Next Article in Journal
Turmeric Powder Counteracts Oxidative Stress and Reduces AFB1 Content in the Liver of Broilers Exposed to the EU Maximum Levels of the Mycotoxin
Previous Article in Journal
The Effect of OnabotulinumtoxinA on Headache Intensity and Number of Monthly Headache Days in Individuals with Chronic Migraine with Different Levels of Neck Disability
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Toxins
Volume 15
Issue 12
10.3390/toxins15120686
toxins-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Secondary Metabolites of Biscogniauxia: Distribution, Chemical Diversity, Bioactivity, and Implications of the Occurrence

by
Sari Purbaya
1,2,
Desi Harneti
2,
Wahyu Safriansyah
2,
Rahmawati
3,
Asri Peni Wulandari
4,
Yeni Mulyani
2 and
Unang Supratman
2,3,*
1
Department of Chemistry, Faculty of Science and Informatics, Universitas Jenderal Achmad Yani, Cimahi 40531, Indonesia
2
Departments of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jatinangor 45363, Indonesia
3
Central Laboratory, Universitas Padjadjaran, Jatinangor 45363, Indonesia
4
Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jatinangor 45363, Indonesia
*
Author to whom correspondence should be addressed.
Toxins 2023, 15(12), 686; https://doi.org/10.3390/toxins15120686
Submission received: 30 September 2023 / Revised: 19 October 2023 / Accepted: 19 October 2023 / Published: 6 December 2023
(This article belongs to the Section Plant Toxins)
Browse Figures
Versions Notes

Abstract

:
The genus Biscogniauxia, a member of the family Xylariaceae, is distributed worldwide with more than 50 recognized taxa. Biscogniauxia species is known as a plant pathogen, typically acting as a parasite on tree bark, although certain members of this genus also function as endophytic microorganisms. Biscogniauxia endophytic strain has received attention in many cases, which includes constituent research leading to the discovery of various bioactive secondary metabolites. Currently, there are a total of 115 chemical compounds belonging to the class of secondary metabolites, and among these compounds, fatty acids have been identified. In addition, the strong pharmacological agents of this genus are (3aS,4aR,8aS,9aR)-3a-hydroxy-8a-methyl-3,5-dimethylenedecahydronaphto [2,3-b]furan-2(3H)-one (HDFO) (antifungal), biscopyran (phytotoxic activity), reticulol (antioxidant), biscogniazaphilone A and B (antimycobacterial), and biscogniauxone (Enzyme GSK3 inhibitor). This comprehensive research contributes significantly to the potential discovery of novel drugs produced by Biscogniauxia and holds promise for future development. Importantly, it represents the first-ever review of natural products originating from the Biscogniauxia genus.
Keywords:
endophytic fungi; Biscogniauxia; biological activity
Key Contribution: The number of reports in the literature relating to secondary metabolites produced by the genus Biscogniauxia from various source. This is the first review focuses on the available data regarding their occurrence, detection, and bioactivity.

1. Introduction

A significant variety of natural products have been isolated and identified from many fungi, consisting of approximately 47% of the roughly 33,500 bioactive microbial metabolites [1]. Endophytic fungi are organisms that live in plant tissues without causing harm and produce biologically active compounds specific to the host plants [2]. They are considered a potential source of new bioactive natural material for new drug development, inhabiting the inner tissues of living plants [3,4]. Some endophytic fungi can produce the same or similar bioactive substances as those found in the host plant, one of which is the genus Biscogniauxia [5].
Biscogniauxia is a genus of fungi in the family Xylariaceae with more than 50 recognized taxa worldwide [6,7]. Biscogniauxia endophytic strain has received attention in many cases, which includes constituent research leading to the discovery of various bioactive secondary metabolites [4]. Since the first report on the secondary metabolites of Biscogniauxia in 2005, a large number of chemical compounds have been isolated [8,9]. Subsequently, an extensive literature review was carried out using databases from SCI-Finder, Google Scholar, Web of Science, Scopus, Science Direct, PubMed, Chemical Abstracts, ACS journals, Springer, Taylor Francis, Bentham Science, and IOP Science. This comprehensive search yielded numerous articles providing an overview of compounds, including secondary metabolites and fatty acids, from approximately nine taxa of Biscogniauxia.
Chromatographic and spectroscopic methods such as nuclear magnetic resonance (NMR), ultraviolet-visible (UV-Vis), infrared (IR), optical rotation (OR), circular dichroism (CD), and mass (MS) explanation of spectroscopy were used in the latest review to elucidate the structures of the 115 isolated compounds. These compounds belong to diverse classes, including azaphilone derivatives, bergamotenes, cerebrosides, coumarins, fatty acids, flavonoids, furan, guaianoids, hydroxycinnamic acids and derivatives, lignans, naphthoquinones, peptides, phenyl and phenol derivatives, phthalide, pyranopyran, α-pyrones, terpenoids and the derivates, tyramines, and others. The composition of the isolated compounds is arranged alphabetically according to their names. In addition, Biscogniauxia exhibits various bioactivities, such as antifungal, antimycobacterial, antiproliferative, antioxidant, anticancer, anti-germinative, inhibition of GSK-3β enzyme activity, phytotoxic activity, and AcHE activity, and its potential applications.

2. Secondary Metabolites

Biscogniauxia produces a large number of low-molecular-weight compounds with native structure and bioactivity. In this situation, these fungi produce metabolites with enormous structural diversity that belong to the various classes of natural products presented in Table 1.

2.1. Azaphilone Derivatives

A new azaphilone derivative was successfully isolated from the n-BuOH soluble fraction of 95% EtOH extract from substrate culture on B. formosana to produce Biscogniazaphilones A (1) and Biscogniazaphilones B (2) [10] (Figure 1). This marks the first report of this compound being isolated from B. formosana. Subsequently, azaphilones or azaphilonoids are fungal polyketides known for the highly oxygenated cyclic pyranoquinone core, usually referred to as isochromenes and quaternary carbon centers, and also known as pigments [24,25]. Compounds 1 and 2 based on the spectra of 1H NMR and 13C NMR are similar, but compound 2 has one γ-lactone group between C-6a and C-9.

2.2. Cerebrosides

Cerebrosides are a family of glycosphingolipids and important components of various tissues and organs in biological systems. Chemically, cerebrosides consist of hexose and ceramide groups, typically consisting of long-chain amino alcohols commonly called “sphingoid bases” (=sphingosine or sphingol) and amide-linked long-chain fatty acids [26]. While cerebrosides can be found in plants, fungi, and animals, distinct variations exist in the structure of the ceramide backbone among these organisms [27]. In the genus Biscogniauxia, Cerebroside A (3) and Cerebroside C (4) (Figure 2) were successfully isolated from the ethyl acetate extract in the stroma of Biscogniauxia whalleyi mushrooms cultivated on potato dextrose agar (PDA) media. Fungal cerebrosides exhibited remarkable structural conservation, with modifications including different unsaturation sites as well as varying lengths of fatty acid residues in the ceramide moiety [28].

2.3. Coumarin

Coumarin is a secondary metabolite derived from 1,2 benzopyrone, formed from the benzene ring, and α-pyrone found in microorganisms and higher plants, originating from the phenylpropanoid pathway [29,30]. Coumarin has been extensively examined as one of the most promising structures for the development of new agents with higher specificity and affinity against molecular targets. Furthermore, it is characterized by its intrinsic properties such as antimicrobial, antioxidant, anti-inflammatory, antiadipogenic, cytotoxic, apoptotic, antiproliferative, antimycobacterial activity against Mycobacterium tuberculosis, antileishmanial, antiviral, anticancer, and cytotoxic agent [31]. Biscogniauxia endophytic strain has garnered attention in constituent research, leading to the discovery of various bioactive secondary metabolites, specifically in the context of coumarins. Given their wide range of pharmacological values, coumarins and their derivatives hold significant importance in synthesis and production. The coumarin is produced from Biscogniauxia and is divided into three groups: coumarin compounds 5–7, isocoumarins 8–9, and dihydroisocoumarin (Melleins) compounds 10–25 (Figure 3).

2.3.1. Coumarin

Isoscopoletin (5), scopoletin (6), and isofraxidin (7) were successfully isolated from the n-BuOH-soluble endophytic fungus Biscogniauxia cylindrospora [4] (Figure 3). Regarding scopoletin (6), before it was successfully isolated from B. cylindrospora, it had been widely produced from plants and could be isolated from various plant parts (roots, fruit, leaves, stems, etc.) such as Nicotiana tabacum, Sinomenium acutum, Helichrysum italicum, Manihot esculenta, Aegle marmelos, Chenopodiastrum murale, Hypochaeris radicata, Cirsium setidens, Aleurites moluccana L., Morinda citrifolia, Ipomoea digitata L., Ipomea reniformis, Artemisia iwayomogi, Macaranga gigantifolia M., Artemisia annua, Tetrapleura tetraptera, Tilia cordata M., Melia azedarach L., Acer saccharum M., Hymenodictyon obovatum, Fagraea ceilanica, and Morus alba L. [32].

2.3.2. Isocoumarin

Chromatographic separation of the EtOAc extract from cultured Biscogniauxia capnodes yielded two isocoumarins, 6-O-methyl-reticulol (8) and reticulol (9). 6-O-methyl-reticulol was previously isolated from Streptomyces mobaraensis with inhibitory activity in the liverwort Wettsteinia ÿschusterana [33](Figure 3).

