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Abstract. Trichoderma species are free-living fungi that are highly interactive in root, soil and foliar environments and have been used successfully in field trials ...

Phytochem Rev (2008) 7:89–123 DOI 10.1007/s11101-006-9032-2

Secondary metabolites from species of the biocontrol agent Trichoderma Jose´ Luis Reino Æ Raul F. Guerrero Æ Rosario Herna´ndez-Gala´n Æ 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 successfully in field trials to control many crop pathogens. Structural and biological studies of the metabolites isolated from Trichoderma species are reviewed. This review, encompassing all the literature in this field 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 metabolites 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-

J. L. Reino  R. F. Guerrero  R. Herna´ndez-Gala´n  I. G. Collado (&) Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Ca´diz, Apdo. 40, 11510 Puerto Real, Ca´diz, Spain e-mail: [email protected]

mental impact. While the natural suppression of plant diseases has been recognized but inadequately 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 beneficial microorganisms. The use of these microorganisms as biological control agents seeks to restore the beneficial balance of natural ecosystems 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 particularly 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, transforming a great variety of natural and xenobiotic compounds and producing varied degradative enzymes such as chitinase (Gloer 1997). It

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appears clear that Trichoderma’s growth inhibiting properties of other fungi are probably due to the combined action of cell-wall degrading enzymes together with the capacity of Trichoderma 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 commercially 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, cucumber, potato and tomato, Chondrosterum purpureum 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 soilborne fungi responsible for leaf-falling disease in several crops, has been prepared by the phytopathology 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, biochemistry and applications of these fungi (Kubicek and Harman 1998). In this paper we summarize the most important secondary metabolite types isolated from Trichoderma spp. emphasizing their biological activities, especially the role that these metabolites play in biological control mechanisms. Some aspects relating to the biosynthesis of these metabolites and related compounds are also discussed. It must be stressed that some of

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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 compounds (Donnelly and Sheridan 1986). In 1999 compounds 1 and 2 were extracted from dry mycelium and culture filtrates 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 production of normal anthraquinones allowing alternative pathways to be expressed (Ghisalberti 2002). Trichodermaol (6) (Fig. 1) is an anthraquinone-derivative isolated from the combined culture of a strain of Trichoderma species and Fusarium oxysporum or F. solani. Spectroscopic methods determined 6 to be a 1,2,3,4,4a,9ahexahydromonoanthraquinone (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; Sivasithamparam and Ghisalberti 1998). While the biological activity of anthraquinones is typically related to pigmentation, other functions 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

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Fig. 1 Anthraquinones and xanthone derivatives

R1

O

OH

O

OH

OH O H

OH HO

HO

R2

OH

H

R

O

O

1 R1 = R2 = H

4 R= H

2 R1 = OH, R2 = H

5 R=COCH3

OH

O

6

3 R1 = R2 = OH OH

OH

O O

HO

O

HO

O O OH

OH

O

7

O

O SACP

S-ketoSyn O

O

O

O

OH O

O

O

O

O

OH

O

SACP

HO O

O

3

OH

OH

O O

OH O

O

OH

O

O

HO

O

HO

O

O O O

SACP

O

O

HO

O

OO OH

OH

O

7

Fig. 2 Biosynthesis of anthraquinone and xanthone polyketides

when treated with the O-acetyl derivatives (Donnelly and Sheridan 1986). Emodin (3) possesses both monoamine oxidase (Fujimoto et al.

1998) and tyrosine kinase (Jayasuriya et al. 1992; Kumar et al. 1998) inhibiting activity. This compound acts also as an antimicrobial, antineoplasic

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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 antibacterial 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 carotanes, are usually confined 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 A–D (10–13) (Fig. 3), were isolated from T. virens, their relative structures being elucidated by spectral analysis. These compounds significantly 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 flavoring agent responsible for the coconut aroma associated with this fungus. Compound 14 was first identified 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 and Fusarium oxysporum f. sp. Lycopersici. The addition of 0.3 mg/ml of 14 to agar medium caused a 69.6%

