Mushroom-Derived Indole Alkaloids - Journal of ... - ACS Publications

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Mushroom-Derived Indole Alkaloids Joshua A. Homer and Jonathan Sperry* School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland 1142, New Zealand ABSTRACT: Mushrooms are known to produce over 140 natural products bearing an indole heterocycle. In this review, the isolation of these mushroom-derived indole alkaloids is discussed, along with their associated biological activities.

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INTRODUCTION Mushrooms have played a key role in human development, serving as both a nutrient-laden food supply and a source of many traditional medicines, particularly in Asian cultures.1 Consequently, mushrooms are a well-established source of bioactive compounds, and much effort has been dedicated to the isolation and structural elucidation of mushroom-derived natural products,1−3 with the isolation of quinoid pigments from the fruiting bodies of the mushroom species Tapinella atrotomentosus and Polyporus purpurascens in 1878 being an early example.4−6 Over the years, lectins, lanostanoids and other terpenoids, sterols, phenolic compounds, and alkaloids have been identified as key compound classes responsible for the variety of medicinal properties associated with mushrooms, including antitumor, anti-inflammatory, antifungal, antimicrobial, and antiviral activity.2 Numerous mushroom-derived natural products have served as lead compounds for the development of new agrochemicals and pharmaceuticals.1,4 Strobilurins A−H (1−8), isolated from Strobilurus tenacellus and numerous other mushroom species, are fungicidal compounds containing a conserved methyl (E)-3-methoxy-2(5-phenylpenta-2,4-dienyl) acrylate functionality.7−9 Later experimental findings revealed that strobilurin D (4) had been misassigned and was actually identical to strobilurin G (7).10 The strobilurins interrupt electron transfer within mitochondria, thus causing fungal death, a characteristic that inspired the development of azoxystrobin (9) by Syngenta, a broad spectrum fungicide launched in 1996 with widespread use in the agricultural sector.7,9,11 The diterpene natural product pleuromutilin (10) was isolated from the mushrooms Pleurotus mutilus and Clitopilus passeckerianus in 1951, and the structure was fully elucidated in 1962.12−14 The potent antibiotic properties of this natural product led to the development of tiamulin (11) and valnemulin (12) for veterinary use and the 2007 approval of retapamulin (13) for topical use in humans.15,16 Current developments have seen the pleuromutilin-derived antibiotic lefamulin (14) enter phase III clinical trials for community-acquired bacterial pneumonia, the first potential systemic use of a pleuromutilin in humans.17 The illudins are a class of antitumoral natural products isolated from © 2017 American Chemical Society and American Society of Pharmacognosy

a variety of mushroom species, most notably Omphalotus olearius.18,19 In 1963, the structures of illudins M (15) and S (16) were fully assigned as sesquiterpenes with a characteristic spirocyclopropane motif.20 The structurally related compounds illudin A (17) and B (18) were identified in 1991 from the species Clitocybe illudens.21 Subsequent efforts to improve the selectivity of these DNA alkylating agents led to irofulven (19),18 which has displayed significant activity against ovarian, prostate, hepatocellular, pancreatic, and

Received: May 4, 2017 Published: July 19, 2017 2178

DOI: 10.1021/acs.jnatprod.7b00390 J. Nat. Prod. 2017, 80, 2178−2187

Journal of Natural Products

Review

phosphatase activity at 50 μg mL−1, specifically enzymes MEG2 and PTP1B, both implicated in breast cancer development.49−51 Indigo (32) is a pigment with a strong blue color and has been found in mutant variants of the North American “meadow mushroom” Agaricus campestris, whereby the mycelium of the mushroom presents as a dark blue color.52,53 The structurally related red indirubin (33) was also tentatively identified in this species based on a characteristic ultraviolet absorption maximum.53 Indirubin (33) has been identified as the active constituent of the traditional Chinese medicine Danggui Longhui Wan, a mixture of plants used to effectively treat chronic myeloid leukemia.54 This molecule inhibits a variety of cyclin-dependent kinases (associated IC50 values ranging from 2.2 to 12 μM) and thus induces cell cycle arrest in cancerous cells.54,55 The edible mushroom Pleurotus salmoneostramineus has a bright pink coloration and is referred to as the pink oyster mushroom; this vibrant coloration has been attributed to 3-indolone (34).56