2.3.3. Dihydroisocoumarin (Melleins)

Mellein is a secondary metabolite of the 3,4-dihydroisocoumarin subgroup, which is a structural isomer of coumarin and belongs to the polyketide class. It is abundant in microorganisms and higher plants and has many biological activities [34]. The content of mellein in Biscogniauxia is higher than that of isocoumarins; namely, 16 compounds were successfully isolated, as shown in Figure 4. One new dihydroisocoumarin (3S)-5-hydroxy-8-O-methylmellein (16), along with the other 3 mellein compounds 5-hydroxymethylmellein (17), 5-formylmellein (18), and mellein-5-carboxylic acid (19), was isolated from the n-BuOH soluble fraction of 70% EtOH extract of rice fermented with the endophytic fungus B. cylindrospora (BCRC 33717) [15]. Mellein compounds have also been isolated from B. rosacearum oak strain IRAN 4194C and are important for producer organisms and included in many biological activities, including phytotoxicity. Several related melleins are (3R)-mellein (20) and (3R,4R)-and (3R,4S)-4-hydroxymellein (12) and (13), (3R)-6-hydroxymellein (14), and (3R)-4-methoxymellein (24) were also isolated from B. rosacearum IRAN 4287C [14]. Two mellein derivatives, namely 3,5-dimethyl-8-methoxy-3,4-dihydroisocoumarin (10) and 3,5-dimethyl-8-hydroxy-3,4-dihydroisocoumarin (11), were isolated from Biscogniauxia nummularia. Furthermoe, in Biscogniauxia mediterranea extract strain LF657, which was isolated from marine sediments east of the Mediterranean Sea, a mellein derivative was identified as 6-methoxy-5-methylmellein (25) [17]. Additionally, B. capnodes yielded 7-hydroxy-5-methylmellein (15), and 5-methylmellein (21) was isolated from various sources, including B. mediterranea (EtOAc), B. mediterranea (DCM), B. capnodes (EtOAc), and B. whalleyi (EtOAc) [11].

2.4. Fatty Acids

From the Biscogniauxia endophytic strain, one fatty acid that was effectively isolated was linoleic acid (26), obtained in the form of a colorless oil. This isolation was achieved from the EtOAc-soluble fraction of a 95% EtOH rice extract that underwent fermentation with B. cylindrospora [4] (Figure 5).

2.5. Flavonoids

One flavonoid was further isolated from the n-BuOH-soluble fraction of the 95% EtOH extract from the solid substrate culture of B. formosana BCRC 33718, namely 5-hydroxy-3,7,4′-trimethoxyflavone (27) [10], which had previously been isolated from the stem wood and bark of Aniba species [35] (Figure 6).

2.6. Furan

(3aS,4aR,8aS,9aR)-3a-hydroxy-8a-methyl-3,5-dimethylenedecahydronaphto [2,3-b]furan-2(3H)-one (HDFO) (28) isolate from Biscogniauxia sp. was used as a control for the detection of the growth inhibition zone O-811 ECF inhibitor compound against M. oryzae. The customized HDFO of O-821-ECF showed inhibitory activity against M. oryzae at <5 ppm [18] (Figure 7).

2.7. Hydroxycinnamic Acids and Derivatives

In the category of hydroxycinnamic acids and derivatives, after a series of isolation stages, dried rice from B. formosana BCRC 33718 was extracted with 95% EtOH and subjected to preparative TLC using MeOH as a developer. This process yielded N-trans-feruloy-3-O-methyl-dopamine (29), the sole compound in the hydroxycinnamic acids and derivatives group. This compound had previously been identified in spinach leaves (Spinacia oleracea) [36] (Figure 8).

2.8. Lignans

Lignans, which are an abundant class of phenylpropanoids, have received wide attention in many fields. This is mainly because these compounds have some medically important biological activities, for example antitumor, antimitotic, and antiviral properties [37]. Three lignans were successfully isolated from the n-BuOH soluble fraction of 95% EtOH extract from B. formosana solid substrate culture, including methyl 3,4-methylenedioxycinnamate (30), 3,4-methylenedioxycinnamic acid (31), and 3,4-methylenedioxybenzoic acid (32) [10] (Figure 9).

2.9. Naphthoquinones

Naphthoquinones are widespread and have been found in higher plants, fungi, and actinomycetes [38]. In the extract of B. mediterranea strain LF657, isolated from deep-sea sediments in the eastern Mediterranean Sea at a water depth of 2800 m, the new isopyrrolonaphthoquinone compound naphtho [2,3]furandione (isofuranonaphthoquinone) (biscogniauxone) (33) was identified [17] (Figure 10). Many researchers have an interest in this class of naphthoquinone compounds because of their wide range of biological activities, such as phytotoxic, insecticidal, antibacterial, and fungicide. In addition, some of these compounds also have cytostatic [39] and anticarcinogenic properties [38]. As for compound (33), it shows inhibitory activity against the GSK-3β enzyme [17], which will be explained further in Section 3.

2.10. Peptides

In the last 20 years, the field of peptides has witnessed major developments, stimulated by the discovery of some bioactive peptides [40], one of which is in fungi. A total of 1133 peptides with antifungal properties have been reported in the Antimicrobial Peptide Database (APD) [41]. The chemical constituents of B. whalleyi (Graph ostomataceae) strain SWUF13-085 were isolated using chromatography techniques, which resulted in the isolation of 35 compounds, one of which was in the peptide group, including cyclic dipeptides in compounds 33–36 [11]. Cyclic dipeptides, known as diketopiperazines (DKP), the simplest cyclic forms of peptides, are widespread and unrivaled in their structural and biofunctional diversity. Subsequently, B. whalleyi successfully isolated include cyclo (l-Pro-Gly) (34), cyclo (ʟ-Pro-ʟ-Leu) (35), cyclo (ʟ-Pro-ʟ-Phe) (36), and cyclo (ʟ-Pro-ʟ-Val) (37) (Figure 11). Besides the use of Preparative HPLC (C18) cyclopeptide, cyclo-(ʟ-Phe-ʟ-Leu-ʟ-Val-ʟ-Leu-ʟ-Leu) (38) (Figure 12) from B. mediterranea was a previously synthesized derivative of the fungal metabolite sansalvamide A [42,43].

2.11. Phenyl and Phenol Derivatives

Four prenyl and phenol derivative compounds were isolated from solid substrate cultures of B. formosana BCRC 33718, including 4-hydroxybenzaldehyde (39), 4-(3-methylbut-2-enyloxy)benzoic acid (41), 4-methoxycinnamaldehyde (42), and 4-methoxy-trans-cinnamic acid (43) (Figure 13). Meanwhile, from the n-BuOH soluble fraction of the 70% EtOH extract of B. cylindrospora, 3 compounds were successfully isolated, namely methylparaben (44), syringaldehyde (46), and vanillic acid (48) (Figure 13). Phenylacetic acid (45) (Figure 13), obtained by EtOAc extraction from the culture filtrate (10 L) of B. mediterranea, was fractionated using a combination of column chromatography and thin layer chromatography to identify the most polar metabolites [8]. Furthermore, the chemical constituents of B. whalleyi, namely 5-hydroxy-2-prenylhydroquinone (40) and tyrosol (47), are metabolites that are commonly produced by plants and microorganisms through the shikimate biosynthetic pathway [44] and are also produced by many fungal species [45] (Figure 13). Tyrosol was also produced from the B. rosacearum oak strain, which had phytotoxic activity showing severe necrosis at the highest concentrations when tested on oak leaves (Quercus ilex L.) [14].

2.12. Phthalides

A new phthalide derivative known as biscogniphthalides A–D (50–53)was successfully isolated from Biscogniauxia sp. (No. 69-8-7-1) along with one known related phthalide, [4-[(acetyloxy)methyl]-7-methoxy-6-methyl-1(3H)-isobenzofuranone (49) [9] (Figure 14). One phthalide was also isolated from B. whalleyi, namely 7-hydroxy-5-methoxy-4,6-dimethylphthalide (54) [11] (Figure 14). These phthalides are isobenzofuranones known as 3H-isobenzofuran-1-one, characterized by a bicyclic core originating from the fusion of γ-lactone (ring A) with benzene (ring B) [46]. Furthermore, phthalide is widely found in plants, fungi, and liverworts and exhibits various interesting biological activities, such as antimicrobial, neuroprotection, anti-anginal, anti-platelet aggregation, anti-smooth muscle proliferation, anti-thrombosis, cardiac function, modulation, and protection against cerebral ischemia [46,47,48]. Compounds 48–52 were tested for anti-acetylcholinesterase (AChE), anti-microbial, and anti-α-glucosidase activities, which will be explained further in Section 3.

2.13. Pyranopyran

Biscopyran 55 is a resubstituted pyranopyran identified using the spectroscopic methods as (Z)-2-methoxy-1-[7-((Z)-2-methoxybut-2-enoyl)-3,4,5,6-tetramethyl,2H,7H-pyrano [2,3-b]pyran-2-yl]but-2-en-1-one. This compound was isolated from liquid culture filtrate of B. mediterranea from infected cork oak (Q. suber) stems collected in Sardinia (Italy) with phytotoxic activity [8] (Figure 15).

2.14. α-Pyrones

α-Pyrones (1, also 2-pyrones) are six-membered cyclic unsaturated esters that share chemical and physical properties reminiscent of alkenes and aromatic compounds. These compounds are abundant in bacteria, microbial systems, plants, insects, and animals [49]. Regarding the α-pyrones derivatives, one of them is B. whalleyi SWUF13-085, distinguishable through the NMR spectra, with data compared to existing literature [11]. Additionally, 7 compounds were successfully isolated, including 6-(1′,2′-dimethyloxiran-1′-yl)-4-methoxy-3-methyl-2H-pyran-2-one (56) [50], gulypyrone B (57) [51], 6-[(1R)-1-hydroxy-1-methyl-2-propenyl]-4-methoxy-3-methyl-2H-pyran-2-one (58) [52], nectriapyrone (59) [51], phomopyrone A (60) [53], and vermopyrone (61) [54] (Figure 16). Nectriapyrone (59), also isolated from B. rosacearum oak strain IRAN 4287C tested on the grapevine, showed the presence of severe necrosis at the highest concentrations. Besides, nectriapyrone (59) was previously isolated as a phytotoxin produced by a phytopathogenic fungus such as Diaporthe angelicae (anamorph Phomopsis foeniculi), which is the causative agent of fennel disease (Foeniculum vulgare) in Bulgaria [55].