15

HO

3

9

1

R

5

HO 11

12

H

7

HO O

14

HO

13

O

O

O

O

O

O

H

14 8 R= H

15

10

9 R= OCO(CH2)7CH=CH(CH2)7CH3 O HO HO

HO H

R1

HO R2

11 R1 = H, R2 = OH

O

16 H

OH

17 O O

13

18

12 R1=R2= OH

Fig. 3 Daucanes

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Fig. 4 Pyrone metabolites

O

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growth reduction in R. solani and a 31.7% reduction 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. harzianum and 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 (15–18) (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-derivatives massoilactone (16) and d-decanolactone (17) were patented by Hill et al. (1995) for their ability to control a range of plant afflictions including, for example, those produced by Botrytis or Phytophtora species. These compounds inhibit the growth of Aspergillus niger, Candida albicans, and Staphylococcus aureus at 31.5–125 lg/ml and 62.5–250 lg/ml, respectively, using the agar dilution method and 96-well microbioassay system with a liquid culture system (Kishimoto et al. 2005). Recently, viridepyronone (18) was isolated from a cultural filtrate 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 A–E (19–23) 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

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subsequently obtained from liquid cultures of two strains of T. harzianum isolated from wheat roots (Almassi et al. 1991). Total synthesis of compounds 19 and 20 allowed for, in 1995 and 2001 respectively, the correction of the relative configurations of koninginin A (19a) and B (20a) and the assignment of the absolute configuration of 19 as lS, 4R, 5S, 6S, 9S, 10S (Xu and Zhu 1995; Liu and Wang 2001). This stereochemistry was confirmed 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). Meanwhile, the derivatives 25 and 26 (Fig. 5) were obtained from T. harzianum (Ghisalberti and Rowland 1993). Compound 25 features an interesting seco-koninginin skeleton indicating that it is most likely a precursor in the biosynthetic pathway to koninginins. Koninginins A–C (19–21), 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 concentration (Cutler et al. 1989, 1991a, Parker et al. 1995a, b). Further assays showed antibiotic activity for 19, 20, 22–24 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

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Fig. 5 Koninginins A–E, G and derivatives

H H

OH

H

H

H

O O

OH

H O

OH

OH

O

19

19a O

O

O

H OH

H OH

OH

20

O OH

20a OH

OH

O

H

O OH

O

21

H OH

O OH

22 O

H

OH

H H OH

O OH

23

H O OH OH OH

24 OH

O H

H HO

OH

25

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

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O

OH

H OH

O OH

26

values for blank and treated plates, total inhibition 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.

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Fig. 6 Trichodermamides

OMe

OMe O

MeO

O

O

MeO OH OH

NH

Cl OH

NH

O

O N

O

N H

O

OH

27

H

OH

28 OMe

OMe MeO

O

O

O NH

O

MeO

S

NH

H

O

NH2 O

OH HN

O

O

H

S

H

OH OH

OH

OH

30 and 31 C-2 epimers

29 OMe MeO

O

O NH O

NH2 H O

OH OH

OH

32 and 33 C-2 epimers

Trichodermamides Two modified dipeptides named trichodermamides 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. Compound 28 displayed significant in vitro cytotoxicity against HCT-116 human colon carcinoma with an IC50 (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 A–E (29–33) (Fig. 6), which feature similar structures (Liu et al. 2005a; Capon et al. 2005).

Viridins The steroidal antibiotics of the viridin series (34–41) (Fig. 7) show selective antifungal activity and specific inhibitory action at specific 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).