gastrointestinal cancers in numerous clinical trials.22,23 The potential of this experimental drug has been limited by hematological side effects, and as such 19 has yet to be approved for clinical use.23 The secondary metabolites of fungi have been reviewed in numerous articles, including medicinally significant nutraceuticals,1 pigment molecules,24−26 fungal volatiles,27 and nitrogencontaining compounds isolated from macromycetes.28 Review articles and book chapters specific to mushrooms have covered a range of bioactive compounds,2 immunomodulating agents,29 toxic compounds,30 antitumor polysaccharides,31,32 and bioactive proteins.33 This review discusses the isolation and biological activity of more than 140 indole alkaloids that are known to be mushroom-derived. The focus on indole alkaloids is warranted given their rich history, their use as pharmaceuticals,34,35 and their broad range of biological properties that has led to the indole heterocycle being classed as a privileged scaffold in drug discovery.36 For the purposes of this review, a mushroom has been defined as a higher Basidiomycota, predominantly the class Agaricomycetes, that produces visible fruiting bodies and generally has stem, cap, and gill structures. Indoles produced by filamentous fungi that do not meet these criteria have been omitted. The natural products presented in this review have been characterized as simple indoles, indoleamines/tryptophols, bisindoles, β-carbolines, pyrroloquinolines, and peptides/peptaibols. Simple Indoles. Auxins are a class of hormones that play an important role in gravitropism: the orientation of plants with respect to gravity.37 Indole-3-acetic acid (20, IAA) is the most abundant auxin, and although the mechanisms of fungus orientation remain poorly understood, its production in several mushroom species has been attributed to a positive impact on organism growth.38 5-Hydroxyindole-3-acetic acid (21) and indole-3-acetonitrile (22) have also been identified in mushroom extracts.39 Certain mushroom species are notorious for their potent, disagreeable odors. The smell of Hygrophorus paupertinus is distinctly fecal in nature, and this has been linked to the odoriferous indole (23), skatole (24), and 3-chloroindole (25).40,41 The isolation of 25 was the first time it had been identified in a terrestrial organism. Indoles 23 and 24 have also been identified within the pungent extracts of numerous members of the genus Tricholoma.41 Indole-3-carboxaldehyde (26), found in the volatile extract of Tricholoma sulphureum, has been associated with an unpleasant coal- or tar-like odor.42,43 Agrocybe cylindracea (also known as Cyclocybe aegerita), an edible mushroom that has long been used in traditional Chinese medicine as a diuretic, is an important source of bioactive metabolites that impart cytotoxic and antifungal properties.44 Two indole derivatives, 6-hydroxyindole-3-carbaldehyde (27) and 6-hydroxyindole-3-acetamide (28), have been isolated from A. cylindracea, with both possessing free radical scavenging activity.45,46 Both 27 and 28 were found to inhibit lipid peroxidation in rat liver microsomes with IC50 values of 4.1 and 3.9 μg mL−1, respectively.45 1-Methylindole-3carbaldehyde (29) and 7-methoxyindole-3-carboxylic acid methyl ester (30) were isolated from Phellinus linteus, a mushroom species used as a treatment for inflammation and a variety of cancers in East Asia.47,48 No biological testing was conducted on these natural products.47 Methylindole-3-carboxylate (31) was isolated from the extracts of Antrodiella albocinnamomea, a mushroom found throughout the subtropical regions of China.49 Investigation into the biological activity of 31 highlighted no significant inhibition of protein-tyrosine

A collection of N-glycosylated indoles (35−38) was isolated from the fruiting bodies of Cortinarius brunneus.57 Investigation into the activity of these molecules via root growth assays revealed no significant auxin-like activity,57 inferring that 35 (the N-glucoside of IAA) has an endogenous role as an inactive storage or detoxification product of the growth hormone, similar to the role of IAA-O-glucose (39) in plant tissues.57 Indoles 36−38 are assumed to be intermediates related to the metabolism of 35. Indoleamines and Tryptophols. L-Typtophan (40) is ubiquitous within mushroom species and is the biogenic source of the large majority of naturally occurring indole alkaloids. Consequently, edible mushrooms are a dietary source of this essential amino acid.58,59 The structurally related indoles 5-hydroxy-L-tryptophan (41), tryptamine (42), serotonin (5-HT, 43), melatonin (44), and bufotenin (45) are found (at varying concentrations) in a diverse range of mushrooms.39,58 This collection of indoleamines display endogenous activity within the human central nervous system.58 The genus Astraeus contains the earthstar mushrooms, which are 2179