2.15. Steroids

Steroids play a crucial role in the active ingredients of medicines found across the animal and plant kingdoms, characterized by a common chemical framework of four fused rings, including three six-membered rings and a five-membered ring [56]. Several steroids are produced from the genus Biscogniauxia, including B. whalleyi, B. formosana, and B. cylindrospora. In the n-BuOH soluble fraction, a 95% EtOH extract of long grain rice produced by the endophytic fungus B. formosana BCRC 33718 was fractionated with a combination of silica gel, RP-18 column, and preparative TLC to produce 12 compounds, and one of them was a steroid group, namely ergosta-4,6,8(14),22-tetraen-3-one (64) [10], which was previously isolated from Ganoderma applanatum [57]. Furthermore, 4 steroid compounds were also isolated from B. whalleyi based on data from intensive comparisons of NMR data, specific optical rotation values, and MS data with those in the literature, indicating that the isolated compound were cerevisterol (62) [58], ergone (63) [59], ergosterol (65) [58], and ergosterol peroxide (66) [60] (Figure 17). Three steroid compounds were also isolated from B. cylindrospora, namely 3β-hydroxystigmast-5-en-7-one (67), which was produced in rice from B. cylindrospora BCRC 33717, then extracted three times with 70% EtOH at room temperature [15] and two steroids, β-sitostenone (68) and β-sitosterol (69), in the EtOAc soluble fraction of B. cylindrospora BCRC 33717 [4] (Figure 17).

2.16. Terpenoids and Their Derivatives

2.16.1. Diterpenoids

Two new diterpenoids, namely biscognisecoisopimarate A (70), including the seco-isopimarane type, and 3β-hydroxyrickitin A (71), the abietane type, were obtained from Biscogniauxia sp. (No. 71-10-1-1) [19]. Subsequently, diterpenoids are natural compounds with a C-20 carbon skeleton that are chemically heterogeneous. They are widely distributed from the condensation of four isoprene units derived from the mevalonate or deoxysylulose phosphate pathway. Diterpenoids can be classified as linear, bicyclic, tricyclic, tetracyclic, pentacyclic, or macrocyclic diterpenes, depending on their core framework. In nature, they are generally found in polyoxygenated forms with keto and hydroxyl groups, which are often esterified by small aliphatic or aromatic acids [61]. Biscognisecoisopimarate A (70) was obtained as colorless needle crystals, while 3β-hydroxyrickitin A (71) (Figure 18) was obtained as a yellowish oil, which was then tested for its biological activity for anti-Alzheimer disease (AD) activity, anti-inflammatory, and cytotoxic activity [20], which will be discussed further in Section 2.

2.16.2. Meroterpenoid

Terpenoids (terpenes and oxygenated derivatives) constitute one of the largest groups of naturally occurring compounds, which are characterized by their very wide distribution in both the plant and animal kingdoms and have also recently been obtained from endophytic fungi [62,63,64]. A terpenoid derivative, namely meroterpenoid, is a compound that is formed from a combination of frameworks between terpenoid and polyketide frameworks, alkaloids, phenols, and amino acids [65,66,67,68]. It can be obtained by bacteria, algae, plants, and animals, as well as endophytic fungi, one of the endophytic fungi producing meroterpenoid compounds, namely Biscogniauxia sp. compounds 72–81 [20]. Biscogniacid B (72), biscogniacid C (73), and biscognienyne D (74) were obtained as colorless needles, while biscognienyne F (75) was obtained as a yellowish oil. Biscognin (A) (76) was obtained as colorless needles having a unique 2-isopropyl-6′-methyloctahydro-1′H-spiro[cyclopropane-1,2′-naphthalene] skeleton. Biscognin B (77) and E (80) were obtained as colorless needles, whereas biscognin C, D, and F (78, 79, and 81) were all obtained as colorless oils [20] (Figure 19).
A new framework of dimericbiscognienynes A (87), namely dimer meroterpenoid type di isoprenyl-cyclohexene, along with three new monomers, including meroterpenoid type diisoprenyl-cyclohexene (biscognienyne A–C, 83–85) and one iso prenyl-benzoic meroterpenoid type biscogniacid acid A (82) successfully obtained from Biscogniauxia sp. (No. 71-10-1-1), were isolated from the lichen Usnea mutabilis Stirt [21]. Additionally, meroterpenoid biscognienyne E (86) was obtained via a different fermentation process, increasing the number of fermentations to 60 Erlenmeyer flasks and extending the fermentation time to 50 days [20]. Two new types of diisoprenyl-cyclohexene were also obtained from Biscogniauxia sp. (No. 71-10-1-1), namely dimericbiscognienynes B and C (88 and 89), adding to the rare class of meroterpenoids [22] (Figure 20).

2.16.3. Sesquiterpenoids

Sesquiterpenoids are derived from three isoprene units and exist in various forms, including linear, monocyclic, bicyclic, and tricyclic frameworks. They are the most diverse group of terpenoids [63]. Seven new sesquiterpenoids of the guanine type, namely biscogniauxiaol A–G (90–96), were successfully isolated from the endophytic fungus Biscogniauxia petrensis MFLUCC 14-0151 on Dendrobium orchids [23]. The isolated biscogniauxiaol A–G (90–96) (Figure 21) is a colorless solid that was then tested for its biological activity for antifungal, anti-inflammatory, and anti-cancer activities, which will be explained further in Section 2. Furthermore, 9 guaiane-type sesquiterpenoids were isolated from B. whalleyi and immediately recognized from the frequently found NMR spectroscopic pattern (compounds 97–105) (Figure 21) in the entire fungal family Graphostomataceae [13,69]. One undescribed compound is (1R*,4S*,5S*,7S*,10R*)-guaia-11(12)-en-7,10-diol (99), along with 8 known compounds, including epi-guaidiol A (97) [70], graphostromane E (98) [71], (1R,4S,5S,7R,10R,11R)-guaiane-10,11,12-triol (100) [72], (1R,4S,5S,7R,10R,11S)-guaiane-10,11,12-triol (101) [72], patchouliguaiol A (102) [73], pogostol (103) [74], xylaranone (104) [13], and xylaranol A (105) [74]. Xylaranone (104), the sesquiterpene guaiane, which was previously reported together with the terpenoid xylaranol B (106), was also isolated from B. nummularia [13].
Bergamotene, a bicyclic sesquiterpene, is found in plants, insects, and fungi with α-trans-bergamotene, which is the most abundant compound [75]. Bergamotene and its related structures (bergamotane sesquiterpenoids) have been shown to have various biological activities such as antioxidant, anti-inflammatory, immunosuppressive, cytotoxic, antimicrobial, antidiabetic, and insecticidal effects [76] Six compounds were isolated from B. whalleyi SWUF13-085 using chromatographic techniques, four of which were xylariterpenoid L (109), xylariterpenoid M (110), xylariterpenoid N (111), and (1R,2S,6R,7S)-1,2-dihydroxy-α-bisabolol (112), which is a newly discovered compound. The remaining two compounds, xylariterpenoids A (107) and xylariterpenoids B (108), were characterized via extensive comparisons of NMR and ECD data with existing literature [69,76,77] (Figure 22).

2.17. Tyramine

Tyramine, a naturally occurring trace amine derived from the amino acid tyrosine, can exist in three isomers: 2-, 3-, or 4-hydroxyphenylethylmaine, which are commonly referred to as ortho-, meta-, and para-tyramine [78]. N-trans-feruloyltyramine (113) and N-cis-feruloyltyramine (114) are tyramines that were isolated from the n-BuOH-soluble fraction of 70% EtOH extract of fermented rice with the endophytic fungus B. cylindrospora (BCRC 33717) [15] (Figure 23).

2.18. Other

Meso-2,3-butanediol (115) is the only phytotoxin isolated from Biscogniauxia rosacearum (IRAN 4194C) (Figure 24). This compound was first identified as a pathogen included in GTD in the Paveh vineyard, Kermanshah Province (west of Iran) [14]. This compound showed no optical activity and was identified based on spectroscopic data, as reported by Gallwey et al., 1990 [79].

3. Biological Activity

Mushrooms, including various fungal species, are a valuable source of numerous secondary metabolites with diverse chemical structures and a wide range of biological activities [25,80]. Fungi, in general, have well-developed secondary metabolic pathways, and the sheer diversity of fungal species and the biosynthetic gene pools suggest a nearly limitless potential for metabolic variation. This diversity serves as an untapped resource for drug discovery and synthetic biology [1]. Among these fungi, one of the fungal species that is rich in biologically active secondary metabolites is endophytic fungi [81]. They are found on a variety of plant hosts, ranging from herbaceous plants in a variety of habitats, including extreme arctic, alpine, and xeric environments, to subtropical and mesic tropical forests [82]. Subsequently, nearly 300,000 plant species on Earth host one or more endophytics [83], and one such endophytic is the Biscogniauxia endophytic strain. Currently, secondary metabolites from Biscogniauxia show a variety of biological activities and have become important candidates for the development of new drugs, which are summarized in Table 2.

3.1. Antifungal

The 5-methylmellein compound (21) showed moderate antifungal activity against phytopathogenic fungi Phomopsis viticola and Phomopsis obscurans (50%–63% inhibition, respectively). However, it showed weak antifungal activity (up to 20% inhibition) against B. cinerea, C. fragariae, and F. oxysporum at 300 µM. The results were derived from testing endophytic fungal communities associated with the medicinal plant cactus Opuntia humifusa (Cactaceae) from the United States, which was isolated from extracts of B. mediterranea Ohu 19B [16]. However, apart from B. mediterranea, compound 20 was also successfully isolated from the endophytic fungus; B. capnodes was isolated from Averrhoa carambola fruit [12], and endophytic fungus B. whalleyi was resurrected to the Graphostomataceae family [11]. 5-methylmellein is a dihydroisocoumarin known for its antibacterial and antifungal properties against various microorganisms [84,85]. Furthermore, Han et al. 2023 isolated 7 new compounds of the guaiane-type sesquiterpenoid group from the endophytic fungus B. petrensis on Dendrobium orchids against Candida albicans (336485). All compounds exhibited inhibitory activity against C. albicans, with biscogniauxiaol A (90), biscogniauxiaol B (91), and biscogniauxiaol F (95) showing strong inhibitory activity with MICs of 1.60, 6.25, and 6.30 µM, respectively (amphotericin B and fluconazole with MICs of 0.43 and 2, respectively; 0.61 µM) [23].