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Fig. 7 Viridin family of steroidal antibiotics

O

O

O

OH

OH

R

OH

R

O

O

MeO

HO

HO

O

O

O

O

34 R= OCH3

35 R= OCH3

36 R= H

37 R= H

O

35a

O

O

O

R H

MeO

O

O H O

O O

H HO

H

O O

O

O O

38 R= OAc

40

41

39 R= H

Viridin (34) was first 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 (Beresteskii et al. 1976), T. viride (Golder and Watson 1980) and T. virens (Singh et al. 2005). An efficient total synthesis from a simple acyclic triyne has recently been published (Aderson et al. 2004). Compound (34) prevents the germination of spores of Botrytis allii, Colletotrichum lini and Fusarium caeruleum (MIC of 0.003–0.006 lg/ml), Penicillium expansum, Aspergillus niger and Stachybotrys atra (6 lg/ml) (Brian and McGowan 1945; Ghisalberti 2002). The related C-3 alcohol viridiol (35) was obtained from T. viride and other Glioclaudium 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 aflatoxin biosynthesis 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

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an unknown fungal strain (Aldridge et al. 1975). Compound 37 was also obtained as a phytotoxic metabolite from the fungus Nodulisporium hinnuleum (Cole et al. 1975). The fungicidal metabolites wortmannin (38) (Brian et al. 1957) and 11-desacetoxywortmannin (39) (Haefliger and Hauser 1973) were first 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 34–37, 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 receptormediated 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

Phytochem Rev (2008) 7:89–123 Fig. 8 Viridiofungins and alkyl citrate derivatives

97 HO

HO

COOH R

HOOC

R2

COOH

R3

HOOC

R4

2

COOH

O

43 44 45 46 47 48 49 50 51

42

HOOC HOOC

O

(CH2)8CH3

O O COOH

R1

R1= Tyrosine; R2, R3 = O; R4= Me R1= Phenylalanine; R2, R3= O; R4= Me R1= Tryptophan; R2, R3= O; R4= Me R1= Tyrosine; R2= OH; R3= H; R4= Me R1= Tyrosine; R2= R3= H; R4= Me R1= Tyrosine; R2, R3= O; R4= H R1= Tyrosine; R2, R3= O; R4= n-Pr R1= Phenylalanine; R2=R3= H; R4= Me R1= OH; R2=R3= H; R4= Me O

O

COOH HOOC

(CH2)7CH3

O COOH O

HO

H COOH

52

53 O

HO HOOC

COOH (CH2)5

O

OH

OAc Ph

COOH

HOOC HOOC

O OH

54

metabolites such as viridiofungins A–C, A1–4, B2 and Z2 (43–51), obtained from the solid fermentation of T. viride (Harris et al. 1993; Mandala et al. 1997); the cytotoxic compound trachyspic acid (52), isolated from Talaromyces trachyspermus (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 (43–50) (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 43–45, as well as that of the trimethyl ester derivative of viridiofungin A (Me3-43) (Harris et al. 1993). The first synthesis

O COOH

55

of Me3-43 was achieved by Esumi et al. (1998) allowing for the designation of the relative and absolute configuration of 43. A modified synthesis of 43 by acidic hydrolysis of the tri-tertbutyl ester derivative (t-Bu)3-43 was reported in 2005 (Morokuma et al. 2005). The viridiofungins (43–51) are potent broadspectrum fungicidal compounds with MFC (minimum fungicidal concentration) of 1–20 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 43–45 also inhibited in vitro the squalene synthase of Saccharomyces cerevisiae and Candida albicans (Onishi et al. 1997) and the serine palmitoyltranferase of C. albicans (Mandala et al. 1997). Cytotoxic effects in nanomolar concentrations were observed towards HeLa cells (Mandala et al. 1997).

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98 Fig. 9 Pyridine ringcontaining fungal metabolites

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MeO

H N

O

MeO

MeO

N OH

MeO OH

O

OH

56 MeO

H N

57

O

MeO

O CH2Cl

MeO OH

O

R

R Cl

O

OH

58 R= Cl

60 R= H

59 R= H

61 R= Cl

Ho¨fle 1983); atpenins (58–60), produced by Penicillium 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 significant antifungal activity against Botrytis cinerea, Rhizoctonia solani (Dickinson et al. 1989) Gaeumannomyces graminis var. tritici

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 harzianopyridone (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