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tin (50) and norbaeocystin (51) are also found as minor components in psychoactive mushrooms from the genus Psilocybe.63,73 The trimethylated derivative of 49, aeruginascin (52), has been isolated from another hallucinogenic mushroom, Inocybe aeruginascens.74,75 This collection of psychoactive

characterized by an exoperidium that opens in a star-like fashion to expose a spore sac.60 The trimethylated derivative of L-tryptophan, hypaphorine (46), was found in specimens of Astraeus odoratus along with its corresponding 5-hydroxy derivative (47).60 Hypaphorine (46) acts as an auxin antagonist, limiting root growth and elongation.60−62 Biological testing of 46 and 47 showed no significant antimycobacterial

compounds contain a 4-hydroxyindole motif, rarely seen among indole alkaloids. Termitomyces titanicus is a large, edible mushroom from West Africa that is noted for its symbiotic relationship with termites; the mushroom is cultivated by the insect as a food source.76 Termitomycamide B (53), a fatty acid amide isolated from this species,77 shows protective activity against endoplasmic reticulum stress induced by tunicamycin, with analogue studies highlighting the fatty acid side-chain as essential for this biological activity.77 The yellow parasol, or Leucocoprinus birnbaumii, is a tropical mushroom known for its bright yellow caps.78 The pigments responsible for this hue have been identified as the indole derivatives birnbaumins A (54) and B (55),78 structurally unprecedented natural products containing an N-hydroxyoxamidine motif and an N-hydroxyindole heterocycle. No biological testing was performed on these alkaloids.79 The mushroom Hericium coralloides has interesting fruiting bodies that are reminiscent of off-white coral.80 This species produces the indole alkaloid corallocin C (56). Although no antiproliferative activity was identified against a variety of cancer cell lines, 56 was found to stimulate neurotrophin expression in human 1321N1 astrocytes; approximately 30% of

activity against Mycobacterium tuberculosis or cytotoxic activity against various cancer cell lines.60 The narcotic effect of certain mushroom species has been well established for thousands of years and has been summarized in numerous reviews.63−66 Psilocin (48) is an indole alkaloid found in the genus Psilocybe that exhibits bioactivity similar to lysergic acid diethylamide (LSD), harmine, and other psychoactive tryptamines (bufotenin, 45, dimethyltryptamine, etc.), inducing psychoactive effects such as changes in perception, alteration to mood, and colorful hallucinations.63,64,67 Its mode of action is believed to occur through nonselective agonism of various serotonin receptors present within the central nervous system, specifically the 5-HT1A, 5-HT2A and 5-HT2C receptors.68,69 The phosphorylated derivative psilocybin (49) is also present and acts a prodrug, which readily converted to 48 in vivo.63,67 Promising results arising from the use of 49 as a treatment for depression and other psychiatric disorders have been disclosed.70−72 Baeocys-

neural PC12 cells differentiated when exposed to a medium containing 19.6 μM 56.80 2180



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The edible Craterellus cornucopioides is commonly referred to as the horn of plenty due to its unusual funnel-shaped fruiting body and highly sought black truffle flavor. This species has been shown to enzymatically couple externally supplied tryptophol (57) with the endogenous fatty acids oleic, linoleic, and dehydrocrepenynic acids to generate esters 58, 59, and 60.81 The physiological significance of these compounds

The generation of pungent molecules in response to structural damage is a defense mechanism employed by various mushrooms.88,89 A collection of 2,2′-bisindoline-3,3′diones were isolated from injured specimens of Collybia peronata and Tricholoma scalpturatum: peronatins A (71) and B (72) from C. peronata and the oxygenated derivatives (73 and 74) from T. scalpturatum.90 It is suspected that these alkaloids form via an enzymatic hydrolysis and radical-mediated oxidative coupling of an unidentified, pungent indole precursor.90 The bioactivities of 71−74 remain to be investigated.