3.2. Antimycobacterial

The biological activity of the endophytic fungus Biscogniauxia formosana BCRC 33718, originating from the bark of the medicinal plant species Cinnamomum sp. was tested in vitro against the antimycobacterial Mycobacterium tuberculosis strain H37Rv. Furthermore, 2 newly discovered constituents, biscogniazaphilones A (1) and B (2), showed the strongest antimycobacterial activity against M. tuberculosis strain H37Rv, with MIC values of 5.12 and 2.52 mg/mL, respectively. These values were stronger than the ethambutol used as a positive control, with a MIC value of 6.25 mg/mL. Compound 2, with one γ-lactone group between C-6a and C-9, was 2-fold more potent than 1, indicating that the presence of one γ-lactone group in the azafilone analog plays an important role in the antimycobacterial activity. Other compounds isolated from B. formosana showing moderate to weak antimycobacterial activity are 5-hydroxy-3,7,4′–trimethoxyflavone (27), N-trans-feruloy-3-O-methyldopamine (29), methyl-3,4-methylenedioxycinnamate (30), 4-methoxycinnamaldehyde (42), and 4-methoxy-trans-cinnamic acid (43), with MIC values of 25.0, 12.5, 58.2, 42.1, and 50.0 mg/mL, respectively. Meanwhile, 3,4-methylenedioxycinnamic acid (31), 3,4-methylenedioxy benzoic acid (32), 4-hydroxy benzaldehyde (39), 4-(3-methylbut-2-enyloxy)benzoic acid (41), and ergosta-4,6,8(14),22-tetraen-3-one (64) did not show antimycobacterial activity [10].

3.3. Cytotoxic Activity

Natural products obtained from endophytic fungi have been identified as a sustainable and productive source of anticancer agents holding significant potential for the advancement of modern anticancer drugs [86]. Among these, an endophytic fungal strain belonging to Biscogniauxia has been identified and reported to produce compounds that are effective in anticancer tests. Some of these compounds include cerebroside A (3), cerebroside C (4), 7-hydroxy-5-methoxy-4,6-dimethylphthalide (54), and 6-[(1R)-1-hydroxy-1-methyl-2-propenyl]-4-methoxy-3-methyl-2H-pyran-2-one (56), nectriapyrone (59) [11], biscogniacid A (82), biscognienyne A-E (83–86), dimericbiscognienynes A–C (87–89) [21,22], biscogniauxiaol A–F (90–95) [23], pogostol (103), xylariterpenoids A–B (107,108), xylariterpenoids L–N (109–111), (1R,2S,6R,7S)-1,2-dihydroxy-α-bisabolol (112) [11]. Subsequently, compounds (54), (103), (105), and (109) showed significant toxicity against HeLa cells with an IC50 range between 8.64 ± 1.22 and 31.16 ± 4.12 μg/mL [11]. Meanwhile, compounds 90–95 showed weak reversal activity against cisplatin-resistant A549/DDP cells [23].

3.4. Antioxidants

Endophytic fungi have gained attention as an alternative source of these valuable compounds due to their potential health benefits [87]. Subsequently, B. capnodes isolated from the fruit of Averrhoa carambola L. (Oxalidaceae), commonly called starfruit, has been found to produce compounds of the isocumarin and dihydroisocoumarin groups. These compounds include 6-O-methyl-reticulol (8), reticulol (9), 7-hydroxy-5-methylmellein (15), and 5-methylmellein (21) [21]. Among these compounds, reticulol (9) exhibited significant DPPH radical scavenging activity with an IC50 value of 58 µg/mL (IC50 of the positive control butylated hydroxyanisole was 5.5 µg/mL) [12]. These compounds are believed to have a strong protective mechanism against the generation of free radicals, which cause several disorders such as aging, cancer, atherosclerosis, coronary heart disease, and diabetes. Reticulol exhibits moderate antioxidant activity; this compound was first discovered in a strain of Streptomyces rubrireliculae [88]. It has been widely reported to have other biological activities, such as its antitumor properties by deactivating Topo I, which is included in tumor metastasis, and exhibiting excellent cytotoxicity against melanoma B16F10 when combined with adriamycin [89]. Additionally, it serves as an inhibitor of cyclic adenosine 3′,5′-monophosphate phosphodiesterase [79] and cyclic nucleotide phosphodiesterase [90]. Recent research showed its ability to significantly reduce degranulation and histamine release [91].

3.5. Antigerminative

The fungus isolated as an endophytic from the plum yew Cephalotaxus harringtonia, namely the B. nummularia strain, was subjected to a chromatography technique to produce chemical constituents, which were then tested for anti-germinative activity to determine any suspected phytopathogenesis. The anti-germinative tests were carried out using radish seeds, with all compounds tested at a maximum concentration of 100 mg/mL, which is comparable to the effective concentration of glyphosate, a commonly used weed killer constituent. Among the compounds tested, xylaranone (104) exhibited the strongest anti-germinative activity with an 85% inhibition rate, surpassing the reference glyphosate (75% inhibition). Xylaranol B also showed significant effectiveness against seed germination, with over 50% inhibition at the tested concentrations. Meanwhile, compounds derived from mellein, namely compounds 10 and 11, had inhibitory effects of less than 50% [13].

3.6. Phytotoxic Activity

Phytotoxins are bioactive substances produced naturally by various plants and microbial species (e.g., bacteria and fungi), some of which can be consumed by humans [92]. Fungal phytotoxins, also known as phytotoxic secondary metabolites from fungi, are substances that are naturally produced by fungi through biochemical reactions, and they have toxic effects on plants [93]. Fungal phytotoxins play an important role in the development of plant disease symptoms, including leaf spot, wilting, chlorosis, and necrosis, as well as growth inhibition and enhancement [94]. Biscogniauxia rosacearum, first recognized as a pathogen causing grape stem disease in Paveh vineyards (western Iran), produces meso-2,3-butanediol (115). (3R)-5-methylmellein (22), (3R)-5-methyl-6-methoxymellein (23), tyrosol (47). In addition, nectriapyrone (59) was produced as a phytotoxin from the same fungal strain isolated from oak trees in the Zagros forest in Gilan-e Gharb, Kermanshah Province. The phytotoxicity of secondary metabolites of B. rosacearum was tested by leaf pricking on Quercus ilex L. and Hedera helix L. and by foliar absorption tests on grapevine (Vitis vinifera L.) at concentrations of 5 × 10−3 and 10−3 M. Among these compounds, 22 and 115 were found to be the most phytotoxic on grapevine. In the case of Q. ilex, compounds 46 and 58 induced severe necrosis at the highest concentration, while none of the compounds exhibited activity on H. helix [14].

3.7. Activity against the Enzyme GSK-3β

The production of bioactive compounds, specifically those with parasitic pathogenic properties or phytotoxic substances, has been extensively examined in various Bioscogniauxia strains. One of these strains, Bioscogniauxia mediterranea strain LF657, which was isolated from deep-sea sediments of the East Mediterranean Sea at a water depth of 2800 m, produces a new compound identified as the isopyrrolonaphthoquinone group, namely biscogniauxone (33) showing activity that inhibits glycogen synthase kinase GSK-3β with an IC50 value of 8.04 µM (±0.28) [17]. In another investigation, the compound bhimamycin H, the isopyrrolonaphthoquinone group, also inhibited the activity of this enzyme in the same range (IC50 value 18 µM) [95]. Therefore, isopyrrolonaphthoquinones and similar structures can be considered potential candidates for drug development to treat diseases associated with GSK-3β biological targets, such as type 2 diabetes, neurological disorders, or cancer [96,97,98].

3.8. Anti-Acetylcholinesterase (AChE) Activity and Anti-Alzheimer Disease (AD)

AD is the leading cause of dementia, contributing to approximately 75% of all dementia cases. The pathophysiological processes described for the development of AD include neuronal and synaptic degeneration, characterized mainly by cholinergic disturbances. As a result, AChE inhibitors represent the primary class of drugs used in the treatment of the dementia phase of AD [99]. Several investigations have explored the search for natural molecules with AChE inhibitory properties. These investigations have examined various compounds, particularly those falling into categories such as alkaloids, monoterpenes, coumarins, triterpenes, flavonoids, benzenoids, diterpenes, heterocyclic oxygen, sesquiterpenes, stilbenes, lignans, sulfur compounds, proteinids, polycyclics, quinoids, benzoxazines, carotenoids, and alicyclics [100]. Recently, anti-AChE activity of the pthalide group has also been reported, namely from a strain (No. 69-8-7-1) isolated from Rimelia reticulata, which was identified as Biscogniauxia sp., then extracted and subjected to isolation and purification to produce a new phthalide derivative, biscogniphthalides A–D (compounds 50–53), together with a known compound, [4-[(acetyloxy)methyl]-7-methoxy-6-methyl-1(3H)-isobenzofuranone (49) [9]. The bioactivity of phthalide was evaluated via an anti-AChE activity test. Results from tests 49, 50, and 51 indicated weak inhibition at a concentration of 100 μM when compared to hurperzena-A, used as a positive control, which showed substantial inhibition of 87.66 ± 0.26% [9]. In addition, the anti-AD activities of compounds isolated from Lichen Usnea Mutabilis Stirt were also evaluated by the AD fly model, with memantine as the positive control. In this model, transgenic AD flies carry the human Aβ 42 gene, which causes expression of the Aβ 42 peptide in the fly brain and induces AD pathological phenotypes. The results suggest the potential of these compounds as anti-AD drugs [21].

4. Conclusions and Future Prospects

Secondary metabolites were produced from Biscogniauxia, resulting in the isolation of 115 chemical compounds belonging to the class of secondary metabolites and fatty acids from approximately 9 taxa. The most frequently isolated chemical compounds were in the terpenoid group and the derivatives, with 43 compounds, followed by the coumarin group with 21 compounds. The use of PDA media was the largest amount, namely 75% of the total metabolite compounds produced from Biscogniauxia. Secondary metabolites of the Biscogniauxia strain have various applications in pharmacology. Many studies were also conducted to confirm associated biological activities, such as antifungal, antimycobacterial, cytotoxic activity, antioxidant, anti-germinative, phytotoxic activity, and the presence of inhibitory activity. GSK-3β enzymes, anti-AChE activity, and anti-AD effect the importance of these resources in supporting the discovery of new drugs produced by Biscogniauxia, with the potential for further development.