Fig. 10 Pirrolidinediones

H N

MeO

OH

O

R2

N

O

HO

N

O

HO

COOH

R1

R O OH

62 R1= Me, R2= Me 65 R= -CH=CH-COOH 63 R1= H, R2= Me 66 R= -COOH 64 R1= Me, R2= Et O

OH H

OH

H

N

R2

O

H O

R1 N H OH OH O

67 R1= Me, R2= H 68 R1= R2= Me

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and Pythium ultimum (Vinale et al. 2006). Meanwhile, laevorotatory form isolated by Cutler and Jacyno (1991) showed weak antifungal and antibacterial activity but significant 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 concentration-dependent manner. These observations suggest that the two enantiomers of harzianopyridone (56) may possess different activities (Sivasithamparam and Ghisalberti 1998). Biosynthetically, this compound was shown to come from a tetraketide with the possible involvement of aspartic acid (Dickinson et al. 1989; Sivasithamparam 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 homoharzianic (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 62–64 seems to be related with the condensation of a pentaketide with amino acids (Sivasithamparam and Ghisalberti 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 UV–visible 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 hemolymph of the silkworm Bombyx mori. Melanoxazal (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 cyclopentenones have been described from fungal sources. Trichodenones A–C (71–73) (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 significant cytotoxicity against cultured P388 cells with ED50 (median effective dose) of 0.21–1.45 lg/ml. A different cyclopentenone identified 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).

OH O OH

Cl

71 Cl

72 OH

O OMe

O

OH

73

74

OR2

OR2 OH

OH

O

N

OH

O

OH OR1

O

OR1

CHO

N

O OH

O

69 Fig. 11 Oxazol derivatives

75 R1= R2= H

78 R1= R2= H

76 R1= Ac, R2= H

79 R1= Ac, R2= H

77 R1= H, R2= Ac

80 R1= H, R2= Ac

HO

70

Fig. 12 Trichodenones and other cyclopentenones

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100

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Pilla 1980; Sono et al. 1980; Smith et al. 1982; Pohmakotr and Popuang 1991) and their analogues epipentenomycin II (79) and III (80) (Sono et al. 1980; Elliott et al. 1983) have been achieved.

Another group with the same ring system are the pentenomycins (75–78) (Fig. 12). Pentenomycin I (75) and II (76) were first isolated from Streptomyces eurythermus in 1973 (Umino et al. 1973), while pentenomycin III (77) was isolated three years later from Strepovertcillium eurocidicum (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 first 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 cyclopentenones have attracted several synthetic studies. A total synthesis carried out in 2000 allowed for the establishment of the (4R,1¢R)- and (1¢R)configurations for 72 and 73, respectively (Usami et al. 2000). The same work also deduced that the major molecule with the R configuration 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

Azaphilones The azaphilones form a structurally diverse family of natural products containing a highly oxygenated bicyclic core and a chiral quaternary center (Fig. 13). Two azaphilone-type compounds, harziphilone (81) and fleephilone (82), were isolated from the butanol–methanol (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 fleephilone (82) have demonstrated inhibitory activity against the binding of REV-proteins to RRE RNA with IC50 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).

Fig. 13 Azaphilones HO

H

O O

O HO

OH

O

O

82

O

O

(CH2)6CH3

O

O

HO

O

CH3(CH2)6

O O

O

83

O O

84

O

Cl O

O

Et

O

N AcO

O

O

O

85

123

OH H

O

81 H

N

O

86

COOH

Phytochem Rev (2008) 7:89–123

101

Recently, two commercial strains of T. harzianum 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 Zopfiella inermis in 2001 (Kono et al. 2001); trichoflectin (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-mevalonolactone (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 stereochemistry (3R,5R) to harzialactone A (Mereyala 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 antiaging effects (Yamashita 2000).

