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Bioactive fungal metabolites
No full textFungi represent one of the seven kingdoms of living organisms [1] and their secondary metabolites display a
broad range of biological activities. We have recently reviewed those fungal metabolites that display anticancer
activity, both from terrestrial [2, 3] and marine [4] origins. We have also highlighted in these three reviews [2-4],
the currently known biological events that enable various types of cancers, including metastatic ones to display high
levels of chemoresistance. Some fungal metabolites are able to overcome certain of these biological barriers leading
to cancer chemoresistance. For example, fusicoccin A, isolated from Fusicoccum amygdali, down-regulates focal
adhesion kinase (FAK) activity and induces cytostatic activity in glioblastoma (GBM) cells [5]. Ophiobolin A, isolated from Bipolaris species, induces paraptosis in GBM cells through the disruption of internal potassium ion homeostasis [6]. GBM are highly chemoresistant [7] as melanomas against which sphaeropsidin A, isolated from Diplodia cupressi, also displays marked anticancer activity through the disruption of melanoma cell ion homeostasis
[8]. We recently highlighted in a special issue of Current Medicinal Chemistry, the potential of targeting ion channels / transporters to combat various types of cancers associated with dismal prognoses [9].
Fungal metabolite-related anticancer activity is further analyzed by two contributions in the current special issue.
Wolf-Rainer Abraham (Helmholtz Centre for Infection Research, Chemical Microbiology, Braunschweig, Germany) has contributed a review entitled “Fumitremorgins and Relatives – from Tremorgenic Compounds to Valuable Anti-Cancer Drugs”. Fumitremorgins are mycotoxins that can also inhibit cancer cell proliferation and impair
their drug resistance.
Cristina Prandi (Department of Chemistry, Universita’ degli Studi di Torino, Torino, Italy) and her collaborators
have contributed a review entitled “Fungal anticancer metabolites: synthesis towards drug discovery”. Prandi and
her colleagues highlight the role of total synthesis in sustaining the pharmacological development of fungal metabolites and as an alternative to isolation in the field of cancer research.
The current special issue then presents five other contributions that do not relate to anticancer activity of fungal
metabolites, while emphasizing a broad spectrum of other biological activities.
Peter Proksch (Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine-Universität Düsseldorf,
Düsseldorf, Germany) and his colleagues have contributed a review entitled “Natural Products from Deep-SeaDerived Fungi ̶ a New Source of Novel Bioactive Compounds?”. As reported by Proksch and colleagues, up to
now, over 200 new metabolites have been identified from deep-sea fungi, and it has been assumed in the literature
that the unique environment of the deep sea will give rise to equally unprecedented natural products. Proksch and
colleagues critically evaluate whether the data published so far really supports the notion that these fungi are a
promising source of new bioactive chemical entities.
Alessio Cimmino (Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Napoli, Italy) and his
colleagues have contributed a review entitled “Bioactive Metabolites from Pathogenic and Endophytic Fungi of
Forest Trees”. As emphasized by Cimmino and his colleagues, fungi play an important role in terrestrial ecosystems
by interacting positively or negatively with plants. Furthermore, temperate forests represent an enormous reservoir
of fungal diversity. The review provided by Cimmino and colleagues focuses on the secondary metabolites produced by pathogenic and endophytic fungi of forest trees with a focus on their biological activities.
Andrea Chini (Departamento de Genética Molecular de Plantas, Centro Nacional de Biotecnología- Consejo Superior de Investigaciones Científicas, Madrid, Spain) and his colleagues have contributed a review entitled “Fungal
production and manipulation of plant hormones”. Chini and colleagues state that among the plant molecules that
regulate plant-fungus interactions, phytohormones play a critical role because they modulate various aspects of
plant development, defenses and stress responses. Chini and colleagues emphasize the fact that, intriguingly, fungi
can also produce phytohormones, although the actual role of fungal-produced phytohormones in plant-fungus interactions is poorly understood. Chini and colleagues thus provide an overview of the recent discoveries in fungal production of phytohormone, their putative role as endogenous fungal signals and how fungi manipulate plant hormone balance to their benefit.
