Acoranes
112 Phytochem Rev (2008) 7:89123
1 3
Miscelanea
Trichoharzin (177) (Fig. 31) was isolated from the
culture broth of a strain of T. harzianum, which
was separated from the marine sponge Mycale
cecilia. This polyketide is characterized by an
alkylated decalin skeleton esteried with 3-meth-
ylglutaconic acid (Kobayashi et al. 1993).
The tetracyclic compound harziandione (178)
(Fig. 31) is claimedtobe the rst diterpene isolated
from Trichoderma species. It was obtained by
Ghisalberti et al. (1992) from T. harzianum.
A coumarin-type metabolite was isolated by
liquid culture of a strain of T. aggresivum and was
identied as 3,4-dihydro-8-hydroxy-3-methyliso-
coumarin, also named mellein (179) (Fig. 31).
This compound, previously isolated from Asper-
gillus sp. (Burton 1950; Sasaki et al. 1970), is
effective against Agaricus bisporus and other
fungal species (Krupke et al. 2003).
The novel acetophenone derivative 2,4-di-
hydroxy-3-methoxymethyl-5-methylacetophe-
none (180) (Fig. 31) and the known 2,4-
dihydroxy-3,5-dimethylacetophenone (clavatol,
181), were isolated from the culture ltrate of a
Chilean strain of T. pseudokoningii (Astudillo
et al. 2000).
In addition, the production of ceramide (182)
(Fig. 31), cyclo-(L-Pro-L-Leu) (183), meth-
ylbenzoate, p-hydroxybenzyl alcohol and uracil
O
O
O O H
H
H
OH
H
COOH
O
O
177 178
O
OH O
OH O
R
O H
(CH
2
)
13
CH
3
OH
N H
O
OH
(CH
2
)
21
CH
3
OH OH
179
180 R= CH
2
OCH
3
181 R= CH
3
182
N H
N
O
O
H
H
O H
H H
H N
H
H
O
O
O
H N
H
H
O
183 184 185
O
O
O
O
O
O
O
186
Fig. 31 Miscelanea
Phytochem Rev (2008) 7:89123 113
1 3
from T. koningii has been established (Huang
et al. 1995a). Moreover, 2,5-dimethylbenzoqui-
none, 2-hydroxymalonic acid, epifriedelinol (184)
(Fig. 31), itaconic acid, methyl-2,4,6-octatriene
carboxylate, succinic acid and trichodermene A
have been detected in culture broth of T. pseudo-
koningii (Kamal et al. 1971).
Valinotricin (185) (Fig. 31) (Fujita et al. 1984)
is an ester which can formally be considered to be
generated by condensation of N-formyl valine
and N-formyl valinol. This compound was
obtained from T. polysporum in 1984 (Fujita
et al. 1984).
The simple compounds isoamyl alcohol, octan-
3-one, 1-octen-3-ol, octanol (Saito et al. 1979),
2-phenylethanol, tyrosol (Tarus et al. 2003) and
mannitol (Hussain et al. 1975) have also been
isolated from Trichoderma species. Carolic acid
(186) (Fig. 31) has been obtained from a Tricho-
derma sp. and has also been shown to exist as a
mixture of E and Z-isomers in solution (Turner
and Aldridge 1983).
Conclusions
As mentioned in this review, Trichoderma spp.
are free-living fungi that are common in soil
and root ecosystems. These fungi are well
known for their ability to produce a wide range
of antibiotic substances and for their ability to
parasitize other fungi. In addition to these
direct effects on other fungi, recent evidence
indicate that many Trichoderma spp., including
Trichoderma virens, Trichoderma atroviride and
Trichoderma harzianum, can induce both local-
ized and systemic resistance in a range of plants
to a variety of plant pathogens, and certain
strains can also have substantial inuence on
plant growth and development (Harman et al.
2004). Trichoderma spp. produce at least three
classes of compounds that elicit plant defense
responses: peptides, proteins and low-molecular-
weight compounds.
The main interest is in those compounds that
exhibit antibiotic activity since they are more
likely to be implicated in the effectiveness of the
strain producing them as a biological control
agent. The synergistic effect with enzymes
produced by them also appears to be important.
As indicated by Cardoza et al. (2005) and
Kubicek and Harman (1998), the different metab-
olites exhibiting antibiotic activity in Trichoderma
can be classied as two main types:
Low molecular weight and volatile metabolites
which include: simple aromatic compounds, some
polyketides such as pyrones and the butenolides,
volatile terpenes, and the isocyane metabolites.
All of these are relatively non-polar substances
with a signicant vapor pressure. These volatile
organic compounds in the soil environment
would be expected to travel over distance through
systems and thus enhance the status of one
organism by affecting the physiology of compet-
itor organisms.
High molecular weight are polar metabolites
which, like peptaibols, may exert their activity on
direct interactions by contact between Trichoder-
ma species and their antagonists.
The correlation between the production of
antibiotics by an isolate and their effectiveness as
biological control agents is still matter of conjec-
ture. Activity in this eld over the last decade has
been remarkable and the interest continues
unabated at the present time, especially after
recent evidence indicating induced localized and
systemic resistance by Trichoderma spp. in a
range of plants to a variety of plant pathogens.
In addition, the study of Trichoderma spp. as a
source of biologically active metabolites is espe-
cially signicant and ensures interest on this
subject for years to come.
References
Abe N, Murata T, Hirota A (1998a) Novel DPPH radical
scavengers, bisorbicillinol and demethyltrichodimerol,
from a fungus. Biosci Biotechnol Biochem 62:661666
Abe N, Murata T, Hirota A (1998b) Novel oxidized
sorbicillin dimers with 1,1-diphenyl-2-picrylhydrazyl
radical scavenging activity from a fungus. Biosci
Biotechnol Biochem 62:21202126
Abe N, Murata T, Yamamoto K, Hirota A (1999)
Bisorbibetanone, a novel oxidized sorbicillin dimer,
with 1,1-diphenyl-2-picrylhydrazyl radical scavenging
activity from a fungus. Tetrahedron Lett 40:52035206
Abe N, Yamamoto K, Hirota A (2000a) Novel fungal
metabolites, demethylsorbicillin and oxosorbicillinol,
isolated from Trichoderma sp. USF-2690. Biosci
Biotechnol Biochem 64:620622
114 Phytochem Rev (2008) 7:89123
1 3
Abe N, Sugimoto O, Tanji K, Hirota A (2000b) Identi-
cation of the quinol metabolite sorbicillinol, a key
intermediate postulated in bisorbicillinoid biosynthe-
sis. J Am Chem Soc 122:1260612607
Abe N, Sugimoto O, Arakawa T, Tanji K, Hirota A (2001)
Sorbicillinol, a key intermediate of bisorbicillinoid
biosynthesis in Trichoderma sp. USF-2690. Biosci
Biotechnol Biochem 65:22712279
Abe N, Arakawa T, Hirota A (2002a) The biosynthesis of
bisvertinolone: evidence for oxosorbicillinol as a
direct precursor. Chem Commun 3:204205
Abe N, Arakawa T, Yamamoto K, Hirota A (2002b)
Biosynthesis of bisorbicillinoid in Trichoderma sp.
USF-2690; evidence for the biosynthetic pathway, via
sorbicillinol, of sorbicillin, bisorbicillinol, bisorbibut-
enolide, and bisorbicillinolide. Biosci Biotechnol
Biochem 66:20902099
Abrahamsson S, Nilsson B (1966) Molecular structure of
trichodermin. Acta Chem Scand 20:10441052
Adachi T, Aoki H, Osawa T, Namiki M, Yamane T,
Ashida T (1983) Structure of trichodermaol, antibac-
terial substance produced in combined culture of
Trichoderma sp. with Fusarium oxysporum or Fusa-
rium solani. Chem Lett 6:923926
Adams PM, Hanson JR (1972) Sesquiterpenoid metabo-
lites of Trichoderma polysporum and T. sporulosum.