CH2Ph O

HO

HO

R

O

O

O

87

88 R= -CH=CH2 88a R= Me

Fig. 14 Harzialactones and derivatives

R2 R1 O

O

O

O

90

89 R1=H, R2=OH 91 R1, R2= O R

HO

O

O

O

O

O

OH

92

93 R= -(CH2)5CH(OH)CH3 94 R= -(CH2)4CH(OH)CH2CH3

Fig. 15 Butenolides

Butenolides Bioactive secondary metabolites with a butenolide ring system have been identified in some fungi (Fig. 15). Harzianolide (89) has been isolated from three different strains of T. harzianum (Almassi et al. 1991; Claydon et al. 1991; Ordentlich 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, 89–91, 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 T39butenolide (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

123

102

Phytochem Rev (2008) 7:89–123

activity (Ehrlich and Daigle 1987). Trichothecenes 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 (D’Mello 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 deoxynivalenol (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 first 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

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 trichothecene metabolites, although these are also produced by other fungal species (Grove, 1988, 1993, 1996). These closely related sesquiterpenoids 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 Fig. 16 Trichothecenes

10

H

9

O

H

13

O

8

O

5

7

OR1

H

OR1

O

3 4

12

H

O

OH O

O R2

OR

H

OR1

OAc

95 R1= Ac, R2= H 97 R= H 96 R1= H, R2= OH 98 R= Ac 99 R1= R2= H H

H

O

H

O

H O O

O

O

OR

O

100 R= Ac 101 R= H

123

102

OH

Phytochem Rev (2008) 7:89–123

T. reesei (Watts et al. 1988). The deacetyl derivative trichodermol (101) was obtained by hydrolysis 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 elucidated and revised by NMR and X-ray crystallography in the mid-60s (Godtfredsen and Vangedal 1965; Abrahamsson and Nilsson 1966). Trichodermin (100) was shown to be an inhibitor of the elongation and termination steps in the protein synthesis (Westerberg et al. 1976). This compound 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. lignorum 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 IC50 values of 0.65 and 5.07 lg/ml, respectively (Lee et al. 2005). A recent study based on metabolite profiles, 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 species have a characteristic five-member ring with various levels of oxidation in the form of alkenyl, hydroxy, and/or epoxide functions. Although approximately 10–20 isonitriles were detected their isolation and separation has proven to be extremely difficult. 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 respectively (Chang 2000).

103 NC

HOOC

103 NC

NC

O HOOC

ROOC

107

105 R= H 106 R= CH 3 HO

NC

HO

HO

NC

HO HOOC

HOOC

108

109 OH

O

O

O

O

NC

110

NC

111

Fig. 17 Dermadin-type cyclopentylisocyanides

The first 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 from T. viride. Subsequently, this compound was named dermadin (105) (Fig. 17) and its antibiotic activity was patented in 1971 (Coats et al. 1971). Dermadin (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 fit 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

123

104

Phytochem Rev (2008) 7:89–123 O

O NC

NC HO

NC

O

O OH

104

H

112

113

O

O

OH

OH

NC

NC

HO

NC

HO OH

OH

OH

114

115 NC

HO

O

HO HO

116 NC

NC HO

HO

OH OH

OH OH

OH

117

118

Cl HO HO

119 NC

NC

O

O

R

HO

OH

120

121

122 R= NC 123 R= NH2 124 R= NHCHO 125 R= N(CH3)2

Fig. 18 Trichoviridin-type cyclopentylisocyanides

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 first isolated in 1975 by Tamura et al. and one year later by Nobuhara et al. (1976) from T. koningii. Antibiotic properties of this compound 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

123

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 first was detected and isolated as a rhodium complex following two-dimensional chromatography and the use of [Rh{(g5-C5Me5)(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 magnitudes 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 first chlorine-substituted cyclopentyl isonitrile, MR566A (120). The IC50 values of 120 and 119 against mushroom tyrosine were 1.72 and 47 lM, respectively. They also inhibited melanin biosynthesis 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 (123–125) (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 fields: (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 Jackson 1972; Brasier 1975); (III) inhibition of the enzyme tyrosinase and its implication for melanin biosynthesis in mammals (Lee et al. 1997a, b).