Maurizio Vurro (Institute of Science of Food Production, National Research Council, Bari, Italy) and his colleagues have contributed a review entitled “Fungal Phytotoxins in Sustainable Weed Management”. Vurro and colleagues reevaluate the fact that fungal phytotoxins are natural secondary metabolites produced by plant pathogenic
fungi during host–pathogen interactions. The review provided by Vurro and colleagues aims to summarize studies
on the possibility of using such metabolites as tools in biological and integrated weed management, for example, as
novel and environmentally friendly herbicides; as biomarkers for the selection of more efficacious biocontrol
agents; as templates for novel compounds; and as sources of novel mechanisms of action. Vurro and colleagues also
discuss the limiting factors for utilizing these metabolites in practice.
Stefano Superchi (Dipartimento di Scienze, Università della Basilicata, Potenza, Italy) and his colleagues have
contributed a review entitled “Absolute Configuration Determination by Quantum Mechanical Calculation of Chiroptical Spectra: Basics and Applications to Fungal Metabolites”. Superchi and colleagues thus review the application of quantum mechanical simulations of chiroptical properties, i.e. electronic circular dichroism, optical rotation,
and vibrational circular dichroism, for the assignment of the absolute configuration of naturally occurring chiral metabolites of fungal origin.
REFERENCES
[1] Ruggiero, M.A.; Gordon, D.P.; Orrell, T.M.; Bailly, N.; Bourgoin, T.; Brusca, R.C.; Cavalier-Smith, T.; Guiry, M.D.; Kirk, P.M. A
higher level classification of all living organisms. PLoS One, 2015, 10, e0119248.
[2] Evidente, A.; Kornienko, A.; Cimmino, A.; Andolfi, A.; Lefranc, F.; Mathieu, V.; Kiss, R. Fungal metabolites with anticancer activity. Nat. Prod. Rep., 2014, 31, 617-627.
[3] Kornienko, A.; Evidente, A.; Vurro, M.; Mathieu, V.; Cimmino, A.; Evidente, M.; van Otterlo, W.A.; Dasari, R.; Lefranc, F.; Kiss, R.
Toward a cancer drug of fungal origin. Med. Res. Rev., 2015, 35, 937-67.
[4] Gomes, N.G.; Lefranc, F.; Kijjoa, A.; Kiss, R. Can some marine-derived fungal metabolites become actual anticancer agents? Mar.
Drugs, 2015, 13, 3950-3991.
[5] Bury, M.; Andolfi, A.; Rogister, B.; Cimmino, A.; Mégalizzi, V.; Mathieu, V.; Feron, O.; Evidente, A.; Kiss, R. Fusiccocin A, a phytotoxic carbotricyclic diterpene glucoside of fungal origin, reduces proliferation and invasion of glioblastoma cells by targeting multiple tyrosine kinases. Trans. Oncol., 2013, 6, 112-123.
[6] Bury, M.; Girault, A.; Mégalizzi, V.; Spiegl-Kreinecker, S.; Mathieu, V.; Berger, W.; Evidente, A.; Kornienko, A.; Gailly, P.; Vandier, C.; Kiss, R. Ophiobolin A induces paraptosis-like cell death in human glioblastoma cells by decreasing BKCa channel activity.
Cell Death Dis., 2013, 4, e561.
[7] Lefranc, F.; Brotchi, J.; Kiss, R. Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the
resistance of migrating glioblastoma cells to apoptosis. J. Clin. Oncol., 2005, 23, 2411-2422.
[8] Mathieu, V.; Chantôme, A.; Lefranc, F.; Cimmino, A.; Miklos, W.; Paulitschke, V.; Mohr, T.; Maddau, L.; Kornienko, A.; Berger,
W.; Vandier, C.; Evidente, A.; Delpire, E.; Kiss, R. Sphaeropsidin A shows promising activity against drug-resistant cancer cells by
targeting regulatory volume increase. Cell Mol. Life Sci., 2015, 72, 3731-3746.