Phytochemistry 11:423
Agarwal SK, Singh SS, Verma S, Kumar S (2000)
Antifungal activity of anthraquinone derivatives from
Rheum emodi. J Ethnopharmacol 72:4346
Aldridge DC, Turner WB, Geddes AJ, Sheldrick B (1975)
Demethoxyviridin and demethoxyviridiol, new fungal
metabolites. J Chem Soc Perkin Trans 1(10):943945
Ali S, Watson MS, Osborne RH (2004) The stimulant
cathartic, emodin, contracts the rat isolated ileum by
triggering release of endogenous acetylcholine. Auton
Autacoid Pharmacol 24:103105
Almassi F, Ghisalberti EL, Narbey MJ, Sivasithamparam
K (1991) New antibiotics from strains of Trichoderma
harzianum. J Nat Prod 54:396402
Amagata T, Usami Y, Minoura K, Ito T, Numata A (1998)
Cytotoxic substances produced by a fungal strain from
a sponge: physico-chemical properties and structures.
J Antibiot 51:3340
Anderson EA, Alexanian EJ, Sorensen EJ (2004) Synthe-
sis of the furanosteroidal antibiotic viridin. Angew
Chem Int Ed 43:19982001
Andrade R, Ayer WA, Mebe PP (1992) The metabolites
of Trichoderma longibrachiatum. Part 1. Isolation of
the metabolites and the structure of trichodimerol.
Can J Chem 70:25262535
Andrade R, Ayer WA, Trifonov LS (1996) The metabo-
lites of Trichoderma longibrachiatum. Part II. The
structures of trichodermolide and sorbiquinol. Can
J Chem 74:371379
Andrade R, Ayer WA, Trifonov LS (1997) The metabo-
lites of Trichoderma longibrachiatum. III. Two new
tetronic acids: 5-hydroxyvertinolide and bislongiqui-
nolide. Aust J Chem 50:255257
Astudillo L, Schmeda-Hirschmann G, Soto R, Sandoval C,
Sfonso C, Gonzalez MJ, Kijjoa A (2000) Acetophe-
none derivatives from Chilean isolated of Trichoder-
ma pseudokoningii Rifai. World J Microbiol
Biotechnol 16:585587
Augustiniak H, Forche E, Reichenbach H, Wray V,
Graefe U, Hoee G (1991) Isolation and structure
elucidation of ergokonin A and B; two new antifungal
sterol antibiotics from Trichoderma koningii. Liebigs
Ann Chem 4:361366
Auvin-Guette C, Rebuffat S, Prigent Y, Bodo B (1992)
Trichogin A IV, an 11-residue lipopeptaibol from
Trichoderma longibrachiatum. J Am Chem Soc
114:21702174
Auvin-Guette C, Rebuffat S, Vuidepot I, Massias M, Bodo
B (1993) Structural elucidation of trikoningins KA
and KB, peptaibols from Trichoderma koningii.
J Chem Soc Perkin Trans 1(2):249255
Baldwin JE, Adlington RM, Chondrogianni J, Edenbor-
ough MS, Keeping JW, Ziegler CB (1985) Structure
and synthesis of new cyclopentenyl isonitriles from
Trichoderma hamatum (Bon.) Bain. aggr. HLX 1379.
J Chem Soc Chem Commun 12:816817
Baldwin JE, Aldous DJ, Chan C, Harwood LM, ONeil
IA, Peach JM (1989) The total synthesis of ()-
isonitrin B (deoxytrichoviridin). Synlett 1:914
Baldwin JE, ONeil IA, Russell AT (1991) Isonitrin A:
revision of the structure and total synthesis in racemic
form. Synlett 8:551552
Baldwin JE, Adlington RM, ONeil IA, Russell AT, Smith
ML (1996) The total synthesis of ()-trichoviridin.
Chem Commun 1:4142
Bamburg JR, Strong FM (1969) Mycotoxins of the
trichothecane family produced by Fusarium tricinc-
tum and Trichoderma lignorum. Phytochemistry
8:24052410
Barnes-Seeman D, Corey EJ (1999) A two-step total
synthesis of the natural pentacycle trichodimerol, a
novel inhibitor of TNF-alpha production. Org Lett
1:15031504
Berestetskii OA, Patyka VF, Nadkernichnyi SP (1976)
Phytotoxic properties of fungi of the Trichoderma
Pers. Genus. Vopr. Ekol. Fiziol. Mikroorg., Is-
polz. Selsk. Khoz.: 5660 (Chem. Abstr. 1978,
88:148647)
Berg A, Grigoriev PA, Degenkolb T, Neuhof T, Haertl A,
Schlegel B, Graefe U (2003) Isolation, structure
elucidation and biological activities of trichofumins
A, B, C and D, new 11 and 13mer peptaibols from
Trichoderma sp. HKI 0276. J Pept Sci 9:810816
Berg A, Wangun HVK, Nkengfack AE, Schlegel B (2004)
Lignoren, a new sesquiterpenoid metabolite from
Trichoderma lignorum HKI 0257. J Basic Microbiol
44:317319
Bernillon J, Favre-Bonvin J, Pommier MT, Arpin N (1989)
First isolation of (+)-epipentenomycin I from Peziza
sp. carpophores. J Antibiot 42:14301432
Betina V, Kubela S

(1987) Uncoupling effect on fungal

hydroxyanthraquinones on mitochondrial oxidative
phosphorylation. Chem Biol Interact 62:179186
Betina V, Sedmera P, Vokoun J, Podojil M (1986)
Anthraquinone pigments from a conidiating mutant
of Trichoderma viride. Experientia 42:196197
Phytochem Rev (2008) 7:89123 115
1 3
Blight MM, Grove JF (1986) Viridin. Part 8. Structures of
the analogs virone and wortmannolone. J Chem Soc
Perkin Trans 1(7):13171322
Boros C, Dix A, Katz B, Vasina Y, Pearce C(2003) Isolation
and identication of cissetin, a setin-like antibiotic with
a novel cis-octalin ring fusion. J Antibiot 56:862865
Boyd RK, McAlees AJ, Taylor A, Walter JA (1991)
Isolation of new isocyanide metabolites of Trichoder-
ma hamatum as their (g5-pentamethylcyclopentadie-
nyl)- or (g5-ethyltetramethylcyclopentadienyl)bis(l-
thiocyanato)rhodium complexes. J Chem Soc Perkin
Trans 1(6):14611465
Brasier CM (1975) Stimulation of sex organ formation in
Phytophthora by antagonistic species of Trichoderma.
I. The effect in vitro. New Phytol 74:183194
Brewer D, Gabe EJ, Hanson AW, Taylor A, Keeping JW,
Thaller V, Das BC (1979) Isonitrile acids from
cultures of the fungus Trichoderma hamatum (Bon.)
Bain. aggr., x-ray structure. J Chem Soc Chem
Commun 23:10611062
Brewer D, Feicht A, Taylor A, Keeping JW, Taha AA,
Thaller V (1982) Ovine ill-thrift in Nova Scotia. 9.
Production of experimental quantities of isocyanide
metabolites of Trichoderma hamatum. Can J Micro-
biol 28:12521260
Brewer D, Calder FW, Jones GA, Tanguay D, Taylor A
(1986) Effect of nickelous and other metal ions on the
inhibition of rumen bacterial metabolism by 3-(3-
isocyanocyclopent-2-enylidene)propionic acid and re-
lated isocyanides. Appl Environ Microbiol 51:138142
Brewer D, Mason FG, Taylor A (1987) The production of
alamethicins by Trichoderma spp. Can J Microbiol
33:619625
Brewer D, Parkinson VO, Taylor A (1990) A note on the
antibacterial properties of 3-(3-isocyanocyclopent-2-
enylidene)propionic acid in the ovine rumen. J Appl
Bacteriol 69:701704
Brian PW (1944) Production of gliotoxin by Trichoderma
viride. Nature 154:667668
Brian PW, McGowan JC (1945) Viridin. A highly fungi-
static substance produced by Trichoderma viride.
Nature 156:144145
Brian PW, Curtis PJ, Hemming HG, Norris GLF (1957)
Wortmannin, an antibiotic produced by Penicillium
wortmanni. Brit Mycol Soc Trans 40:365368
Brown AG, Smale TC, King TJ, Hasenkamp R, Thompson
RH (1976) Crystal and molecular structure of comp-
actin, a new antifungal metabolite from Penicillium
brevicompactum. J Chem Soc Perkin Trans
1(11):11651170
Brueckner H, Graf H, Bokel M (1984) Paracelsin; char-
acterization by NMR spectroscopy and circular
dichroism, and hemolytic properties of a peptaibol
antibiotic from the cellulolytically active mold Tricho-
derma reesei. Part B. Experientia 40:11891197
Brueckner H, Koenig WA, Aydin M, Jung G (1985)
Trichotoxin A40. Purication by counter-current dis-
tribution and sequencing of isolated fragments. Bio-
chim Biophys Acta 827:5162
Burmeister HR (1974) Antibiotic equisetin. US Pat. Appl.