Phytochem Rev (2008) 7:89–123

105

Setin-like metabolites The dual culture of T. harzianum and Catharanthus roseus callus produced an antimicrobial compound named trichosetin (126) (Fig. 19), with remarkable activity against the Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis (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 (Burmeister 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 setinlike fungal metabolite is phomasetin (128) which was isolated from a Phoma species and also shows O

HO

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 4–8 times more active than 126 and 127 against penicillinresistant 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 occurring 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 demethylsorbicillin (132), oxosorbicillinol (133) (Abe et al. 2000b) and epoxysorbicillinol (134) (Fig. 20) (Sperry et al. 1998), have also been obtained from several Trichoderma species. O

R N

OH

OH O

O

H HO

OH

O

OH

130

H

126 R= H

OH

131 OH

O

O

127 R= Me

OH O

H

132

N

O OH

O

HO

N

HO

HO

O

HO

133

OH O

O

OH

H

O O

H

128 Fig. 19 Setin-like antibiotics

H

129

OH

134 Fig. 20 Sorbicillin derivatives

123

106

Phytochem Rev (2008) 7:89–123 HO

OH O

O

O

O

OH

OH

O R HO

OH

O

O

O

O

OH

OH

137

135 R= Me 136 R= H OH

OH

O

O OH

HO

O O

O

O O

OH

O

OH O

HO

138

139 OH

OH

O

O

O

O

OH

O

140 Fig. 21 Bisorbicillinoids 1

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 significant 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 bisorbibetanone (137) (Abe et al. 1999), were obtained from the Trichoderma USF-2690 strain. Subsequent fermentations of this strain also afforded bisorbicillinol (138) (Abe et al. 1998a), bisorbibutenolide (139) and bisorbicillinolide (140) (Abe et al. 1998b). All of these compounds exhibited antioxidant properties.

123

Furthermore, fermentation of T. longibrachiatum has allowed for the attainment of bisvertinolone (141) (Andrade et al. 1992; Abe et al. 1998a), and its reduced form bisvertinol (142) (Andrade et al. 1992), bislongiquinolide (bisorbibutenolide) (139) (Andrade et al. 1997), trichodermolide (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 isolated from Trichoderma sp. Trichotetronine (145) and its dihydro congener 146 (Fig. 22), possess a tetronic acid moiety and their relative and absolute 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-

Phytochem Rev (2008) 7:89–123

107 HO

HO

OH

OH

O

O

O

OH

OH

2'

3'

H

O

OH

O

O 2''

H

OH

O

HO

OH

3''

141

142

147 2’,3’-dihydro 148 2’,3’,2’’,3’’-tetrahydro O

O

HO

O

OH

O

O H

H

H

O

O HO

O

OH

143

144 O 25

O HO

OH

O

24

O OH

H3C O

145 Fig. 22 Bisorbicillinoids 2

146 24,25-dihydro

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; BarnesSeeman and Corey 1999).

Diketopiperazines Gliotoxin (149) (Fig. 24) was the first member of this class of compounds to be identified.

123

108

Phytochem Rev (2008) 7:89–123

A AcO

O

KOH then HCl (aq) or conc/HCl

HO

OH

OH

O

O

OH

O

O

dienophile

1. 2. 3.

B

O

HO

NaOMe, MeOH NaH2PO4-H2O HCl, MeOH

diene

Diels-Alder reaction

OH

O

OH O

O

O

OH O

R OH HO

OH

O

O

O

HO HO

138 135

Fig. 23 Biomimetic total syntheses of 138 by Nicolaou et al. (Path A) and of 135 by Barnes–Seeman and Corey (Path B)

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 immunosuppressive properties (Hebbar and Lumsden 1998). Gliovirin (150) (Fig. 24) was isolated from the fungus Glioclaudium virens (Trichoderma 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. harzianum, T. hamatum and T. koningii) was performed (Haggag and Abo-Sedera 2005). In addition, an isolate of T. longibrachiatum, cultured 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 antagonistic to Rhizoctonia solani (Jones and Pettit 1987), whereas those producing gliovirin (150) were effective against Pythium ultimum (Howell and Stipanovic 1983).

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Ergosterol derivatives Sterol production in Trichoderma species was first detected by Kamal et al. (1971) in the fermentation 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. koningii (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 antifungal analogue, ergokonin C (157), was isolated from a Tolyplocadium inflatum mutant (Graefe et al. 1991).