Author Contributions

Conceptualization, S.P., W.S. and R.; methodology, S.P.; validation, S.P., W.S. and R.; formal analysis, W.S. and R.; resources, S.P. and Y.M.; data curation, S.P.; writing—original draft preparation, S.P.; writing—review and editing, S.P., W.S., R., D.H., U.S. and A.P.W.; visualization, W.S. and R.; supervision, U.S., D.H. and A.P.W.; project administration, U.S., D.H. and A.P.W.; funding acquisition, U.S., D.H. and A.P.W. All authors have read and agreed to the published version of the manuscript.

Funding

The Ministry of Education and Culture, Indonesia, for providing the funds for this research under the Doctoral Dissertation Research Grant, no: 1827/UN6.3.1/LT/2020 by Unang Supratman.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

This research did not report any data.

Acknowledgments

This research was financially supported by the Ministry of Education, Culture, Research, and Technology of the Republic of Indonesia.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

References

  1. Bills, G.F.; Gloer, J.B. Biologically Active Secondary Metabolites from the Fungi. Microbiol. Spectr. 2016, 4, 1087–1119. [Google Scholar] [CrossRef] [PubMed]
  2. Suzuki, T.; Ariefta, N.R.; Koseki, T.; Furuno, H.; Kwon, E.; Momma, H.; Harneti, D.; Maharani, R.; Supratman, U.; Kimura, K.I.; et al. New Polyketides, Paralactonic Acids A–E Produced by Paraconiothyrium Sp. SW-B-1, an Endophytic Fungus Associated with a Seaweed, Chondrus ocellatus Holmes. Fitoterapia 2019, 132, 75–81. [Google Scholar] [CrossRef]
  3. Ye, K.; Ai, H.L.; Liu, J.K. Identification and Bioactivities of Secondary Metabolites Derived from Endophytic Fungi Isolated from Ethnomedicinal Plants of Tujia in Hubei Province: A Review. Nat. Prod. Bioprospect. 2021, 11, 185–205. [Google Scholar] [CrossRef] [PubMed]
  4. Der Wu, M.; Cheng, M.J.; Lin, R.J.; Chan, H.Y.; Hsieh, S.Y.; Chang, H.S.; Lin, C.L.; Chen, J.J. Chemcial Constituents of the Fungus Biscogniauxia cylindrospora. Chem. Nat. Compd. 2019, 55, 924–926. [Google Scholar] [CrossRef]
  5. Zhao, J.; Shan, T.; Mou, Y.; Zhou, L. Plant-Derived Bioactive Compounds Produced by Endophytic Fungi. Mini-Rev. Med. Chem. 2011, 11, 159–168. [Google Scholar] [CrossRef]
  6. Ju, Y.M.; Rogers, J.D. New and Interesting Biscogniauxia Taxa, with a Key to the World Species. Mycol. Res. 2001, 105, 1123–1133. [Google Scholar] [CrossRef]
  7. Nugent, L.K.; Sihanonth, P.; Thienhirun, S.; Whalley, A.J.S. Biscogniauxia: A Genus of Latent Invaders. Mycologist 2005, 19, 40–43. [Google Scholar] [CrossRef]
  8. Evidente, A.; Andolfi, A.; Maddau, L.; Franceschini, A.; Marras, F. Biscopyran, a Phytotoxic Hexasubstituted Pyranopyran Produced by Biscogniauxia mediterranea, a Fungus Pathogen of Cork Oak. J. Nat. Prod. 2005, 68, 568–571. [Google Scholar] [CrossRef]
  9. Liu, Y.Y.; Zhao, H.; Xie, J.; Zou, J.; Hu, D.; Guo, L.D.; Chen, G.D.; Yao, X.S.; Gao, H. New Phthalide Derivatives from the Biscogniauxia sp. and Their Activities. Fitoterapia 2019, 137, 104184. [Google Scholar] [CrossRef]
  10. Cheng, M.J.; Der Wu, M.; Yanai, H.; Su, Y.S.; Chen, I.S.; Yuan, G.F.; Hsieh, S.Y.; Chen, J.J. Secondary Metabolites from the Endophytic Fungus Biscogniauxia formosana and Their Antimycobacterial Activity. Phytochem. Lett. 2012, 5, 467–472. [Google Scholar] [CrossRef]
  11. Jantaharn, P.; Mongkolthanaruk, W.; Suwannasai, N.; Senawong, T.; Tontapha, S.; Amornkitbumrung, V.; Boonmak, J.; Youngme, S.; McCloskey, S. Anti-Inflammatory and Anti-Proliferative Activities of Chemical Constituents from Fungus Biscogniauxia whalleyi SWUF13-085. Phytochemistry 2021, 191, 112908. [Google Scholar] [CrossRef] [PubMed]
  12. Sritharan, T.; Savitri Kumar, N.; Jayasinghe, L.; Araya, H.; Fujimoto, Y. Isocoumarins and Dihydroisocoumarins from the Endophytic Fungus Biscogniauxia capnodes Isolated from the Fruits of Averrhoa carambola. Nat. Prod. Commun. 2019, 14, 1–3. [Google Scholar] [CrossRef]
  13. Amand, S.; Langenfeld, A.; Blond, A.; Dupont, J.; Nay, B.; Prado, S. Guaiane Sesquiterpenes from Biscogniauxia nummularia Featuring Potent Antigerminative Activity. J. Nat. Prod. 2012, 75, 798–801. [Google Scholar] [CrossRef]
  14. Masi, M.; Bashiri, S.; Cimmino, A.; Bahmani, Z.; Abdollahzadeh, J.; Evidente, A. Phytotoxins Produced by Two Biscogniauxia rosacearum Strains, Causal Agents of Grapevine Trunk Diseases, and Charcoal Canker of Oak Trees in Iran. Toxins 2021, 13, 812. [Google Scholar] [CrossRef] [PubMed]
  15. Cheng, M.J.; Der Wu, M.; Hsieh, S.Y.; Chen, I.S.; Yuan, G.F. Secondary Metabolites Isolated from the Fungus Biscogniauxia cylindrospora BCRC 33717. Chem. Nat. Compd. 2011, 47, 527–530. [Google Scholar] [CrossRef]
  16. Silva-Hughes, A.F.; Wedge, D.E.; Cantrell, C.L.; Carvalho, C.R.; Pan, Z.; Moraes, R.M.; Madoxx, V.L.; Rosa, L.H. Diversity and Antifungal Activity of the Endophytic Fungi Associated with the Native Medicinal Cactus Opuntia humifusa (Cactaceae) from the United States. Microbiol. Res. 2015, 175, 67–77. [Google Scholar] [CrossRef]
  17. Wu, B.; Wiese, J.; Schmaljohann, R.; Imhoff, J.F. Biscogniauxone, a New Isopyrrolonaphthoquinone Compound From the Fungus Biscogniauxia mediterranea Isolated from Deep-Sea Sediments. Mar. Drugs 2016, 14, 204. [Google Scholar] [CrossRef]
  18. Origuchi, Y.M.; Ihara, J.K.; Eno, M.U. Suppression Effects of a Secondary Metabolite of Biscogniauxia Sp. Strain O-811 Obtained from Mushrooms against the Rice Blast Fungus Magnaporthe oryzae. Bull. Fac. Life Environ. Sci. Shimane Univ. 2019, 24, 14–18. [Google Scholar]
  19. Zhao, H.; Liu, Y.; Zhang, M.; Chen, G.D.; Hu, D.; Guo, L.D.; Zhao, Z.X.; Zhi, H.; Gao, H. Two New Diterpenoids from Biscogniauxia sp. and Their Activities. Front. Chem. 2021, 9, 749272. [Google Scholar] [CrossRef]
  20. Zhao, H.; Zou, J.; Xu, W.; Hu, D.; Guo, L.; Chen, J.; Chen, G.; So, K.; Yao, X.; Gao, H. Diisoprenyl-Cyclohexene/Ane-Type Meroterpenoids from Biscogniauxia sp. and Their Anti-inflammatory Activities. J. Org. Chem. 2021, 86, 11177–11188. [Google Scholar] [CrossRef]
  21. Zhao, H.; Chen, G.D.; Zou, J.; He, R.R.; Qin, S.Y.; Hu, D.; Li, G.Q.; Guo, L.D.; Yao, X.S.; Gao, H. Dimericbiscognienyne A: A Meroterpenoid Dimer from Biscogniauxia sp. with New Skeleton and Its Activity. Org. Lett. 2017, 19, 38–41. [Google Scholar] [CrossRef] [PubMed]
  22. Zhao, H.; Wang, M.; Chen, G.; Hu, D.; Li, E.; Qu, Y.; Zhou, L.; Guo, L.; Yao, X.; Gao, H. Dimericbiscognienynes B and C: New Diisoprenyl-Cyclohexene-Type Meroterpenoid Dimers from Biscogniauxia sp. Chin. Chem. Lett. 2019, 30, 51–54. [Google Scholar] [CrossRef]
  23. Han, L.; Zheng, W.; Qian, S.Y.; Yang, M.F.; Lu, Y.Z.; He, Z.J.; Kang, J.C. New Guaiane-Type Sesquiterpenoids Biscogniauxiaols A–G with Anti-Fungal and Anti-Inflammatory Activities from the Endophytic Fungus Biscogniauxia petrensis. J. Fungi 2023, 9, 393. [Google Scholar] [CrossRef] [PubMed]
  24. Gao, J.; Yang, S.; Qin, J. Azaphilones: Chemistry and Biology. Chem. Rev. 2012, 113, 4755–4811. [Google Scholar] [CrossRef] [PubMed]
  25. Pavesi, C.; Flon, V.; Mann, S.; Leleu, S.; Prado, S.; Franck, X. Biosynthesis of Azaphilones: A Review. Nat. Prod. Rep. 2021, 38, 1058–1071. [Google Scholar] [CrossRef] [PubMed]