467548, 6 May 1974
Burton HS (1950) Antibiotics from Aspergillus melleus.
Nature 165:274275
Cane DE, Sohng JK (1994) Inhibition of glyceraldehyde-3-
phosphate dehydrogenase by pentalenolactone. 2.
Identication of the site of alkylation by tetrahydro-
pentalenolactone. Biochemistry 33:65246530
Capon RJ, Ratnayake R, Stewart M, Lacey E, Tennant S,
Gill JH (2005) Aspergillazines A-E: novel heterocy-
clic dipeptides from an Australian strain of Aspergil-
lus unilateralis. Org Biomol Chem 3:123129
Cardoza RE, Hermosa MR, Vizcaino JA, Sanz L, Monte
E, Gutierrez S (2005) Secondary metabolites pro-
duced by Trichoderma and their importance in the
biocontrol process. In: Mellado-Dura n E, Barredo JL
(eds) Microorganisms for industrial enzymes and
biocontrol. Research Signpost, India, p 207
Chang CWJ (2000) Naturally occurring isocyano/isothio-
cyanato and related compounds. Prog Chem Org Nat
Prod 80:1186
Choi SU, Choi EJ, Kim KH, Kim NY, Kwon BM, Kim SU,
Bok SH, Lee SY, Lee CO (1996) Cytotoxicity of
trichothecenes to human solid tumor cells in vitro.
Arch Pharmacol Res 19:611
Chukwujekwu JC, Coombes PH, Mulholland DA, van
Staden J (2006). Emodin, an antibacterial anthraqui-
none from the roots of Cassia occidentalis. J Bot
72:295297
Claydon N, Allan M, Hanson JR, Avent AG (1987)
Antifungal alkyl pyrones of Trichoderma harzianum.
Trans Br Mycol Soc 88:503513
Claydon N, Hanson JR, Truneh A, Avent AG (1991)
Harzianolide, a butenolide metabolite from cultures
of Trichoderma harzianum. Phytochemistry 30:3802
3803
Coats JH, Meyer CE, Pyke TR (1971) Antibiotic derm-
adin. US Patent 3627882, 14 Dec 1971
Cole RJ, Kirksey JW, Springer JP, Clardy J, Cutler HG,
Garren KH (1975) Desmethoxyviridiol, a new toxin
from Nodulisporium hinnuleum. Phytochemistry
14:14291432
Collins RP, Halim AF (1972) Characterization of the
major aroma constituent of the fungus Trichoderma
viride. J Agric Food Chem 20:437438
Corley DG, Miller-Wideman M, Durley RC (1994) Isola-
tion and structure of harzianum A: a new trichothe-
cene from Trichoderma harzianum. J Nat Prod
57:422425
Cutler SJ, Cutler HG (1999) Biologically active natural
products: pharmaceuticals. CRC Press, New York
Cutler HG, Jacyno JM (1991) Biological activity of (-)-
harzianopyridone isolated from Trichoderma harzia-
num. Agric Biol Chem 55:26292631
Cutler HG, Himmelsbach DS, Arrendale RF, Cole PD,
Cox RH (1989) Koninginin A: a novel plant growth
regulator from Trichoderma koningii. Agric Biol
Chem 53:26052611
Cutler HG, Himmelsbach DS, Yagen B, Arrendale RF,
Jacyno JM, Cole PD, Cox RH (1991a) Koninginin
B: a biologically active congener of koninginin A
from Trichoderma koningii. J Agric Food Chem
39:977980
116 Phytochem Rev (2008) 7:89123
1 3
Cutler HG, Jacyno JM, Phillips RS, vonTersch RL, Cole
PD, Montemurro N (1991b) Cyclonerodiol from a
novel source, Trichoderma koningii: plant growth
regulatory activity. Agric Biol Chem 55:243244
Cutler HG, Cutler SJ, Ross SA, El Sayed K, Dugan FM,
Bartlett MG, Hill AA, Hill RA, Parker SR (1999)
Koninginin G, a new metabolite from Trichoderma
aureoviride. J Nat Prod 62:137139
DMello JPF, Porter JK, Macdonald AMC, Placonta CM
(1997) Fusarium mycotoxins. In: DMello JPF (ed)
Handbook of plant and fungal toxicants. CRC Press,
New York, p 287
De Stefano S, Nicoletti R (1999) Pachybasin and chry-
sophanol, two anthraquinones produced by the fungus
Trichoderma aureoviride. Il Tabacco 7:2124
Dickinson JM, Hanson JR, Hitchcock PB, Claydon N
(1989) Structure and biosynthesis of harzianopyri-
done, an antifungal metabolite of Trichoderma har-
zianum. J Chem Soc Perkin Trans 1(11):18851887
Dodge JA, Sato M, Vlahos CJ (1995) Inhibition of
phosphatidylinositol 3-kinase with viridin and analogs
thereof. Eur. Patent Appl. 648492, 19 Apr 1995
Donnelly DMX, Sheridan MH (1986) Anthraquinones
from Trichoderma polysporum. Phytochemistry
25:23032304
Dunlop RW, Simon A, Sivasithamparam K, Ghisalberti
EL (1989) An antibiotic from Trichoderma koningii
active against soilborne plant pathogens. J Nat Prod
52:6774
Edenborough MS, Herbert RB (1988) Naturally occurring
isocyanides. Nat Prod Rep 5:229245
Ehrlich KC, Daigle KW (1987) Protein synthesis inhibition
of 8-oxo-12,13-epoxytrichothecenes. Biochim Biophys
Acta Gen Subj 923:206213
El Hajji M, Rebuffat S, Lecommandeur D, Bodo B (1987)
Isolation and sequence determination of trichorzia-
nines A antifungal peptides from Trichoderma har-
zianum. Int J Pept Protein Res 29:207215
Elliott JD, Hetmanski M, Palfreyman MN, Purcell N,
Stoodley RJ (1983) Syntheses of ()- and (-)-O-
pentenomycin I. Tetrahedron Lett 24:965968
Endo A (1985) Compactin (ML-236B) and related com-
pounds as potential cholesterol-lowering agents that
inhibit HMG-CoA reductase. J Med Chem 28:401
405
Endo A, Hasumi K, Sakai K, Kanbe T (1985) Specic
inhibition of glyceraldehyde-3-phosphate dehydroge-
nase by koningic acid (heptelidic acid). J Antibiot
38:920925
Endo A, Hasumi K, Yamada A, Shimoda R, Takeshima H
(1986) The synthesis of compactin (ML-236B) and
monacolin K in fungi. J Antibiot 39:16091610
Esumi T, Iwabuchi Y, Irie H, Hatakeyama S (1998)
Synthesis of viridiofungin A trimethyl ester and
determination of the absolute structure of viridiofun-
gin A. Tetrahedron Lett 39:877880
Evidente A, Randazzo G, Ballio A (1986) Structure
determination of seiridin and isoseiridin, phytotoxic
butenolides from culture ltrate of Seiridium cardi-
nale. J Nat Prod 49:593601
Evidente A, Cabras A, Maddau L, Serra S, Andol A,
Motta A (2003) Viridepyronone, a new antifungal 6-
substituted 2H-pyran-2-one produced by Trichoderma
viride. J Agric Food Chem 51:69576960
Faull JL, Graeme-Cook KA, Pilkington BL (1994) Pro-
duction of an isonitrile antibiotic by an UV-induced
mutant of Trichoderma harzianum. Phytochemistry
36:12731276
Fujimoto H, Satoh Y, Yamaguchi K, Yamazaki M (1998)
Monoamine oxidase inhibitory constituents from
Anixiella micropertusa. Chem Pharm Bull 46:1506
1510
Fujita T, Takaishi Y, Okamura A, Fujita E, Fuji K,
Hiratsuka N, Komatsu M, Arita I (1981) New peptide
antibiotics, trichopolyns I and II, from Trichoderma
polysporum. J Chem Soc Chem Commun 12:585587
Fujita T, Takaishi Y, Takeda Y, Fujiyama T, Nishi T
(1984) Fungal metabolites. II. Structural elucidation
of minor metabolites, valinotricin, cyclonerodiol
oxide, and epicyclonerodiol oxide, from Trichoderma
polysporum. Chem Pharm Bull 32:44194425
Fujita T, Wada S, Iida A, Nishimura T, Kanai M, Toyama
N (1994) Fungal metabolites. XIII. Isolation and
structural elucidation of new peptaibols, trichodece-
nins-I and -II, from Trichoderma viride. Chem Pharm
Bull 42:489494
Fujiwara A, Okuda T, Masuda S, Shiomi Y, Miyamoto C,
Sekine Y, Tazoe M, Fujiwara M (1982) Isonitrile
antibiotics, a new class of antibiotics with an isonitrile
group. I. Fermentation, isolation and characterization
of isonitrile antibiotics. Agric Biol Chem 46:1803
1809
Gallos JK, Damianou KC, Dellios CC (2001) A new total
synthesis of pentenomycin. Tetrahedron Lett 42:5769
5771
Garo E, Starks CM, Jensen PR, Fenical W, Lobkovsky E,
Clardy J (2003) Trichodermamides A and B, cytotoxic
modied dipeptides from the marine-derived fungus
Trichoderma virens. J Nat Prod 66:423426
Ghisalberti EL (2002) Anti-infective agents produced by
the hyphomycetes general Trichoderma and Glioclau-
dium. Curr Med Cem 1:343374
Ghisalberti EL, Rowland CY (1993) Antifungal metabo-
lites from Trichoderma harzianum. J Nat Prod
56:17991804
Ghisalberti EL, Hockless DCR, Rowland C, White AH
(1992) Harziandione, a new class of diterpene from
Trichoderma harzianum. J Nat Prod 55:16901694
Gloer JB (1997) Environmental and microbial relation-
ships. In: Wicklow DT (ed) The mycota, vol IV.