Phytochem Rev (2008) 7:89–123

109

Fig. 24 Diketopiperazines

O

H OH

NS SN O

OH

149

O O

O

N

HO

OMe

HO OH H

OH

S

O O

OMe

S H H NH O

R

150

OH

N

S

OMe

S

OMe

NH

O

151a R= Cl 151b R=Br

Peptaibols

2-amino-isobutyric acid (Aib). Unusual amino and imino acids found in peptaibols include isovaline, b-alanine, hydroxyproline and pipecolic acid. The first 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

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 7–20 amino acids and characteristically have an acylated N-terminal group, a C-terminal amino alcohol, and a high content of Fig. 25 Sterols H

R H HO

H

HO

153 R= β-Me

152

154 R= α-Me HO2C

RO

O

OH

155 R= COCH(NH2)CH(OSO3H)CHMe2 156 R= H 157 R= COC(NH2)Me2

123

110 Fig. 26 Peptaibols structures

Phytochem Rev (2008) 7:89–123 Ac-Aib-Pro-Aib-Ala-Aib-Ala-Gln-Aib-Val-Aib-Gly-Leu-Aib-Pro-Val-Aib-Aib-Glu-Gln-Phe-OH

158

Me(CH2)4CH=CH(CH2)3CO-Gly-Gly-Leu-Aib-Gly-Ile-Leucinol

159

(R)-2- methyldecanoyl-Pro-

H N

O Ala-Aib-Aib-Ile-Ala-Aib-Aib

HN H

O

N CH3

OH

160 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-terminal amino acid, a 2-amino-6-hydroxy-4-methyl8-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-3pentenyl 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 Gibberella 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, cyclonerodiol oxide (162) and epicyclonerodiol oxide (163), were isolated from T. polysporum (Fujita

123

et al. 1984). In addition, a compound with santalane-like structure named lignoren (164), was recently isolated from T. lignorum by chromatographic 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 voltageclamped frog skeletal muscle fibers (Sauviat et al. 1992). Additionally, lignoren (164) displays moderate antimicrobial activity towards Bacillus subtilis, 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 production, statins inhibit the pathway leading to the generation of farnesylpyrophosphate and geranylgeranyl pyrophosphate, two pyrophosphates

Phytochem Rev (2008) 7:89–123

111

Table 1 Examples of peptaibols T. viride Suzukacillin A Trichotoxin A40 Trichovirins II Trichorovins Trichodecenins I, II Trichocellins T. polysporum Polysporins A–D Trichosporin B–V T. reesei Paracelsin T. saturnisporum Paracelsin E Saturnisporins SA II, SA IV T. koningii Trichokonins V–VIII Trikoningin KA, KB T. longibrachiatum Trichobrachin A I–IV, B I– IV Tricholongins B I, B II Longibrachin LGBII, LGBIII Trichogin A IV T. harzianum Trichorzianines A, B Trichokindins I–VII Harzianins HC Trichorozins I–IV T. atroviride Atroviridins A–C Trichoderma sp. Trichofumin A–D

Krause et al. (2006) Brueckner et al. (1985) Jaworski et al. (1999) Fujita et al. (1994) Fujita et al. (1994) Fujita et al. (1994)

O R2

R1

165 R1= R2= H 166 R1= α-Me, R2= H 167 R1= R2= α-Me

Ritieni et al. (1995) Rebuffat et al. (1993)

Huang et al. (1995b) Auvin-Guette et al. (1993) Mohamed-Benkada et al. (2006) Rebuffat et al. (1991) Leclerc et al. (2001) Auvin-Guette et al. (1992) El Hajji et al. (1987), Rebuffat et al. (1989) Iida et al. (1994) Rebuffat et al. (1995) Iida et al. (1995) Oh et al. (2000) Berg et al. (2003)

O

R

H OH

162 R= β-CMe2OH

161

H H

Breuckner et al. (1984)

OH

O

O

New et al. (1996) Iida et al. (1993)

HO

OH

O

163 R= α-CMe2OH

Fig. 28 Statins

which are critical for the induction of a variety of signal transduction pathways, which promote a cascade of events leading to endothelial dysfunction, inflammation, proliferation, apoptosis and other effects important for atherogenesis (Jakobisiak and Golab 2003). Compactin (165) (Fig. 28), also named mevastatin, has been isolated from different sources including several fungi such as Penicillium brevicompactum (Brown et al. 1976), T. longibrachiatum 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).