[9] Kiss, R. Ion channels and cancers. Curr. Med. Chem., 2012, 19, 625-626
Fusaproliferin, Terpestacin and Their Derivatives Display Variable Allelopathic Activity Against Some Ascomycetous Fungi
No full textHerbivorous mammal dung supports a large variety of fimicolous fungi able to produce different bioactive secondary metabolites to compete with other organisms. Recently, the organic extracts of the Solid State Fermentation (SSF) cultures of Cleistothelebolus nipigonensis and Neogymnomyces virgineus, showing strong antifungal activity, were preliminarily investigated. This manuscript reports the isolation of the main metabolites identified, using spectroscopic and optical methods, as fusaproliferin (1) and terpestacin (2). Furthermore, some key hemisynthetic derivatives were prepared and their antifungal activity was tested against the same fungi previously reported to be affected by the organic extracts obtained from SSF. These metabolites and their derivatives resulted able to reduce the growth of Alternaria brassicicola, Botrytis cinerea and Fusarium graminearum in a variable extent strongly dependent from chemical modifications and test fungi. The hydroxy enolic group at C(17) appeared to be a structural feature important to impart activity. This study represents the first report of these secondary metabolites produced by C. nipigonensis and N. virgineus
Metabolites inhibiting germination of Orobanche ramosa seeds produced by Myrothecium verrucaria and Fusarium compactum
No full textMyrothecium verrucaria and Fusarium compactum were isolated from diseased Orobanche ramosa plants collected in southern Italy to find potential biocontrol agents of this parasitic weed. Both fungi grown in liq. culture produced metabolites that inhibited the germination of O. ramosa seeds at 1-10 M. Eight metabolites were isolated from M. verrucaria culture exts. The main metabolite was identified as verrucarin E, a disubstituted pyrrole not belonging to the trichothecene group. Seven compds. were identified by spectroscopic methods as macrocyclic trichothecenes, namely, verrucarins A, B, M, and L acetate, roridin A, isotrichoverrin B, and trichoverrol B. The main metabolite produced by F. compactum was neosoloaniol monoacetate, a trichothecene. All the trichothecenes proved to be potent inhibitors of O. ramosa seed germination and possess strong zootoxic activity when assayed on Artemia salina brine shrimps. Verrucarin E is inactive on both seed germination and zootoxic assay
On the phytotoxins with potential herbicidal activity produced by different species of Diaporthe
No full textCarthamus lanatus L. ssp. lanatus (common name: saffron thistle) is a widespread winter-growing annual thistle weed belonging to the Asteraceae family causing severe crop and pasture losses in Australia. Introduced from the Mediterranean region it is considered the most economically important thistle species in New South Wales (1). Among the numerous pathogens isolated from naturally infected saffron thistle plants, strains of Phomopsis sp. were considered suitable as potential mycoherbicides for its biological control (2). Recently the teleomorph of this pathogen was classified as Diaporthe gulyae by morphological, genetics and phytopathological studies (3). More recently, a study carried out on the bioactive metabolites of this fungus led to the isolation of the main phytotoxin produced in liquid culture, identified as a new geranylhydroquinone and named phomentrioloxin (1). The structure of 1 was determined by spectroscopic, X-ray, and chemical methods as (1R,2R,3R,4R)-3-methoxy-6-(7-methyl-3-methylene-oct-6-en-1-ynyl)-cyclohex-5-ene-1,2,4-triol (4).
Considering the novelty of this compound, a study on the structure-activity relationships
was then carried out by preparing seven derivatives obtained by chemical modifications of the main functional groups of the toxin. Moreover, recently two pathogenic species related to D. gulyae, identified as Diaporthe kochmanii sp. nov. and Diaporthe kongii sp. nov. and isolated from diseased sunflower in Australia were also considered for the production of bioactive metabolites. Strains of the three species were grown in both liquid and solid media and their metabolic profiles were compared. In this communication the results of structure-activity relationship study on phomentrioloxin will be discussed. Furthermore, the preliminary data on the chemical and biological characterization of the metabolites isolated from the three species of Diaporthe will be illustrated.
(1) BRIESE, D. T. Plant. Prot. 1988, 3, 135.
(2) ASH, G.J.; SODART, B.; SAKUANRUNGSIRIKUL, S.; ANSCHAW, E.; CRUMP, N.; HAILSTONES, D.; HARPER, D.I. Plant. Prot. Quart. 2010, 5, 14-17.