remains unknown, although similar esters are produced by a variety of bacteria and plant species, suggesting an evolutionarily conserved process.81,82 Bisindoles. The genus Tricholoma of mushrooms produces a number of indole alkaloids containing a methyl group at the C2-position. This unique structural feature can be traced back to lascivol (61), a bitter component isolated from Tricholoma lascivum that is proposed to be the biogenic precursor to these natural products.28,83 Indoles 62−65 have been isolated and characterized from the fruiting bodies of Tricholoma sciodes and Tricholoma virgatum.84,85 4-Methoxymethyl-5-methylindole (66) has also been identified in the aroma bouquet of the related species Tricholoma caligatum.43,86 The associated bisindoles 67−69 and sciodole (70) were also found in various Tricholoma extracts.85,87 No biological activity has been identified for indoles 62−70.

β-Carbolines. Hygrophorus eburneus, a white, edible mushroom characterized by its extremely slimy cap, has been found to produce norharmane (75) along with harmane (76),91 a tremorogenic neurotoxin that acts as both a monoamine oxidase inhibitor and a potent inhibitor of the benzodiazepine receptor.92 The olive-colored fruiting bodies of the inedible mushroom Cortinarius inf ractus have been found to produce the highly fluorescent β-carboline derivatives infractines A (77) and B (78).93 β-Carboline-1-propanoic acid (79) and its methylated derivative (80) have been identified in specimens of Boletus curtisii, a mushroom that forms a mycorrhizal relationship with hardwood and conifer trees across North America.94 Cytotoxic assessment of 79 highlighted no inhibitory activity against five cancer cell lines,95 although it has been suggested this molecule could interact with both the benzodiazepine and GABA receptors.96 Brunneins A−C

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(81−83) along with 3-(7-hydroxy-9H-β-carboline-1-yl)propanoic acid (84) are 7-hydroxylated β-carboline pigments produced by Cortinarius brunneus.97 Brunnein A (81) has also been found in the fruiting bodies of Hygrophorus hyacinthinus.91 Biological testing of 81 showed very low acetylcholinesterase inhibition (less than 50% inhibition at a concentration of 10−4 M against both acetylcholinesterase and the related enzyme butyrylcholinesterase) with no associated cytotoxicity.97,98 The fruiting bodies of Cortinarius inf ractus also contain infractopicrin (85) and 10-hydroxyinfractopicrin (86).98,99 The acetylcholinesterase-inhibiting activity of these compounds (IC50 values of 9.72 and 12.7 μM, respectively) is comparable to that of galantamine, a drug used for the treatment of mild to moderate Alzheimer’s disease.98,99 Good selectivity for acetylcholinesterase infers these alkaloids are excellent lead compounds for further development.98,99 The aforementioned Boletus curtisii produces an interesting collection of sulfurcontaining β-carboline derivatives.94 The bright yellow coloration of this species has been attributed to the optically active, sulfoxide-containing pigments curtisin (87) and 9-deoxycurtisin (88).94 These compounds are derived from canthin-6-one (89), which was also identified in the extracts of B. curtisii along with four thiomethyl β-carboline derivatives (90−93).94 Canthin-6-one (89) is found in a variety of higher plants and possesses antifungal and cytotoxic properties.100 The furyl-linked β-carboline flazin (94) has been isolated from Suillus granulatus, the so-called weeping bolete that grows in a symbiotic relationship with pine trees, as well as the fruiting bodies of Boletus umbriniporus.101,102 Flazin (94) was found to exhibit anti-HIV activity with an EC50 of 2.36 μM and a therapeutic index of 12.1; consequently a series of flazin

Table 1. Metatacarbolines

name metatacarboline A (95) metatacarboline B (96) metatacarboline C (97) metatacarboline D (98) metatacarboline E (99) metatacarboline F (100) metatacarboline G (101) 6-hydroxymetatacarboline 6-hydroxymetatacarboline 6-hydroxymetatacarboline 6-hydroxymetatacarboline 6-hydroxymetatacarboline 6-hydroxymetatacarboline 6-hydroxymetatacarboline 6-hydroxymetatacarboline 6-hydroxymetatacarboline

A (102) B (103) C (104) D (105) E (106) F (107) G (108) H (109) I (110)