So derstro m Springer-Verlag, Berlin, p 249
Godtfredsen WO, Vangedal S (1964) Trichodermin, a new
antibiotic related to trichothecin. Proc Chem Soc
(June):188189
Godtfredsen WO, Vangedal S (1965) Trichodermin, a new
sesquiterpene antibiotic. Acta Chem Scand 19:1088
1102
Golder WS, Watson TR (1980) Lanosterol derivatives as
precursors in the biosynthesis of viridin. Part 1.
J Chem Soc Perkin Trans 1(2):422425
Phytochem Rev (2008) 7:89123 117
1 3
Goldstein JL, Helgeson JAS, Brown MS (1979) Inhibition
of cholesterol synthesis with compactin renders
growth of cultured cells dependent on the low density
lipoprotein receptor. J Biol Chem 254:54035409
Gottasova R, Betina V, Lesko J, Hrdlickova L, Chovanec
P (1998) Secondary metabolites of a brown mutant of
Trichoderma viride. Their isolation, purication and
biological activities. Chem Pap 52:569
Graefe U, Ihn W, Schlegel B, Hoee G, Augustiniak H,
Sandor P (1991) Structure of ergokonin C, a new
carboxysterol antifungal antibiotic from a Tolypocla-
dium inatum mutant. Pharmazie 46:613614
Grove JF (1988) Non-macrocyclic trichothecenes. Nat
Prod Rep 5:187209
Grove JF (1993) Macrocyclic trichothecenes. Nat Prod
Rep 10:429448
Grove JF (1996) Non-macrocyclic trichothecenes. Part 2.
Prog Chem Org Nat Prod 69:170
Haeiger W, Hauser D (1973) Isolation and structure
elucidation of 11-desacetoxywortmannin. Helv Chim
Acta 56:29012904
Haggag WM, Abo-Sedera SA (2005) Characteristics of
three Trichoderma species in peanut haulms compost
involved in biocontrol of cumin wilt disease. Int
J Agric Biol 7:222229
Hanson JR (1995) The viridin family of steroidal antibi-
otics. Nat Prod Rep 12:381384
Harman GE, Howell CR, Viterbo A, Chet I, Lorito M
(2004) Trichoderma species-opportunistic, avirulent
plant symbionts. Nat Rev Microbiol 2:4356
Harris GH, Jones ETT, Meinz MS, Nallin-Omstead M,
Helms GL, Bills GF, Zink D, Wilson KE (1993)
Isolation and structure elucidation of viridiofungins
A, B and C. Tetrahedron Lett 34:52355238
Harris GH, Dufresne C, Joshua H, Koch LA, Zink DL,
Salmon PM, Goklen KE, Kurtz MM, Rew DJ,
Bergstrom JD, Wilson KE (1995) Isolation, structure
determination and squalene synthase activity of L-
731,120 and L-731,128, alkyl citrate analogs of zar-
agozic acids A and B. Bioorg Med Chem Lett 5:2403
2408
Hashimoto R, Takahashi S, Hamano K, Nakagawa A
(1995) A new melanin biosynthesis inhibitor, mela-
noxadin from fungal metabolite by using the larval
haemolymph of the silkworm, Bombyx mori. J Anti-
biot 48:10521054
Hebbar KP, Lumsden RD (1998) Joint action of microbi-
als for disease control. In: Menn JJ, Hall FR (eds)
Biopesticides: use and delivery. Humana Press, Inc.,
Totawa, p 103
Hetmanski M, Purcell N, Stoodley RJ, Palfreyman MN
(1984) Studies related to cyclopentanoid natural
products. Part 3. Synthesis of pentenomycin and its
racemate. J Chem Soc Perkin Trans 1(9):20892096
Hill RA, Cutler HG, Parker SR (1995) Trichoderma and
metabolites as control agents for microbial plant
diseases. PCT Int Appl 9520879, 10 Aug 1995
Howell CR, Stipanovic RD (1983) Gliovirin, a new
antibiotic from Gliocladium virens, and its role in
the biological control of Pythium ultimum. Can J
Microbiol 29:321324
Howell CR, Stipanovic RD (1994) Effect of sterol biosyn-
thesis inhibitors on phytotoxin (viridiol) production
by Gliocladium virens in culture. Phytopathology
84:969972
Huang Q, Tezuka Y, Hatanaka Y, Kikuchi T, Nishi A,
Tubaki K (1995a) Studies on metabolites of myco-
parasitic fungi. III. New sesquiterpene alcohol from
Trichoderma koningii. Chem Pharm Bull 43:1035
1038
Huang Q, Tezuka Y, Kikuchi T, Nishi A, Tubaki K,
Tanaka K (1995b) Studies on metabolites of myco-
parasitic fungi. II. Metabolites of Trichoderma kon-
ingii. Chem Pharm Bull 43:223239
Huang Q, Shen HM, Shui G, Wenk M, Ong CN (2006)
Emodin inhibits tumor cell adhesion through disrup-
tion of the membrane lipid raft-associated integrin
signaling pathway. Cancer Res 66:58075815
Hussain SA, Noorani R, Qureshi IH (1975) Microbial
chemistry. Part I. Isolation and characterization of
gliotoxin, ergosterol, palmitic acid and mannitol
metabolic products of Trichoderma hamatum Bainier.