(3) THOMPSON, S. M.; TAN Y. P.; YOUNG, A. J.; NEATE, S.M.; AITEKEN, A.A.B.; SHIVAS, R. G. Persoonia 2011, 27, 80-89
7'-hydroxyseiridin and 7'-hydroxyisoseiridin, 2 New Phytotoxic Delta(alpha,beta)-butenolides From 3 Species of Seiridium Pathogenic To Cypresses
No full textTwo new phytotoxic Delta(alpha,beta)-butenolides, 7'-hydroxyseiridin [1] and 7'-hydroxyisoseiridin [2], were isolated from culture filtrates of three species of Seiridium (S. cardinale, S. cupressi, and S. unicorne). These fungi are associated with the canker diseases of cypress trees (Cupressus sempervirens) in the Mediterranean area. The structures of butenolides 1 and 2 were established using spectroscopic and chemical methods in comparison with seiridin [5] and isoseiridin [6], two phytotoxic metabolites produced in higher concentration by the same fungal species. Necrotic and chlorotic symptoms were produced on cuttings of both host and non-host plants by absorption of 100 or 50 mu M solutions, respectively, of compounds 1 and 2
ISOLATION AND CHARACTERISATION OF THE LIPOPOLYSACCHARIDE FROM XANTHOMONAS HORTORUM PV. VITIANS
No full textAbsolute configuration of natural cyclohexene oxides by time dependent density functional theory calculation of the optical rotation: the absolute configuration of (-)-sphaeropsidone and (-)-episphaeropsidone revised
No full textThe optical rotatory power of some natural cyclohexene oxides, such as (+)-chaloxone, 1, (+)-epiepoformine, 2, (+)-epoformine, 3, (+)-epoxidone, 5, (-)-sphaeropsidone, 6, (-)-episphaeropsidone, 7, and the synthetic compound (+)-epitheobroxide, 4, has been calculated by means of the TDDFT/B3LYP method using the 6-31G(d) and aug- cc-pVDZ basis sets, both in the gas phase and in solution by means of the polarizable continuum model. For compounds 1 and 2, which possess high (about 300 units) optical rotations, gas-phase calculations with the smaller basis set are able to reproduce the experimental values both in sign and order of magnitude. By contrast, a larger basis set is required to satisfactorily simulate the OR values of 3 and 4, which show smaller (about 100 units or less) rotations. The inclusion of the solvent effects is different for different compounds; for 1 and 2, it leads to a better agreement between experiment and prediction, while for 3 and 4, the presence of hydrogen bonding groups makes the application of continuum solvation models less satisfactory. For the flexible system 5, the absolute configuration could not be determined using gas-phase calculations and the smaller basis set, but both inclusion of solvent and larger basis set effects are compulsory. It is noteworthy that calculations both in the gas phase and in the solvent lead to a positive rotatory power for the laevorotatory natural compounds 6 and 7 if the ACs reported in the literature are employed to do the theoretical prediction. This strongly indicates that the ACs previously assigned to these compounds in the literature are not correct and that the TDDFT prediction of OR values has become by now a practicable tool for AC assignments
Cytochalasins From Phoma-exigua Var Heteromorpha
No full textThree further cytochalasins from Phoma exigua var. heteromorpha, grown on wheat, were isolated and characterized by spectroscopic methods and by chemical correlation with cytochalasin B. They were identified as cytochalasin T, a new 24-oxa[14]cytochalasan, cytochalasin F and 7-O-acetylcytochalasin B, both isolated for the first time from this fungus. Cytochalasin F showed significant activity in the brine shrimp assay and on tomato seedling growth
Bioactive Metabolites Produced by Pathogenic Fungi of Forest Plants
No full textPathogenic fungi are the main causes of diseases in forest plants, which determine losses to the forest, ornamental and landscape heritage and to the wood and nursery industries. These fungi are able to produce phytotoxins (i.e. secondary bioactive metabolites), which are involved in plant-pathogen interaction inducing disease symptoms. The discovery of new bioactive compounds is becoming a priority thanks to their wide-ranging applications, such as antibiotics, antivirals, chemotherapeutic agents and biopesticides with a low toxicity and eco-friendly.
Many metabolites were previously isolated from pathogenic fungi of forest plants and they belong to different classes of naturally occurring compounds includings coumarins and isocoumarins, furopyrans, nonenolides, pyrones, terpenes, and some others.1 Among them, sphaeropsidin A (Fig. 1) was isolated from different fungi belonging to Diplodia species and showed some interesting activities such as phytotoxic, antifungal, antibacterial, anticancer, mosquito biting deterrent, larvicidal. In this communication the isolation and the chemical and biological characterization of phytotoxins produced by other pathogenic fungi of forest plants will be illustrated as well as the role of these toxins in the symptoms inducing
Analytic Methods of Bioactive Metabolites Produced by plants and Microorganisms
No full textA review. HPLC and/or HPTLC, mass spectrometric and immunochem. methods for the anal. of natural bioactive metabolites are described. In particular, methods developed for the anal. of metabolites from plants and microorganisms in complex mixts. represent an important tool to investigate the biosynthesis and the mode of action of these metabolites for their large scale prodn. and for their practical applications
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