O

Heptelidic acid and derivatives 164 Fig. 27 Cyclonerodiol derivatives

The sesquiterpene heptelidic acid (168) (Fig. 29), also named koningic acid, was found in the

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O

O

H

HO

O

H

phytic fungi and protozoa. It also inhibits replication of DNA viruses such as HSV-1 and HSV-2, the causal agents of herpes simplex (Cane and Sohng 1994)

Cl

O

COOH

H

H

168

COOH

169 H COOH

O O

O

170 Fig. 29 Heptelidic acid and closely related compounds

culture filtrate of three different strains of fungi isolated from soil samples. These strains were identified as Gliocladium virens, Chaetomium globosum, and Trichoderma viride (Itoh et al. 1980). The antimicrobial spectrum of the antibiotic 168 showed its specific activity against anaerobic bacteria, especially against Bacteroides fragilis (Itoh et al. 1980). Isolation from Trichoderma koningii and subsequent bioactivity assays revealed its potent ability to alter ATP generation through inhibition of the D-glycealdehyde-3-phosphate 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 0.13–0.74 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-

123

Acoranes Acoranes are a family of spiro-sesquiterpenic compounds obtained from different sources. Trichoacorenol (171) (Fig. 30) was isolated from T. koningii (Huang et al. 1995a). It was hailed as a new compound, but in fact it is identical to coccinol which was previously isolated from Fusidium coccineum. The acorane-type 15-hydroxyacorenone (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

HO

R2

R1

172 R1= α -Me, R2= OH

171

173 R1= α -Me, R2= H 175 R1= β-Me, R2= H O

R

174 R= α-Me 176 R= β-Me Fig. 30 Acoranes

Phytochem Rev (2008) 7:89–123 Fig. 31 Miscelanea

113 O

HO

O

H

H O COOH

O

H

O

OH

177

178 OH

O

O

OH

R

OH

(CH2)21CH3

HN

O

OH

HO

O

(CH2)13CH3 OH

OH

179

182

180 R= CH2OCH3 181 R= CH3

O

O H

N

H

H

H

N H O H N

HN O

HO

H

H

H O H

O

183

184

185

O O

O O

O

O O

186

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 esterified with 3-methylglutaconic acid (Kobayashi et al. 1993). The tetracyclic compound harziandione (178) (Fig. 31) is claimed to be the first 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 identified as 3,4-dihydro-8-hydroxy-3-methyliso-

coumarin, also named mellein (179) (Fig. 31). This compound, previously isolated from Aspergillus 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¢-dihydroxy-3¢-methoxymethyl-5¢-methylacetophenone (180) (Fig. 31) and the known 2¢,4¢dihydroxy-3¢,5¢-dimethylacetophenone (clavatol, 181), were isolated from the culture filtrate 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), methylbenzoate, p-hydroxybenzyl alcohol and uracil

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114

from T. koningii has been established (Huang et al. 1995a). Moreover, 2,5-dimethylbenzoquinone, 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. pseudokoningii (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, octan3-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 Trichoderma 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 localized and systemic resistance in a range of plants to a variety of plant pathogens, and certain strains can also have substantial influence 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-molecularweight 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

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produced by them also appears to be important. As indicated by Cardoza et al. (2005) and Kubicek and Harman (1998), the different metabolites exhibiting antibiotic activity in Trichoderma can be classified 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 significant 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 competitor organisms. High molecular weight are polar metabolites which, like peptaibols, may exert their activity on direct interactions by contact between Trichoderma 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 conjecture. Activity in this field 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 especially significant and ensures interest on this subject for years to come.

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