Pak J Sci Ind Res 18:221223
Hussein HS, Brasel JM (2001) Toxicity, metabolism and
impact of mycotoxins on humans and animals. Tox-
icology 167:101134
Iida A, Uesato S, Shingu T, Nagaoka Y, Kuroda Y, Fujita
T (1993) Fungal metabolites. Part 7. Solution struc-
ture of an antibiotic peptide, trichosporin B-V, from
Trichoderma polysporum. J Chem Soc Perkin Trans
1(3):375379
Iida A, Sanekata M, Fujita T, Tanaka H, Enoki A, Fuse G,
Kanai M, Rudewicz PJ, Tachikawa E (1994) Fungal
metabolites. XVI. Structures of new peptaibols,
trichokindins I-VII, from the fungus Trichoderma
harzianum. Chem Pharm Bull 42:10701075
Iida A, Sanekata M, Wada S, Fujita T, Tanaka H, Enoki
A, Fuse G, Kanai M, Asami K (1995) Fungal
metabolites. XVIII. New membrane-modifying pep-
tides, trichorozins I-IV, from the fungus Trichoderma
harzianum. Chem Pharm Bull 43:392397
Itoh Y, Kodama K, Furuya K, Takahashi S, Haneishi T,
Takiguchi Y, Arai M (1980) A new sesquiterpene
antibiotic, heptelidic acid producing organisms, fer-
mentation, isolation and characterization. J Antibiot
33:468473
Jakobisiak M, Golab J (2003) Potential antitumor effects
of statins (review). Int J Oncol 23:1055
Jansen R, Ho e G (1983) Revised stereochemistry of
piericidin A1. Tetrahedron Lett 24:54855486
Jaworski A, Kirschbaum J, Bruckner H (1999) Structures
of trichovirins II, peptaibol antibiotics from the mold
Trichoderma viride NRRL 5243. J Pept Sci 5:341351
Jayasuriya H, Koonchanok NM, Geahlen RL, McLaughlin
JL, Chang CJ (1992) Emodin, a protein tyrosine
kinase inhibitor from Polygonum cuspidatum. J Nat
Prod 55:696698
Jones PH (1990) Lovastatin and simvastatin prevention
studies. Am J Cardiol 66:39B43B
Jones RW, Pettit RE (1987) Variation in sensitivity among
anastomosis groups of Rhizoctonia solani to the
antibiotic gliotoxin. Plant Dis 71:3436
118 Phytochem Rev (2008) 7:89123
1 3
Kamal A, Akhtar R, Qureshi AA (1971) Biochemistry of
microorganisms. XX. 2,5-Dimethoxybenzoquinone,
tartronic acid, itaconic acid, succinic acid, pyrocalciferol,
epifriedlinol, lanosta-7,9(11), 24-triene-3-b-21-diol,
trichodermene-A, methyl 2,4,6-octatrienecarboxylate,
cordycepic acid, Trichoderma metabolic products. Pak
J Sci Ind Res 14:7178
Kato M, Sakai K, Endo A (1992) Koningic acid (heptelidic
acid) inhibition of glyceraldehyde-3-phosphate dehy-
drogenases from various sources. Biochim Biophys
Acta 1120:113116
Kawada M, Yoshimoto Y, Kumagai H, Someno T,
Momose I, Kawamura N, Isshiki K, Ikeda D (2004)
PP2A inhibitors, harzianic acid and related com-
pounds produced by fungal strain F-1531. J Antibiot
57:235237
Kawashima J, Ito F, Kato T, Niwano M, Koshino H,
Uramoto M (1994) Antitumor activity of heptelidic
acid chlorohydrin. J Antibiot 47:15621563
Kirby GW, Robins DJ (1980) The biosynthesis of gliotoxin
and related epipolythiodioxopiperazines. Biosynth
Mycotoxins: Study Second Metab 301326
Kishimoto N, Sugihara S, Mochida K, Fujita T (2005) In
vitro antifungal and antiviral activities of c- and d-
lactone analogs utilized as food avoring. Biocontrol
Sci 10:3136
Kobayashi M, Uehara H, Matsunami K, Aoki S, Kitagawa
I (1993) Trichoharzin, a new polyketide produced by
the imperfect fungus Trichoderma harzianum sepa-
rated from the marine sponge Mycale cecilia. Tetra-
hedron Lett 34:79257928
Kono K, Tanaka M, Ono Y, Hosoya T, Ogita T, Kohama
T (2001) S-15183a and b, new sphingosine kinase
inhibitors, produced by a fungus. J Antibiot 54:415
420
Kontani M, Sakagami Y, Marumo S (1994) First b-1,6-
glucan biosynthesis inhibitor, bisvertinolone isolated
from fungus, Acremonium strictum and its absolute
stereochemistry. Tetrahedron Lett 35:25772580
Krause C, Kirschbaum J, Jung G, Brueckner H (2006)
Sequence diversity of the peptaibol antibiotic suzuka-
cillin-A from the mold Trichoderma viride J Pept Sci
12:321327
Krupke OA, Castle AJ, Rinker DL (2003) The North
American mushroom competitor, Trichoderma ag-
gressivum f. aggressivum, produces antifungal com-
pounds in mushroom compost that inhibit mycelial
growth of the commercial mushroom Agaricus bisp-
orus. Mycol Res 107:14671475
Kubicek CP, Harman GE (eds) (1998) Trichoderma and
Glioclaudium, vols 1 and 2. Taylor & Francis Ltd,
London
Kumagai H, Nishida H, Imamura N, Tomoda H, Omura S,
Bordner J (1990) The structures of atpenins A4, A5
and B, new antifungal antibiotics produced by Peni-
cillium sp. J Antibiot 43:15531558
Kumar A, Dhawan S, Aggarwal BB (1998) Emodin (3-
methyl-1,6,8-trihydroxy-anthraquinone) inhibits TNF-
induced NF-kB activation, IkB degradation, and
expression of cell surface adhesion proteins in human
vascular endothelial cells. Oncogene 17:913918
Kumeda Y, Asao T, Iida A, Wada S, Futami S, Fujita T
(1994) Effects of ergokonin A produced by Tricho-
derma viride on the growth and morphological devel-
opment of fungi. Bokin Bobai 22:663670
Leclerc G, Goulard C, Prigent Y, Bodo B, Wroblewski H,
Rebuffat S (2001) Sequences and antimycoplasmic
properties of longibrachins LGB II and LGB III, two
novel 20-residue peptaibols from Trichoderma lon-
gibrachiatum. J Nat Prod 64:164170
Lee SH, Hensens OD, Helms GL, Liesch JM, Zink DL,
Giacobbe RA, Bills GF, Stevens-Miles S, Garcia ML,
Schmalhofer WA, McManus OB, Kaczorowski GJ
(1995a) L-735,334, a novel sesquiterpenoid potassium
channel-agonist from Trichoderma virens. J Nat Prod
58:18221828
Lee CH, Koshino H, Chung MC, Lee HJ, Kho YH (1995b)
MR304A, a new melanin synthesis inhibitor produced
by Trichoderma harzianum. J Antibiot 48:11681170
Lee CH, Chung MC, Lee HJ, Bae KS, Kho YH (1997a)
MR566A and MR566B, new melanin synthesis inhib-
itors produced by Trichoderma harzianum. I. Taxon-
omy, fermentation, isolation and biological activities.
J Antibiot 50:469473
Lee CH, Koshino H, Chung MC, Lee HJ, Hong JK, Yoo
JS, Kho YH (1997b) MR566A and MR566B, new
melanin synthesis inhibitors produced by Trichoder-
ma harzianum. II. Physico-chemical properties and
structural elucidation. J Antibiot 50:474478
Lee HB, Kim Y, Jin HZ, Lee JJ, Kim CJ, Park JY, Jung
HS (2005) A new Hypocrea strain producing harzia-
num A cytotoxic to tumour cell lines. Lett Appl
Microbiol 40:497503
Liu G, Wang Z (2001) Total synthesis of koninginin D, B
and E. Synthesis 1:119127
Liu R, Gu QQ, Zhu WM, Cui CB, Fan GT (2005a)
Trichodermamide A and aspergillazine A, two cyto-
toxic modied dipeptides from a marine-derived
fungus Spicaria elegans. Arch Pharmacol Res
28:10421046
Liu W, Gu Q, Zhu W, Cui C, Fan G (2005b) Two new
benzoquinone derivatives and two new bisorbicilli-
noids were isolated from a marine-derived fungus
Penicillium terrestre. J Antibiot 58:441446
Macias FA, Varela RM, Simonet AM, Cutler HG,
Cutler SJ, Eden MA, Hill RA (2000) Bioactive
carotanes from Trichoderma virens. J Nat Prod
63:11971200
Mandala SM, Thornton RA, Frommer BR, Dreikorn S,
Kurtz MB (1997) Viridiofungins, novel inhibitors of
sphingolipid synthesis. J Antibiot 50:339343
Manyu SKK (1980) The physiologically active substance
SC2051. Jpn Kokai Tokkyo Koho 80:54,897 (Chem.
Abstr. 1980, 93:112329)
Marfori EC, Kajiyama S, Fukusaki E, Kobayashi A (2002)
Trichosetin, a novel tetramic acid antibiotic produced
in dual culture of Trichoderma harzianum and Cath-
aranthus roseus callus. Z Naturforsch C: J Biosci
57:465470
Marfori EC, Kajiyama S, Fukusaki E, Kobayashi A (2003).
Phytotoxicity of the tetramic acid metabolite trich-
osetin. Phytochemistry 62:715721
Phytochem Rev (2008) 7:89123 119
1 3
Mazzucco CE, Warr G (1996) Trichodimerol (BMS-
182123) inhibits lipopolysaccharide-induced eicosa-
noid secretion in THP-1 human monocytic cells.