  26. Tan, R.X.; Chen, J.H. The Cerebrosides. Nat. Prod. Rep. 2003, 20, 509–534. [Google Scholar] [CrossRef]
  27. Barreto-Bergter, E.; Sassaki, G.L.; de Souza, L.M. Structural Analysis of Fungal Cerebrosides. Front. Microbiol. 2011, 2, 239. [Google Scholar] [CrossRef]
  28. Barreto-Bergter, E.; Pinto, M.R.; Rodrigues, M.L. Structure and Biological Functions of Fungal Cerebrosides. An. Acad. Bras. Cienc. 2004, 76, 67–84. [Google Scholar] [CrossRef]
  29. Venugopala, K.N.; Rashmi, V.; Odhav, B. Review on Natural Coumarin Lead Compounds for Their Pharmacological Activity. Biomed Res. Int. 2013, 2013, 963248. [Google Scholar] [CrossRef]
  30. Bourgaud, F.; Hehn, A.; Larbat, R.; Doerper, S.; Gontier, E.; Kellner, S.; Matern, U. Biosynthesis of Coumarins in Plants: A Major Pathway Still to Be Unravelled for Cytochrome P450 Enzymes. Phytochem. Rev. 2006, 5, 293–308. [Google Scholar] [CrossRef]
  31. Tsivileva, O.M.; Koftin, O.V.; Evseeva, N.V. Coumarins as Fungal Metabolites with Potential Medicinal Properties. Antibiotics 2022, 11, 1156. [Google Scholar] [CrossRef] [PubMed]
  32. Firmansyah, A.; Winingsih, W.; Manobi, J.D.Y. Review of Scopoletin: Isolation, Analysis Process, and Pharmacological Activity. Biointerface Res. Appl. Chem. 2021, 11, 12006–12019. [Google Scholar] [CrossRef]
  33. Kiang, F.M.; Chang, S.J.; Wu, C.L. Naphthalene and Isocoumarin Derivatives from the Liverwort Wettsteinia inversa. Phytochemistry 1994, 37, 1459–1461. [Google Scholar] [CrossRef]
  34. Reveglia, P.; Masi, M.; Evidente, A. Melleins—Intriguing Natural Compounds. Biomolecules 2020, 10, 772. [Google Scholar] [CrossRef]
  35. Rossi, M.H.; Yoshida, M.; Maia, J.G.S. Neolignans, Styrylpyrones and Flavonoids from an Aniba Species. Phytochemistry 1997, 45, 1263–1269. [Google Scholar] [CrossRef]
  36. Suzuki, T.; Holden, I.; Casida, J.E. Diphenyl Ether Herbicides Remarkably Elevate the Content in Spinacia olerácea of (E)-3-(4-Hydroxy-3-Methoxyphenyl)-JV-[2-(4-Hydroxy-3-Methoxyphenyl)Ethyl]-2- Propenamide. J. Agric. Food Chem. 1981, 29, 992–995. [Google Scholar] [CrossRef]
  37. Umezawa, T. Diversity in Lignan Biosynthesis. Phytochem. Rev. 2003, 2, 371–390. [Google Scholar] [CrossRef]
  38. Medentsev, A.G.; Akimenko, V.K. Naphthoquinone Metabolites of the Fungi. Phytochemistry 1998, 47, 935–959. [Google Scholar] [CrossRef]
  39. Kurobane, I.; Zaita, N.; Fukuda, A. New Metabolites of Fusarium Martii Related to Dihydrofusarubin. J. Antibiot. 1986, 39, 205–214. [Google Scholar] [CrossRef]
  40. Rose, G.D.; Glerasch, L.M.; Smith, J.A. Turns in Peptides and Proteins. Adv. Protein Chem. 1985, 37, 1–109. [Google Scholar] [CrossRef]
  41. Fernández de Ullivarri, M.; Arbulu, S.; Garcia-Gutierrez, E.; Cotter, P.D. Antifungal Peptides as Therapeutic Agents. Front. Cell. Infect. Microbiol. 2020, 10, 105. [Google Scholar] [CrossRef]
  42. Belofsky, G.N.; Jensen, P.R.; Fenical, W. Sansalvamide: A New Cytotoxic Cyclic Depsipeptide Produced by a Marine Fungus of the Genus Fusarium. Tetrahedron Lett. 1999, 40, 2913–2916. [Google Scholar] [CrossRef]
  43. Liu, S.; Gu, W.; Lo, D.; Ding, X.Z.; Ujiki, M.; Adrian, T.E.; Soff, G.A.; Silverman, R.B. N-Methylsansalvamide a Peptide Analogues. Potent New Antitumor Agents. J. Med. Chem. 2005, 48, 3630–3638. [Google Scholar] [CrossRef]
  44. Tolve, R.; Pasini, G.; Vignale, F.; Favati, F.; Simonato, B. Effect of Grape Pomace Addition on the Technological, Sensory, and Nutritional Properties of Durum Wheat Pasta. Foods 2020, 9, 354. [Google Scholar] [CrossRef]
  45. Albuquerque, P.; Casadevall, A. Quorum Sensing in Fungi a Review. Med. Mycol. 2012, 50, 337–345. [Google Scholar] [CrossRef] [PubMed]
  46. Karmakar, R.; Pahari, P.; Mal, D. Phthalides and Phthalans: Synthetic Methodologies and Their Applications in the Total Synthesis. Chem. Rev. 2014, 114, 6213–6284. [Google Scholar] [CrossRef]
  47. Jin, L.; Song, Z.; Cai, F.; Ruan, L.; Jiang, R. Chemistry and Biological Activities of Naturally Occurring and Structurally Modified Podophyllotoxins. Molecules 2023, 28, 302. [Google Scholar] [CrossRef]
  48. Chen, L.Z.; Wu, J.; Li, K.; Wu, Q.Q.; Chen, R.; Liu, X.H.; Ruan, B.F. Novel Phthalide Derivatives: Synthesis and Anti-Inflammatory Activity in Vitro and in Vivo. Eur. J. Med. Chem. 2020, 206, 112722. [Google Scholar] [CrossRef] [PubMed]
  49. McGlacken, G.P.; Fairlamb, I.J.S. 2-Pyrone Natural Products and Mimetics: Isolation, Characterisation and Biological Activity. Nat. Prod. Rep. 2005, 22, 369–385. [Google Scholar]
  50. Lu, X.; Xu, N.; Dai, H.F.; Mei, W.L.; Yang, Z.X.; Pei, Y.H. Three New Compounds from Endophytic Fungus L10 of Cephalotaxus hainanensis. J. Asian Nat. Prod. Res. 2009, 11, 397–400. [Google Scholar] [CrossRef]
  51. Gong, T.; Zhen, X.; Li, B.J.; Yang, J.L.; Zhu, P. Two New Monoterpenoid α-Pyrones from a Fungus Nectria Sp. HLS206 Associated with the Marine Sponge Gelliodes carnosa. J. Asian Nat. Prod. Res. 2015, 17, 633–637. [Google Scholar] [CrossRef] [PubMed]
  52. Andolfi, A.; Boari, A.; Evidente, M.; Cimmino, A.; Vurro, M.; Ash, G.; Evidente, A. Gulypyrones A and B and Phomentrioloxins B and C Produced by Diaporthe gulyae, a Potential Mycoherbicide for Saffron Thistle (Carthamus lanatus). J. Nat. Prod. 2015, 78, 623–629. [Google Scholar] [CrossRef]
  53. Cai, R.; Chen, S.; Liu, Z.; Tan, C.; Huang, X.; She, Z. A New α-Pyrone from the Mangrove Endophytic Fungus Phomopsis Sp. HNY29-2B. Nat. Prod. Res. 2017, 31, 124–130. [Google Scholar] [CrossRef]
  54. Geiseler, O.; Podlech, J. Total Synthesis of Infectopyrone, Aplysiopsenes A-C, Ent-Aplysiopsene D, Phomapyrones A and D, 8,9-Dehydroxylarone, and Nectriapyrone. Tetrahedron 2012, 68, 7280–7287. [Google Scholar] [CrossRef]
  55. Evidente, A.; Rodeva, R.; Andolfi, A.; Stoyanova, Z.; Perrone, C.; Motta, A. Phytotoxic Polyketides Produced by Phomopsis foeniculi, a Strain Isolated from Diseased Bulgarian Fennel. Eur. J. Plant Pathol. 2011, 130, 173–182. [Google Scholar] [CrossRef]
  56. Nassiri-Koopaei, N.; Faramarzi, M.A. Recent Developments in the Fungal Transformation of Steroids. Biocatal. Biotransformation 2015, 33, 1–28. [Google Scholar] [CrossRef]
  57. Gan, K.H.; Kuo, S.H.; Lin, C.N. Steroidal Constituents of Ganoderma applanatum and Ganoderma neo-japonicum. J. Nat. Prod. 1998, 61, 1421–1422. [Google Scholar] [CrossRef]
  58. Ragasa, C.Y.; Tan, M.C.S.; De Castro, M.E.; De Los Reyes, M.M.; Oyong, G.G.; Shen, C.C. Sterols from Lentinus tigrinus. Pharmacogn. J. 2018, 10, 1079–1081. [Google Scholar] [CrossRef]
  59. Wi, Y.L.; Park, Y.; Ahn, J.K.; Park, S.Y.; Lee, H.J. Cytotoxic Activity of Ergosta-4,6,8(14),22-Tetraen-3-One from the Sclerotia of Polyporus umbellatus. Bull. Korean Chem. Soc. 2005, 26, 1464–1466. [Google Scholar] [CrossRef]
  60. Krzyczkowski, W.; Malinowska, E.; Suchocki, P.; Kleps, J.; Olejnik, M.; Herold, F. Isolation and Quantitative Determination of Ergosterol Peroxide in Various Edible Mushroom Species. Food Chem. 2009, 113, 351–355. [Google Scholar] [CrossRef]
  61. Ramawat, K.G.; Mérillon, J.M. Natural Products: Phytochemistry, Botany and Metabolism of Alkaloids, Phenolics and Terpenes. Nat. Prod. Phytochem. Bot. Metab. Alkaloids Phenolics Terpenes 2013, 1, 1–4242. [Google Scholar] [CrossRef]