R1

R2

H H H H H H H OH OH OH OH OH OH OH OH OH

OH Gln Ser Thr Ala Val Ile OH Gln Ser Thr Ala Val Ile Phe Leu

demonstrated limited antiproliferative activity against glioma cell lines, with IC50 values of 150 and 250 μM, respectively.105 Pyrroloquinolines. Numerous pyrroloquinoline natural products have been isolated as pigment molecules from the genus Mycena.24 Two red alkaloids, mycenarubin A (111) and the associated dimer mycenarubin B (112), were found in the species Mycena rosea, or rosy bonnet.106 This was the first isolation of a dimeric pyrroloquinoline from a natural source.106 The monomer 111 showed no antimicrobial activity against a variety of bacteria and fungi, consistent with the diminished bioactivities of other o-quinones comparative to their p-quinone counterparts.106 The blue pyrroloquinolines sanguinones A (113) and B (114) were isolated from the mushroom Mycena sanguinolenta,107 along with the decarboxylated species (115) and a red alkaloid, sanguinolentaquinone (116).107 The related mushroom Mycena hematopus, or bleeding mycena, exudes a bright red liquid if the fruiting bodies are damaged.108 This mushroom has been found to produce the red pyrroloquinolines mycenarubins D−F (117−119) as well as hematopodin (120) and hematopodin B (121).108,109 Comparative metabolic profiling also indicated the presence of the aforementioned mycenarubin A (111) and sanguinolentaquinone (116).108 The so-called black-edged bonnet, Mycena pelianthina, is a purple mushroom widely found throughout Europe and North America.110 Two novel pyrroloquinolines were identified in the fruiting bodies of this species and structurally assigned as pelianthinarubins A (122) and B (123); both contain a trimethylated histidine (S-hercynine) residue.110 Biological testing indicated no antibacterial or herbicidal activity.110 Peptides and Peptaibols. Lentinus strigellus, a medicinal mushroom from South America, has been found to produce the triprenylated tryptophan-based diketopiperazine echinulin (124) under a variety of culture conditions.111 This bioactive secondary metabolite has modest activity against Mycobacterium tuberculosis H37Ra (MIC value of 169.92 μM) and is cytotoxic to HeLa cells at 100 μg mL−1.112,113 Macrolepiotin (125), isolated from the poisonous mushroom Macrolepiota neo-

analogues have been synthesized to explore this activity further.103 The inedible mushroom Mycena metata has been found to produce the 16 β-carboline natural products metatacarbolines A−G (95−101) and 6-hydroxymetatacarbolines A−I (102−110) bearing a variety of different amino acids coupled to the C3 carboxyl moiety (Table 1).104 High-resolution matrix-assisted laser desorption-ionization mass spectrometry (HR-MALDI-MS) imaging was used to identify these alkaloids.104 Compounds 95 and 97−100 have been synthesized and subjected to cytotoxicity evaluation; metatacarbolines D (98) and F (100) 2182



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I. obliquus afforded the tripeptide 127, a molecule that exhibited platelet aggregation inhibitory activity of 83.3% in a mouse antithrombotic assay at a dose of 20 mg kg−1.115 Amanita phalloides, aptly referred to as the death cap, contains a cocktail of toxic peptides and, as such, has been implicated in the majority of human deaths resulting from mushroom consumption.28 The cyclic peptides produced by Amanita mushrooms, covered in numerous review articles,116,117 are categorized into three groups: amatoxins, phallotoxins, and virotoxins. The nine amatoxins 128−136 constitute the largest subgroup and have also been identified in mushrooms of the Galerina and Lepiota genera (Table 2).118,119 The first Table 2. Amatoxins

name

R1

R2

R3

R4

R5

α-amanitin (128) β-amanitin (129) γ-amanitin (130) ε-amanitin (131) amanullin (132) amanullinic acid (133) amaninamide (134) amanin (135) proamanullin (136)