J Leukocyte Biol 60:271277
McKean C, Tang L, Billam M, Tang M, Theodorakis CW,
Kendall RJ, Wang JS (2006) Comparative acute and
combinative toxicity of aatoxin B1 and T-2 toxin in
animals and immortalized human cell lines. J Appl
Toxicol 26:139147
Meinz MS, Pelaez F, Omstead MN, Milligan JA, Diez MT,
Onishi JC, Bergstrom JA, Jenkins RF, Harris GH,
Jones ETT, Huang L, Kong YL, Lingham RB, Zink D
(1993) Cholesterol-lowering agents, their manufacture
with Trichoderma, and their use as fungicides or as
medicines. Eur. Pat. Appl. 526936, 10 Feb 1993
Mereyala HB, Joe M, Gadikota RR (2000) Synthesis of
harzialactone A and its isomers from D-glucose and
assignment of absolute stereochemistry. Tetrahedron:
Asymmetry 11:40714081
Meyer CE (1966) U-21,963, a new antibiotic. II. Isolation
and characterization. Appl Microbiol 14:511512
Meyer CE, Reusser F (1967) A polypeptide antibacte-
rial agent from Trichoderma viride. Experientia
23:8586
Michael AP, Grace EJ, Kotiw M, Barrow RA (2003)
Isochromophilone IX, a novel GABA-containing
metabolite isolated from a cultured fungus, Penicil-
lium sp. Aust J Chem 56:1315
Mihara T, Iida A, Akimoto N, Fujita T, Takaishi Y, Inoue
K, Kushimoto S (1994) Structures of antibiotic pep-
tides, trichopolyns, from the fungus Trichoderma
polysporum. Tennen Yuki Kagobutsu Toronkai Koen
Yoshishu 36:713720
Moffatt JS, BuLock JD, Yuen TH (1969) Viridiol, a
steroid-like product from Trichoderma viride. J Chem
Soc Chem Commun 14:839
Mohamed-Benkada M, Montagu M, Biard J, Mondeguer
F, Verite P, Dalgalarrondo M, Bissett J, Pouchus YF
(2006) New short peptaibols from a marine Tricho-
derma strain. Rapid Commun Mass Spectrom
20:11761180
Mori K, Bando M, Abe K (2002) Determination of the
stereochemistry of (-)-koninginin A by an X-ray
analysis of its synthetic sample. Biosci Biotechnol
Biochem 66:17791781
Morokuma K, Takahashi K, Ishihara J, Hatakeyama S
(2005) Total synthesis of viridiofungin A. Chem
Commun 17:22652267
Mukhopadhyay T, Roy K, Sawant SN, Deshmukh SK,
Ganguli BN, Fehlhaber HW (1996) On an unstable
antifungal metabolite from Trichoderma koningii.
Isolation and structure elucidation of a new cyclo-
pentenone derivative (3-dimethylamino-5-hydroxy-5-
vinyl-2-cyclopenten-1-one). J Antibiot 49:210211
Nakano H, Hara M, Mejiro T, Ando K, Saito Y, Morimoto
M (1990) DC1149B, DC1149R, and their manufacture
with Trichoderma. Jpn. Kokai Tokkyo Koho, JP
Patent 02218686, 31 Aug 1990
New AP, Eckers C, Haskins NJ, Neville WA, Elson S,
Hueso-Rodriguez JA, Rivera-Sagredo A (1996)
Structures of polysporins A-D, four new peptaibols
isolated from Trichoderma polysporum. Tetrahedron
Lett 37:30393042
Nicolaou KC, Simonsen KB, Vassilikogiannakis G,
Baran PS, Vidali VP, Pitsinos EN, Couladouros
EA (1999) Biomimetic explorations towards the
bisorbicillinoids: total synthesis of bisorbicillinol,
bisorbibutenolide, and trichodimerol. Angew Chem
Int Ed 38:35553559
Nicolaou KC, Vassilikogiannakis G, Simonsen K, Baran
PS, Zhong YL, Vidali VP, Pitsinos EN, Couladouros
EA (2000) Biomimetic total synthesis of bisorbicillin-
ol, bisorbibutenolide, trichodimerol, and designed
analogues of the bisorbicillinoids. J Am Chem Soc
122:30713079
Nielsen KF, Graefenhan T, Zafari D, Thrane U (2005)
Trichothecene production by Trichoderma brevicom-
pactum. J Agric Food Chem 53:81908196
Nobuhara M, Tazima H, Shudo K, Itai A, Okamoto T,
Iitaka Y (1976) A fungal metabolite, novel isocyano
epoxide. Chem Pharm Bull 24:832834
Nowak A, Steffan B (1997) Physarorubinic acid, a polye-
noyltetramic acid type plasmodial pigment from the
slime mold Physarum polycephalum. Liebigs Ann
Recl 9:18171821
Nowak A, Steffan B (1998) Polycephalin B and C: unusual
tetramic acids from plasmodia of the slime mold
Physarum polycephalum (myxomycetes). Angew
Chem Int Ed 37:31393141
Nozoe S, Goi M, Morisaki N (1970) Structure of cyclon-
erodiol. Tetrahedron Lett 15:12931296
Oh SU, Lee SJ, Kim JH, Yoo ID (2000) Structural
elucidation of new antibiotic peptides, atroviridins A,
B and C from Trichoderma atroviride. Tetrahedron
Lett 41:6164
Ollis WD, Rey M, Godtfredsen WO, Rasrup-Andersen N,
Vangedal S, King TJ (1980) The constitution of the
antibiotic trichoviridin. Tetrahedron 36:515520
Omura S, Tomoda H, Kimura K, Zhen DZ, Kumagai H,
Igarashi K, Imamura N, Takahashi Y, Tanaka Y, Iwai
Y (1988) Atpenins, new antifungal antibiotics pro-
duced by Penicillium sp. Production, isolation, phys-
ico-chemical and biological properties. J Antibiot
41:17691773
Ondeyka JG, Ball RG, Garcia ML, Dombrowski AW,
Sabnis G, Kaczorowski GJ, Zink DL, Bills GF, Goetz
M, Schmalhofer WA, Singh SB (1995) A carotane
sesquiterpene as a potent modulator of the Maxi-K
channel from Arthrinium phaeospermum. Bioorg Med
Chem Lett 5:733734
Onishi JC, Milligan JA, Basilio A, Bergstrom J, Curotto J,
Huang L, Meinz M, Nallin-Omstead M, Pelaez F,
Rew D, Salvatore M, Thompson J, Vicente F, Kurtz
MB (1997) Antimicrobial activity of viridiofungins.
J Antibiot 50:334338
Ordentlich A, Wiesman Z, Gottlieb HE, Cojocaru M,
Chet I (1992) Inhibitory furanone produced by the
biocontrol agent Trichoderma harzianum. Phyto-
chemistry 31:485486
Oshino K, Kumagai H, Tomoda H, Omura S (1990)
Mechanism of action of atpenin B on Raji cells.
J Antibiot 43:10641068
120 Phytochem Rev (2008) 7:89123
1 3
Otsuka T, Takase S, Terano H, Okuhara M (1992) New
angiogenesis inhibitors, WF-16775 A1 and A2. J Anti-
biot 45:19701973
Papavizas GC (1985) Trichoderma and Glioclaudium:
biology, ecology and potential for biocontrol. Ann
Rev Phytopathol 23:2354
Parker SR, Cutler HG, Schreiner PR (1995a) Koninginin
C: a biologically active natural product from Tricho-
derma koningii. Biosci Biotechnol Biochem 59:1126
1127
Parker SR, Cutler HG, Schreiner PR (1995b) Koninginin
E: isolation of a biologically active natural product
from Trichoderma koningii. Biosci Biotechnol Bio-
chem 59:17471749
Parker RS, Cutler HG, Jacyno JM, Hill RA (1997)
Biological activity of 6-pentyl-2H-pyran-2-one and
its analogs. J Agric Food Chem 45:27742776
Pitel DW, Arsenault GP, Vining LC (1971) Cyclonerodiol,
a sesquiterpene metabolite of Gibberella fujikuroi.