  62. Smith, M.M.; Khatoon, T. Biological Activity of the Terpenoids and Their Derivatives. Fortschr. Arzneimittelforsch. 1963, 42, 279–346. [Google Scholar] [CrossRef]
  63. Ludwiczuk, A.; Skalicka-Woźniak, K.; Georgiev, M.I. Terpenoids. In Pharmacognosy: Fundamentals, Applications and Strategy; Elsevier: Amsterdam, The Netherlands, 2017; pp. 233–266. ISBN 9780128020999. [Google Scholar]
  64. De Souza, J.J.; Vieira, I.J.C.; Rodrigues-Filho, E.; Braz-Filho, R. Terpenoids from Endophytic Fungi. Molecules 2011, 16, 10604–10618. [Google Scholar] [CrossRef] [PubMed]
  65. Yaoita, Y.; Kikuchi, M.; Machida, K. Terpenoids and Sterols from Mushrooms. In Studies in Natural Products Chemistry; Elsevier B.V.: Amsterdam, The Netherlands, 2015; Volume 44, pp. 1–32. ISBN 9780444634603. [Google Scholar]
  66. Gomm, A.; Nelson, A. A Radical Approach to Diverse Meroterpenoids. Nat. Chem. 2020, 12, 109–111. [Google Scholar] [CrossRef]
  67. Nazir, M.; Saleem, M.; Tousif, M.I.; Anwar, M.A.; Surup, F.; Ali, I.; Wang, D.; Mamadalieva, N.Z.; Alshammari, E.; Ashour, M.L.; et al. Meroterpenoids: A Comprehensive Update Insight on Structural Diversity and Biology. Biomolecules 2021, 11, 957. [Google Scholar] [CrossRef]
  68. Russo, D.; Milella, L. Analysis of Meroterpenoids. In Recent Advances in Natural Products Analysis; Elsevier Inc.: Amsterdam, The Netherlands, 2020; pp. 477–501. ISBN 9780128164556. [Google Scholar]
  69. Niu, S.; Xie, C.L.; Zhong, T.; Xu, W.; Luo, Z.H.; Shao, Z.; Yang, X.W. Sesquiterpenes from a Deep-Sea-Derived Fungus Graphostroma Sp. MCCC 3A00421. Tetrahedron 2017, 73, 7267–7273. [Google Scholar] [CrossRef]
  70. Xu, Y.; Zhang, H.W.; Wan, X.C.; Zou, Z.M. Complete Assignments of 1H and 13C NMR Data for Two New Sesquiterpenes from Cyperus rotundus L. Magn. Reson. Chem. 2009, 47, 527–531. [Google Scholar] [CrossRef] [PubMed]
  71. Niu, S.; Xie, C.L.; Xia, J.M.; Luo, Z.H.; Shao, Z.; Yang, X.W. New Anti-Inflammatory Guaianes from the Atlantic Hydrotherm-Derived Fungus Graphostroma Sp. MCCC 3A00421. Sci. Rep. 2018, 8, 530. [Google Scholar] [CrossRef] [PubMed]
  72. Wu, S.H.; He, J.; Li, X.N.; Huang, R.; Song, F.; Chen, Y.W.; Miao, C.P. Guaiane Sesquiterpenes and Isopimarane Diterpenes from an Endophytic Fungus Xylaria Sp. Phytochemistry 2014, 105, 197–204. [Google Scholar] [CrossRef]
  73. Zhou, Q.M.; Chen, M.H.; Li, X.H.; Peng, C.; Lin, D.S.; Li, X.N.; He, Y.; Xiong, L. Absolute Configurations and Bioactivities of Guaiane-Type Sesquiterpenoids Isolated from Pogostemon cablin. J. Nat. Prod. 2018, 81, 1919–1927. [Google Scholar] [CrossRef]
  74. Barra, L.; Schulz, B.; Dickschat, J.S. Pogostol Biosynthesis by the Endophytic Fungus Geniculosporium. ChemBioChem 2014, 15, 2379–2383. [Google Scholar] [CrossRef]
  75. Corey, E.J.; Cane, D.E.; Libit, L. The Synthesis of Racemic α-Trans- and β-Trans-Bergamotene. J. Am. Chem. Soc. 1971, 93, 7016–7021. [Google Scholar] [CrossRef]
  76. Li, Y.; Zhang, F.; Banakar, S.; Li, Z. Bortezomib-Induced New Bergamotene Derivatives Xylariterpenoids H-K from Sponge-Derived Fungus Pestalotiopsis maculans 16F-12. RSC Adv. 2019, 9, 599–608. [Google Scholar] [CrossRef] [PubMed]
  77. Wu, Z.Y.; Wu, Y.; Chen, G.D.; Hu, D.; Li, X.X.; Sun, X.; Guo, L.D.; Li, Y.; Yao, X.S.; Gao, H. Xylariterpenoids A-D, Four New Sesquiterpenoids from the Xylariaceae Fungus. RSC Adv. 2014, 4, 54144–54148. [Google Scholar] [CrossRef]
  78. Sevillo, L.; Castaldo, D.; Giovane, A.; Casale, R.; D’Onofrio, N.; Cautela, D.; Balestrieri, M.L. Tyramine Pathways in Citrus Plant Defense: Glycoconjugates of Tyramine and Its N-Methylated Derivatives. J. Agric. Food Chem. 2017, 65, 892–899. [Google Scholar] [CrossRef]
  79. Gallwey, F.B.; Hawkes, J.E.; Haycock, P.; Lewis, D. LH NM R Spectra and Conformations of Propane-l.2-Dio1, Meso- and Racemic Butane-2,3-Diols, and Some Alditols in Non-Aqueos Media. J. Chem. Soc. Perkin Trans. 1990, 2, 1979–1985. [Google Scholar] [CrossRef]
  80. Schneider, P.; Misiek, M.; Hoffmeister, D. In Vivo and in Vitro Production Options for Fungal Secondary Metabolites. Mol. Pharm. 2008, 5, 234–242. [Google Scholar] [CrossRef]
  81. Schulz, B.; Boyle, C.; Draeger, S.; Römmert, A.K.; Krohn, K. Endophytic Fungi: A Source of Novel Biologically Active Secondary Metabolites. Mycol. Res. 2002, 106, 996–1004. [Google Scholar] [CrossRef]
  82. Zhang, H.W.; Song, Y.C.; Tan, R.X. Biology and Chemistry of Endophytes. Nat. Prod. Rep. 2006, 23, 753–771. [Google Scholar] [CrossRef] [PubMed]
  83. Jha, D.K. Bioprospecting for Microbial Endophytes and Their Natural Products. NBU J. Plant Sci. 2015, 9, 1–13. [Google Scholar] [CrossRef]
  84. Krohn, K.; Bahramsari, R.; Flörke, U.; Ludewig, K.; Kliche-Spory, C.; Michel, A.; Aust, H.J.; Draeger, S.; Schulz, B.; Antus, S. Dihydroisocoumarins from Fungi: Isolation, Structure Elucidation, Circular Dichroism and Biological Activity. Phytochemistry 1997, 45, 313–320. [Google Scholar] [CrossRef]
  85. Kokubun, T.; Veitch, N.C.; Bridge, P.D.; Simmonds, M.S.J. Dihydroisocoumarins and a Tetralone from Cytospora eucalypticola. Phytochemistry 2003, 62, 779–782. [Google Scholar] [CrossRef]
  86. Uzma, F.; Mohan, C.D.; Hashem, A.; Konappa, N.M.; Salomone, S. Endophytic Fungi—Alternative Sources of Cytotoxic Compounds: A Review. Front. Pharmacol. 2018, 9, 309. [Google Scholar] [CrossRef]
  87. Goutam, J.; Singh, R.; Vijayaraman, R.S.; Meena, M. Endophytic Fungi: Carrier of Potential Antioxidants. In Fungi and Their Role in Sustainable Development: Current Perspective; Springer Nature Singapore Pte Ltd.: Singapore, 2018; pp. 539–551. ISBN 9789811303937. [Google Scholar]
  88. Mitscher, L.A.; Andres, W.W.; McCrae, W. Reticulol, a New Metabolic Isocoumarin. Breves Commun. Kurze Mitteilungen 1962, 5, 258–259. [Google Scholar] [CrossRef] [PubMed]
  89. Lim, D.S.; Kwak, Y.S.; Kim, J.H.; Ko, S.H.; Yoon, W.H.; Kim, C.H. Antitumor Efficacy of Reticulol from Streptoverticillium against the Lung Metastasis Model B16F10 Melanoma: Lung Metastasis Inhibition by Growth Inhibition of Melanoma. Chemotherapy 2003, 49, 146–153. [Google Scholar] [CrossRef] [PubMed]
  90. Furutani, Y.; Shimada, M.; Hamada, M.; Takeuchi, T.; Umezawa, H.; Furutani, Y.; Shimada, M. Reticulol, an Inhibitor of Cyclic Nucleotide Phosphodiesterases. Agric. Biol. Chem. 1977, 41, 989–993. [Google Scholar] [CrossRef]
  91. Niu, S.; Liu, Q.; Xia, J.M.; Xie, C.L.; Luo, Z.H.; Shao, Z.; Liu, G.; Yang, X.W. Polyketides from the Deep-Sea-Derived Fungus Graphostroma Sp. MCCC 3A00421 Showed Potent Antifood Allergic Activities. J. Agric. Food Chem. 2018, 66, 1369–1376. [Google Scholar] [CrossRef] [PubMed]
  92. Chen, H.; Singh, H.; Bhardwaj, N.; Bhardwaj, S.K.; Khatri, M.; Kim, K.; Peng, W. An Exploration on the Toxicity Mechanisms of Phytotoxins and Their Potential Utilities. Crit. Rev. Environ. Sci. Technol. 2022, 52, 395–435. [Google Scholar] [CrossRef]
  93. Xu, D.; Xue, M.; Shen, Z.; Jia, X.; Hou, X.; Lai, D. Phytotoxic Secondary Metabolites from Fungi. Toxins 2021, 13, 261. [Google Scholar] [CrossRef] [PubMed]
  94. Pontes, J.G.M.; Fernandes, L.S.; Vander, R.; Tasic, L.; Fill, T. Virulence Factors in the Phytopathogen-Host Interactions: An Overview Virulence Factors in the Phytopathogen-Host Interactions: An Overview. J. Agric. Food Chem. 2020, 68, 7555–7570. [Google Scholar] [CrossRef]