OH OH OH OH H H OH OH H

OH OH H H H H OH OH H

NH2 OH NH2 OH NH2 OH NH2 OH NH2

OH OH OH OH OH OH H H OH

OH OH OH OH OH OH OH OH H

amatoxin to be isolated was α-amanitin (128) by Wieland and co-workers in 1941.120 The amatoxins are bicyclic octapeptides (seven members of the group, 128−133 and 136, contain a rare 6-hydroxy-L-tryptophan residue) that act as selective inhibitors of RNA polymerase II, a vital enzyme in the synthesis of mRNA.116 Pivotal X-ray crystallographic data presented by Bushnell and co-workers explored the binding mechanism of α-amanitin (128) in great detail; binding of 128 to RNA polymerase II prevents the conformational changes required to conduct transcription, thus reducing DNA translocation from several thousand to a handful of nucleotides per minute.121 Although inhibition of protein synthesis causes widespread damage in the human body, it is irreversible lesions to the heart and liver cells that prove fatal.122 α-, β-, and γ-Amanitins 128−130 have been identified as the most potent members of this compound family, with LD50 values in the range of 0.2 to 0.5 mg kg−1.116 The closely related phallotoxins 137−143 are a group of seven bicyclic heptapeptides also isolated from the genus Amanita (Table 3).28,116 Phalloidin (137) was the first toxic peptide to be isolated from the genus Amanita in 1937.123 The phallotoxins damage hepatocytes, interact with cellular actin, and disrupt microfilament depolymerization.122,124 This interaction with actin has led to the use of phalloidin (137) as an imaging tool in biomedical research, with fluorescent analogues used to visualize actin filaments in living and fixed cells, as well as in vivo.125 Although extremely toxic when administered intravenously, the phallotoxins have been found

mastoidea, comprises the dipeptide Trp-Ile coupled to lepiotin B (126).114 No significant biological activity was found when tested against A549, SK-OV-3, SK-MEL-2, or HCT-15 cancer cell lines.114 The relative and absolute stereochemistry of 125 was not determined.114 Inonotus obliquus is a widespread parasitic mushroom that has been used for centuries in traditional Russian medicine for its antitumor and immunostimulating properties.115 Investigation into the bioactive compounds present within

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Table 3. Phallotoxins

name

R1

R2

R3

R4

R5

phalloidin (137) prophalloin (138) phalloin (139) phallisin (140) phallacidin (141) phallacin (142) phallisacin (143)

OH H OH OH OH OH OH

Me Me Me CH2OH Me Me CH2OH

CH2OH Me Me CH2OH CH2OH Me CH2OH

Me Me Me Me CHMe2 CHMe2 CHMe2

Me Me Me Me CO2H CO2H CO2H

to contribute little to the genus’s lethality due to poor gut uptake when consumed orally.28,116 The virotoxins (Table 4) are six monocyclic peptides that induce hemorrhagic hepatic necrosis in mice through a similar nephrotoxic activity; an average oral LD50 value in mice of 39 mg kg−1 of body weight and intraperitoneal LD50 in mice of 5 mg kg−1 of body weight have been reported, although clinical data suggest a greater sensitivity to the toxin in humans than mice.132 Additionally, a strong fluorescence is associated with orellinine (154) and orelline (155), the decomposition products of 153, which is likely the same fluorescence originally attributed to the putative cortinarins.129 Further investigation is required to clarify the existence of the cortinarin family of cyclic peptides. Omphalotins A−I (156−164) are a family of dodecapeptides isolated from the jack-o’-lantern mushroom Omphalotus olearius, a poisonous, orange species noted for its bioluminescence.133 Members of this family exhibit strong, selective nematicidal activity against the economically important plant pathogen Meloidogyne incognita, with LD90 values falling between 2 and 5 μg mL−1 and low associated cytotoxicity

Table 4. Virotoxins

name

R1

R2

R3

viroidin (144) desoxoviroidin (145) alaviroidin (146) aladesoxoviroidin (147) viroisin (148) desoxoviroisin (149)

SO2Me SOMe SO2Me SOMe SO2Me SOMe

Me Me Me Me CH2OH CH2OH

CHMe2 CHMe2 Me Me CHMe2 CHMe2

Table 5. Omphalotins actin-binding mode of action displayed by the phallotoxins.124,126 As with the phallotoxins, the virotoxins (144−149) are not considered to have any significant toxic effects after oral consumption.116 Another mushroom notorious for its acute toxicity is Cortinarius speciosissimus.127 Early investigation by Tebbett and Caddy into the toxic components of this species led to the isolation of cortinarins A−C (150−152), cyclic peptides with a characteristic fluorescence structurally reminiscent of the aforementioned phallotoxins.127 It was hypothesized that these cyclic peptides are converted in vivo to an unknown active metabolite that induces the observed toxicity.128 However, several research groups have been unable to replicate these studies, most notably work by Laatsch and co-worker, who were unable to isolate any cyclic peptides similar to the cortinarins from specimens of C. speciosissimus.129,130 Furthermore, it has been strongly suggested that the dimeric pyridine N-oxide orellanine (153), repeatedly isolated from other members of the genus Cortinarius and found as the corresponding diglycoside in vivo, is the potent compound responsible for the toxicity of these mushrooms.129,131,132 Biological studies conducted on 153 revealed significant