J Antibiot 24:483484
Pohmakotr M, Popuang S (1991) Intramolecular acylation
of a-sulnyl carbanion: a facile synthesis of ()-
pentenomycin I and ()-epipentenomycin I. Tetrahe-
dron Lett 32:275278
Poole PR, Ward BG, Whitaker G (1998) The effects of
topical treatments with 6-pentyl-2-pyrone and struc-
tural analogs on stem end post-harvest rots in kiwi
fruit due to Botrytis cinerea. J Agric Food Chem
77:8186
Pratt BH, Sedgley JH, Heather WA, Sheperd CJ (1972)
Oospore production in Phytophtora cinnamomi in the
presence of Trichoderma koningii. Aust J Biol Sci
25:861863
Pyke TR, Dietz A (1966) U-21,963, a new antibiotic.
I. Discovery and biological activity. Appl Microbiol
14:506510
Qian-Cutrone J, Huang S, Chang LP, Pirnik DM, Klohr
SE, Dalterio RA, Hugill R, Lowe S, Alam M, Kadow
KF (1996) Harziphilone and eephilone, two new
HIV REV/RRE binding inhibitors produced by
Trichoderma harzianum. J Antibiot 49:990997
Rebuffat S, El Hajji M, Hennig P, Davoust D, Bodo B
(1989) Isolation, sequence, and conformation of seven
trichorzianines B from Trichoderma harzianum. Int
J Pept Protein Res 34:200210
Rebuffat S, Prigent Y, Auvin-Guette C, Bodo B (1991)
Tricholongins B I and B II, 19-residue peptaibols from
Trichoderma longibrachiatum. Solution structure
from two-dimensional NMR spectroscopy. Eur J Bio-
chem 201:66174
Rebuffat S, Conraux L, Massias M, Auvin-Guette C, Bodo
B (1993) Sequence and solution conformation of the
20-residue peptaibols, saturnisporins SA II and SA
IV. Int J Pept Protein Res 41:7484
Rebuffat S, Goulard C, Bodo B (1995) Antibiotic peptides
from Trichoderma harzianum: harzianins HC, pro-
line-rich 14-residue peptaibols. J Chem Soc Perkin
Trans 1(14):18491855
Reeves RJ, Jackson RM (1972) Induction of Phytophthora
cinnamomi oospores in soil by Trichoderma viride.
Trans Br Mycol Soc 59:156159
Reichenbach H, Forche E, Gerth K, Irschik H, Kunze B,
Sasse F, Hoee G, Augustiniak H, Bedorf N (1990)
Fungicidal steroids from Trichoderma. Ger. Offen.,
DE Patent 3823068, 11 Jan 1990
Ritieni A, Fogliano V, Nanno D, Randazzo G, Altomare
C, Perrone G, Bottalico A, Maddau L, Marras F
(1995) Paracelsin E, a new peptaibol from Trichoder-
ma saturnisporum. J Nat Prod 58:17451748
Rosen T, Taschner MJ, Heathcock CH (1983) Synthetic
and biological studies of compactin and related
compounds. 2. Synthesis of the lactone moiety of
compactin. J Org Chem 49:39944003
Roush WR, Russo-Rodriguez S (1987) Trichothecene
degradation studies. 3. Synthesis of 12,13-deoxy-
12,13-methanoanguidine and 12-epianguidine, two
optically active analogs of the epoxytrichothecene
mycotoxin anguidine. J Org Chem 52:603606
Saito M, Yamanishi T, Tsuruta O (1979) Studies on the
odor substances of fungi. Part I. Identication of the
fungal odors produced on the synthetic medium.
Shokuhin Sogo Kenkyusho Kenkyu Hokoku 34:67
69
Sakai K, Hasumi K, Endo A (1988) Inactivation of rabbit
muscle glyceraldehyde-3-phosphate dehydrogenase
by koningic acid. Biochim Biophys Acta 952:297303
Sakuno E, Yabe K, Hamasaki T, Nakajima HA (2000)
New inhibitor of 5-hydroxyaverantin dehydrogenase,
an enzyme involved in aatoxin biosynthesis, from
Trichoderma hamatum. J Nat Prod 63:16771678
Sasaki M, Kaneko Y, Oshita K, Takamatsu H, Asao Y,
Yokotsuka T (1970) Compounds produced by molds.
VII. Isolation of isocoumarin compounds. Agric Biol
Chem 34:12961300
Sauviat MP, Laurent D, Koehler F, Pellegrin F (1992)
Blockage of the sodium conductance by the myco-
toxin cyclonerodiol in voltage-clamped frog skeletal
muscle bers. Recent Adv Toxinol Res 3:266271
Sawa R, Mori Y, Iinuma H, Naganawa H, Hamada M,
Yoshida S, Furutani H, Kajimura Y, Fuwa T, Takeu-
chi T (1994) Harzianic acid, a new antimicrobial
antibiotic from a fungus. J Antibiot 47:731732
Scarselletti R, Faull JL (1994) In vitro activity of
6-pentyl-a-pyrone, a metabolite of Trichoderma
harzianum, in the inhibition of Rhizoctonia solani
and Fusarium oxysporum f. sp. lycopersici. Mycol
Res 98:12071209
Seepersaud M, Al-Abed Y (2000) The polyhydroxy
cyclopentene, a total synthesis of (-)-pentenomycin.
Tetrahedron Lett 41:42914293
Shiozawa H, Takahashi M, Takatsu T, Kinoshita T,
Tanzawa K, Hosoya T, Furuya K, Takahashi S,
Furihata K, Seto H (1995) Trachyspic acid, a new
metabolite produced by Talaromyces trachyspermus,
that inhibits tumor cell heparanase: taxonomy of the
producing strain, fermentation, isolation, structural
elucidation, and biological activity. J Antibiot 48:357
362
Shirota O, Pathak V, Hossain CF, Sekita S, Takatori K,
Satake M (1997) Structural elucidation of trichotetro-
nines: polyketides possessing a bicyclo[2.2.2]octane
skeleton with a tetronic acid moiety isolated from
Phytochem Rev (2008) 7:89123 121
1 3
Trichoderma sp. J Chem Soc Perkin Trans 1(20):2961
2964
Shomura T, Yoshida J, Kondo Y, Watanabe H, Omoto S,
Inouye S, Niida T (1976) A new antibiotic SF-1768
substance. Meiji Seika Kenkyu Nenpo 16:19
Simon A, Dunlop RW, Ghisalberti EL, Sivasithamparam
K (1988) Trichoderma koningii produces a pyrone
compound with antibiotic properties. Soil Biol Bio-
chem 20:263264
Singh SB, Zink DL, Goetz MA, Dombrowski AW,
Polishook JD, Hazuda DJ (1998) Equisetin and a
novel opposite stereochemical homolog phomasetin,
two fungal metabolites as inhibitors of HIV-1 integr-
ase. Tetrahedron Lett 39:22432246
Singh SB, Zink DL, Doss GA, Polishook JD, Ruby C,
Register E, Kelly TM, Bonglio C, Williamson JM,
Kelly R (2004) Citrafungins A and B, two new fungal
metabolite inhibitors of GGTase I with antifungal
activity. Org Lett 6:337340
Singh S, Dureja P, Tanwar RS, Singh A (2005) Production
and antifungal activity of secondary metabolites of
Trichoderma virens. Pestic Res J 17:2629
Sivasithamparam K, Ghisalberti EL (1998) Secondary
metabolism in Trichoderma and Glioclaudium. In:
Kubicek CP, Harman GE (eds) Trichoderma and
Glioclaudium, vol 1. Taylor & Francis Ltd, London
Slater GP, Haskins RH, Hogge LR, Nesbitt LR (1967)
Metabolic products from a Trichoderma viride. Can
J Chem 45:9296
Smith AB III, Pilla NN (1980) A stereospecic total
synthesis of ()-epipentenomycin I, ()-epipenteno-
mycin II, and ()-epipentenomycin III. Tetrahedron
Lett 21:46914694
Smith AB III, Branca SJ, Pilla NN, Guaciaro MA (1982)
Stereocontrolled total synthesis of ()-pentenomycins
I-III, their epimers, and dehydropentenomycin I.
J Org Chem 47:18551869
Sono T, Matsumura Y, Yamane S, Suzuki M (1980) First
synthesis of an epimer of ()-pentenomycin I. Chem
Lett 12:16191620
Sparapano L, Evidente A (1995) Studies on structure-
activity relationship of seiridins, phytotoxins pro-
duced by three species of Seiridium. Nat Toxins
3:166173
Sparapano L, Evidente A, Ballio A, Graniti A, Randazzo
G (1986) New phytotoxic butenolides produced by
Seiridium cardinale, the pathogen of cypress canker
disease. Experientia 42:627628
Sperry S, Samuels GJ, Crews P (1998) Vertinoid polyke-
tides from the saltwater culture of the fungus Tricho-
derma longibrachiatum separated from a Haliclona
marine sponge. J Org Chem 63:1001110014
Stipanovic RD, Howell CR (1982) The structure of
gliovirin, a new antibiotic from Gliocladium virens.
J Antibiot 35:13261330
Stokker GE, Hoffman WF, Alberts AW, Cragoe EJ Jr,
Deana AA, Gilllan JL, Huff JW, Novello FC, Prugh
JD, Smith RL (1985) 3-Hydroxy-3-methylglutaryl-
coenzyme A reductase inhibitors. 1. Structural mod-
ication of 5-substituted 3,5-dihydroxypentanoic acids
and their lactone derivatives. J Med Chem 28:347358
Strunz GM, Ren WY, Stillwell MA, Valenta Z (1977)
Structure and synthesis of a new cyclopentenone
derivative from Trichoderma album. Can J Chem
55:26102612
Sugahara T, Ogasawara K (1999) Baylis-Hillmann proto-
col in an enantiocontrolled synthesis of pentenomycin
I. Synlett 4:419420
Takahashi N, Suzuki A, Tamura S (1965) Structure of
piercidin A. J Am Chem Soc 87:20662068
Takahashi S, Hashimoto R, Hamano K, Suzuki T, Nakag-
awa A (1996) Melanoxazal, new melanin biosynthesis
inhibitor discovered by using the larval haemolymph
of the silkworm, Bombyx mori. Production, isolation,
structural elucidation, and biological properties.
J Antibiot 49:513518
Takashima J, Wataya Y (1999) Trichothecene derivatives
as antimalarial agents. Jpn. Kokai Tokkyo Koho, JP
Patent 11228408, 24 Aug 1999
Tamura A, Kotani H, Naruto S (1975) Trichoviridin and
dermadin from Trichoderma sp. TK-1. J Antibiot
28:161162
Tanaka Y, Shiomi K, Kamei K, Sugoh-Hagino M, Enom-
oto Y, Fang F, Yamaguchi Y, Masuma R, Zhang CG,
Zhang XW, Omura S (1998) Antimalarial activity of
radicicol, heptelidic acid and other fungal metabolites.
J Antibiot 51:153160
Tarus PK, Langat-Thoruwa CC, Wanyonyi AW, Chhabra
SC (2003) Bioactive metabolites from Trichoderma
harzianum and Trichoderma longibrachiatum. B
Chem Soc Ethiopia 17:185190
Tezuka Y, Tasaki M, Huang Q, Hatanaka Y, Kikuchi T
(1997) Studies on metabolites of mycoparasitic fungi.
Part 6. 15-Hydroxyacorenone. New acorane-type
sesquiterpene from the culture broth of the mycopar-
asitic fungus Trichoderma harzianum. Liebigs Ann
Recl 12:25792580
Thines E, Anke H, Sterner O (1998) Trichoectin, a
bioactive azaphilone from the ascomycete Trich-
opezizella nidulus. J Nat Prod 61:306308
Turner WB, Aldridge DC (eds) (1983) Fungal metabolites
II. Academic Press, London
Umino K, Furumai T, Matsuzawa N, Awataguchi Y, Ito Y,
Okuda T (1973) Pentenomycins. I. Production, isola-
tion, and properties of pentenomycins I and II, new
antibiotics from Streptomyces eurythermus MCRI
0738. J Antibiot 26:506512
Umino K, Yamaguchi T, Ito Y (1974) Pentenomycins.
IV. Preparation and antimicrobial activities of
pentenomycin derivatives. Chem Pharm Bull
22:21132117
Usami Y, Ikura T, Amagata T, Numata A (2000) First
total syntheses and congurational assignments of
cytotoxic trichodenones A-C. Tetrahedron: Asymme-
try 11:37113725
Vicente MF, Cabello A, Platas G, Basilio A, Diez MT,
Dreikorn S, Giacobbe RA, Onishi JC, Meinz M,
Kurtz MB, Rosenbach M, Thompson J, Abruzzo G,
Flattery A, Kong L, Tsipouras A, Wilson KE, Pelaez
F (2001) Antimicrobial activity of ergokonin A from
Trichoderma longibrachiatum. J Appl Microbiol
91:806813
122 Phytochem Rev (2008) 7:89123
1 3
Vinale F, Marra R, Scala F, Ghisalberti EL, Lorito M,
Sivasithamparam K (2006) Major secondary metabo-
lites produced by two commercial Trichoderma strains
active against different phytopathogens. Lett Appl
Microbiol (Available on-line from Blackwell-synergy
webpage)
Warr GA, Veitch JA, Walsh AW, Hesler GA, Pirnik DM,
Leet JE, Lin PF, Medina IA, McBrien KD, Forenza S,
Clark JM, Lam KS (1996) BMS-182123, a fungal
metabolite that inhibits the production of TNF-alpha
by macrophages and monocytes. J Antibiot 49:234
240
Watanabe N, Yamagishi M, Mizutani T, Kondoh H,
Omura S, Hanada K, Kushida K (1990) CAF-603: a
new antifungal carotane sesquiterpene. Isolation and
structure elucidation. J Nat Prod 53:11761181
Watts R, Dahiya J, Chaudhary K, Tauro P (1988) Isolation
and characterization of a new antifungal metabolite of
Trichoderma reesei. Plant Soil 107:8184
Westerberg UB, Bolcsfoldi G, Eliasson E (1976) Control
of transfer RNA synthesis in the presence of inhib-
itors of protein synthesis. Biochim Biophys Acta
447:203213
Wheeler MH, Stipanovic RD, Puckhaber LS (1999)
Phytotoxicity of equisetin and epi-equisetin isolated
from Fusarium equiseti and F. pallidoroseum. Mycol
Res 103:967973
Wicklow DT (1998) In: Pirosynzki KA, Hawksworth D
(eds) Coevolution of fungi with plants and animals.
Academic Press, New York, p 174
Wilson KE, Burk RM, Biftu T, Ball RG, Hoogsteen K
(1992) Zaragozic acid A, a potent inhibitor of squa-
lene synthase: initial chemistry and absolute stereo-
chemistry. J Org Chem 57:71517158
Wipf P, Halter RJ (2005) Chemistry and biology of
wortmannin. Org Biomol Chem 3:20532061
Wipf P, Kerekes AD (2003) Structure reassignment of
the fungal metabolite TAEMC161 as the phytotoxin
viridiol. J Nat Prod 66:716871
Worasatit N, Sivasithamparam K, Ghisalberti EL, Row-
land C (1994) Variation in pyrone production, pectic
enzymes and control of rhizoctonia root rot of wheat
among single-spore isolates of Trichoderma koningii.
Mycol Res 98:13571363
Wright JM (1954) The production of antibiotics in soil. I.
Production of gliotoxin by Trichoderma viride. Ann
Appl Biol 41:280289
Wu YW, Ouyang J, Xiao X, Gao WY, Liu Y (2006)
Antimicrobial properties and toxicity of anthraqui-
nones by microcalorimetric bioassay. Chin J Chem
24:4550
Xu XX, Zhu YH (1995) Total synthesis of koninginin A
and its diastereoisomer. Tetrahedron Lett 36:9173
9176
Yamano T, Hemmi S, Yamamoto I, Tsubaki K (1970)
Trichoviridin, a new antibiotic. Jpn. Tokkyo Koho, JP
Patent 45015435, 29 May 1970
Yamashita H (2000) Commercial production of mevalon-
olactone by fermentation and the application to skin
cosmetics with anti-aging effect. Frag J 28:6265
Yedidia I, Shoresh M, Kerem Z, Benhamou N, Kapulnik
Y, Chet I (2003) Concomitant induction of systemic
resistance to Pseudomonas syringae pv. lachrymans in
cucumber by Trichoderma asperellum (T-203) and
accumulation of phytoalexins. Appl Environ Micro-
biol 69:73437353
Zhu J, Germain AR, Porco JA Jr (2004) Synthesis of
azaphilones and related molecules by employing
cycloisomerization of o-alkynylbenzaldehydes. An-
gew Chem Int Ed 43:12391243
Phytochem Rev (2008) 7:89123 123
1 3