name omphalotin omphalotin omphalotin omphalotin omphalotin omphalotin omphalotin omphalotin 2184

B (157) C (158) D (159) E (160) F (161) G (162) H (163) I (164)

R1

R2

R3

O2CCH2C(Me)2OH O2CCH2C(Me)2OH OAc H H H OAc O2CCH2C(Me)2OH

OH OAc OAc H H OH OAc OAc

H H H H OH OH OH OH



Review

Table 6. Chrysospermins and Boletusin amino acid residue compound

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

167 168 169 170 171

AcPhe AcPhe AcPhe AcPhe AcPhe

Aib Aib Aib Aib Aib

Ser Ser Ser Ser Ala

Aib Aib Aib Aib Aib

Aib Aib Iva Iva Iva

Leu Leu Leu Leu Leu

Gln Gln Gln Gln Gln

Gly Gly Gly Gly Gly

Aib Aib Aib Aib Aib

Aib Aib Aib Aib Aib

Ala Ala Ala Ala Ala

Ala Ala Ala Ala Ala

Aib Aib Aib Aib Aib

Pro Pro Pro Pro Pro

Aib Iva Aib Iva Aib

Aib Aib Aib Aib Aib

Aib Aib Aib Aib Aib

Gln Gln Gln Gln Gln

Trpol Trpol Trpol Trpol Trpol

(at concentrations below 50 μg mL−1).133−135 This collection of peptides have been found to comprise a characteristically large number of both valine residues and methylated α-nitrogens. Omphalotins B−I contain an unusual oxidatively modified tricyclic tryptophan residue, with F−I also bearing an intriguing N-hydroxyl motif.133,134 Peptaibols are a class of fungal peptides characterized by a C-terminal amino alcohol in conjunction with an N-alkylated terminus and a high content of α,α-dialkylated amino acids such as α-aminoisobutyric acid (Aib).136 These compounds have pronounced antibiotic activity and act through the formation of transmembrane, voltage-gated ion channels that subsequently disrupt cell wall permeability and ultimately cause bacterial cell death.136−139 Two such peptaibols, tylopeptins A (165) and B (166), were isolated from the mushroom Tylopilus neofelleus.136,140 Biological testing via the agar diffusion test indicated activity against various Gram-positive bacteria with inhibition zones ranging from 13 to 18 mm.136

constitute a promising collection of potential lead compounds for medicinal chemistry studies. We hope this review will stimulate further research into this class of natural products, especially considering the lack of biological data associated with many of the alkaloids reported herein.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jonathan Sperry: 0000-0001-7288-3939 Notes

The authors declare no competing financial interest.

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REFERENCES

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Chrysospermins A−D (167−170) and boletusin (171) were isolated from the methanol extract of the fruiting body of the mushroom Boletus spp. (Table 6).141 These peptaibols contain a labile Aib−Pro bond, an acetylated N-terminus, and a C-terminal tryptophanol (trpol) residue.141 Investigation into the antimicrobial activity of 168, 170, and 171 by the agar diffusion method showed inhibition zones ranging from 9 to 25 mm against numerous Gram-positive bacteria, the mode of action for these compounds being related to that of the previously mentioned peptaibols.139,141 Peptaibols 167−170 have been since patented as nematicidal and anthelminthic agents.142

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CONCLUSIONS Collating all of the known indole alkaloids derived from mushrooms has revealed an array of structural diversity and interesting biological activities. When considering the reputation of indole alkaloids (and the indole heterocycle) in human medicine and that mushrooms are a rich source of bioactive secondary metabolites that have inspired the development of society-enhancing agrochemicals and pharmaceuticals, it is reasonable to assume that mushroom-derived indole alkaloids 2185



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