  95. Jetter, P.; Steinert, C.; Knauer, M.; Zhang, G.; Bruhn, T.; Wiese, J.; Imhoff, J.F.; Fiedler, H.; Bringmann, G. New Bhimamycins from Streptomyces Sp. AK 671*. J. Antibiot. 2013, 66, 719–726. [Google Scholar] [CrossRef] [PubMed]
  96. Bhat, R.V.; Haeberlein, S.L.B.; Avila, J. Glycogen Synthase Kinase 3: A Drug Target for CNS Therapies. J. Neurochem. 2004, 89, 1313–1317. [Google Scholar] [CrossRef] [PubMed]
  97. Mccubrey, J.A.; Steelman, L.S.; Bertrand, F.E.; Davis, N.M.; Sokolosky, M.; Abrams, S.L.; Montalto, G.; Assoro, A.B.D.; Libra, M.; Nicoletti, F.; et al. GSK-3 as Potential Target for Therapeutic Intervention in Cancer. Oncotarget 2014, 5, 2881–2911. [Google Scholar] [CrossRef] [PubMed]
  98. Min, K.; Lee, K.; Young, G.; Jin, H. Molecular and Cellular Endocrinology Anti-Diabetic Efficacy of KICG1338, a Novel Glycogen Synthase Kinase- 3β Inhibitor, and Its Molecular Characterization in Animal Models of Type 2 Diabetes and Insulin Resistance. Mol. Cell. Endocrinol. 2015, 409, 1–10. [Google Scholar] [CrossRef]
  99. Dos Santos, T.C.; Gomes, T.M.; Pinto, B.A.S.; Camara, A.L.; De Andrade Paes, A.M. Naturally Occurring Acetylcholinesterase Inhibitors and Their Potential Use for Alzheimer’s Disease Therapy. Front. Pharmacol. 2018, 9, 1192. [Google Scholar] [CrossRef]
  100. Barbosa Filho, J.M.; Medeiros, K.C.P.; Diniz, M.D.F.F.M.; Batista, L.M.; Athayde-Filho, P.F.; Silva, M.S.; da Cunha, E.V.L.; Almeida, J.R.G.S.; Quintans-Júnior, L.J. Natural Products Inhibitors of the Enzyme Acetylcholinesterase. Rev. Bras. Farmacogn. 2006, 16, 258–285. [Google Scholar] [CrossRef]
Toxins 15 00686 g001
Figure 1. Structures of azaphilone derivatives Biscogniazaphilones A (1) and Biscogniazaphilones B (2).
Figure 1. Structures of azaphilone derivatives Biscogniazaphilones A (1) and Biscogniazaphilones B (2).
Toxins 15 00686 g001
Toxins 15 00686 g002
Figure 2. Cerebroside A (3) and Cerebroside C (4).
Figure 2. Cerebroside A (3) and Cerebroside C (4).
Toxins 15 00686 g002
Toxins 15 00686 g003
Figure 3. Structures of coumarin and isocoumarin (5–9).
Figure 3. Structures of coumarin and isocoumarin (5–9).
Toxins 15 00686 g003
Toxins 15 00686 g004
Figure 4. Melleins structures (10–25).
Figure 4. Melleins structures (10–25).
Toxins 15 00686 g004
Toxins 15 00686 g005
Figure 5. Linoleic acid (26).
Figure 5. Linoleic acid (26).
Toxins 15 00686 g005
Toxins 15 00686 g006
Figure 6. 5-hydroxy-3,7,4′-trimethoxyflavone (27).
Figure 6. 5-hydroxy-3,7,4′-trimethoxyflavone (27).
Toxins 15 00686 g006
Toxins 15 00686 g007
Figure 7. (3aS,4aR,8aS,9aR)-3a-hydroxy-8a-methyl-3,5-dimethylenedecahydronaphto [2,3-b]furan-2(3H)-one (HDFO) (28).
Figure 7. (3aS,4aR,8aS,9aR)-3a-hydroxy-8a-methyl-3,5-dimethylenedecahydronaphto [2,3-b]furan-2(3H)-one (HDFO) (28).
Toxins 15 00686 g007
Toxins 15 00686 g008
Figure 8. Structure of N-trans-feruloy-3-O-methyl-dopamine (29).
Figure 8. Structure of N-trans-feruloy-3-O-methyl-dopamine (29).
Toxins 15 00686 g008
Toxins 15 00686 g009
Figure 9. Structure of lignan (30–32).
Figure 9. Structure of lignan (30–32).
Toxins 15 00686 g009
Toxins 15 00686 g010
Figure 10. Structure of naphtho [2,3-c]furandione (isofuranonaphthoquinone) (33).
Figure 10. Structure of naphtho [2,3-c]furandione (isofuranonaphthoquinone) (33).
Toxins 15 00686 g010
Toxins 15 00686 g011
Figure 11. Structures of cyclic dipeptides (34–37).
Figure 11. Structures of cyclic dipeptides (34–37).
Toxins 15 00686 g011
Toxins 15 00686 g012
Figure 12. Structure of cyclo-(ʟ-Phe-ʟ-Leu-ʟ-Val-ʟ-Leu-ʟ-Leu) (38).
Figure 12. Structure of cyclo-(ʟ-Phe-ʟ-Leu-ʟ-Val-ʟ-Leu-ʟ-Leu) (38).
Toxins 15 00686 g012
Toxins 15 00686 g013
Figure 13. Structures of phenyl and phenol derivatives (39–48).
Figure 13. Structures of phenyl and phenol derivatives (39–48).
Toxins 15 00686 g013
Toxins 15 00686 g014
Figure 14. Structure of phthalide (49–54).
Figure 14. Structure of phthalide (49–54).
Toxins 15 00686 g014
Toxins 15 00686 g015
Figure 15. Structure of biscopyran (55).
Figure 15. Structure of biscopyran (55).
Toxins 15 00686 g015
Toxins 15 00686 g016
Figure 16. Structures of α-pyrones (56–61).
Figure 16. Structures of α-pyrones (56–61).
Toxins 15 00686 g016
Toxins 15 00686 g017
Figure 17. Structures of steroid, (62–69).
Figure 17. Structures of steroid, (62–69).
Toxins 15 00686 g017
Toxins 15 00686 g018
Figure 18. Structures of diterpenoids (70) and (71).
Figure 18. Structures of diterpenoids (70) and (71).
Toxins 15 00686 g018
Toxins 15 00686 g019
Figure 19. Structures of meroterpenoids (72–81).
Figure 19. Structures of meroterpenoids (72–81).
Toxins 15 00686 g019
Toxins 15 00686 g020
Figure 20. Meroterpenoid structures (82–89).
Figure 20. Meroterpenoid structures (82–89).
Toxins 15 00686 g020
Toxins 15 00686 g021
Figure 21. Structures of sesquiterpenoids (90–106).
Figure 21. Structures of sesquiterpenoids (90–106).
Toxins 15 00686 g021
Toxins 15 00686 g022
Figure 22. Structures of sesquiterpenoids (107–112).
Figure 22. Structures of sesquiterpenoids (107–112).
Toxins 15 00686 g022
Toxins 15 00686 g023
Figure 23. Structures of N-trans-feruloyltyramine (113) and N-cis-feruloyltyramine (114).
Figure 23. Structures of N-trans-feruloyltyramine (113) and N-cis-feruloyltyramine (114).
Toxins 15 00686 g023
Toxins 15 00686 g024
Figure 24. Structure of meso-2,3-butanediol (115).
Figure 24. Structure of meso-2,3-butanediol (115).
Toxins 15 00686 g024
Table 1. List of secondary metabolites produced by Biscogniauxia collected from the literature.
Table 1. List of secondary metabolites produced by Biscogniauxia collected from the literature.
No.Compound NameFungal Strains
(Solvent Used for Extraction)		FormulasNominal MassRef.
Azaphilone Derivatives
1.Biscogniazaphilone AB. formosana (EtOH)C24H34O4409.23[10]
2.Biscogniazaphilone BB. formosana (EtOH)C25H32O5435.21[10]
Cerebrosides
3.Cerebroside AB. whalleyi (EtOAc)C41H75NO9748.53[11]
4.Cerebroside CB. whaleyi (EtOAc)C43H79NO9754.1[11]
Coumarins
(a) 
Isocoumarins
5.IsoscopoletinB. cylindrospora (EtOH)C10H8O4192.17[4]
6.ScopoletinB. cylindrospora (EtOH)C10H8O4192.04[4]
7.IsofraxidineB. cylindrospora (EtOH)C11H10O5222.05[12]
(b) 
Coumarins
8.6-O-methyl-reticulolB. capnodes (EtOAc)C12H12O5236.07[12]
9.ReticulolB. capnodes (EtOAc)C11H10O5222.19[12]
(c) 
Dihydroisocoumarin (Melleins)
10.3,5-dimethyl-8-methoxy-3,4-dihydroisocoumarinB. nummularia (EtOAc)C11H12O4208.21[13]
11.3,5-dimethyl-8-hydroxy-3,4-dihydroisocoumarinB. nummularia (EtOAc)C12H14O3206.24[13]
12.(3R,4R)-4-hydroxymelleinB. rosacearum (EtOAc)C10H10O4194.18[14]
13.(3R,4S)-4- hydroxymelleinB. rosacearum (EtOAc)C10H10O4194.18[14]
14.(3R)-6-hydroxymelleinB. rosacearum (EtOAc)C10H10O4194.18[14]
15.7-hydroxy-5-methylmelleinB. capnodes (EtOAc)C11H12O4208.21[12]
16.(3S)-5-hydroxy-8-O-methylmelleinB. cylindrospora (EtOH 70%)C11H12O4208.21[15]
17.5-hydroxymethylmelleinB. cylindrospora (EtOH 70%)C11H12O4208.07[15]
18.5-formylmelleinB. cylindrospora (EtOH 70%)C11H10O4206.06[15]
19.Mellein-5-carboxylic acidB. cylindrospora (EtOH 70%)C11H10O5222.05[15]
20.(3R)-melleinB. rosacearum (EtOAc)C10H10O3178.18[8]
21.5-methylmelleinB. mediterranea (EtOAc)
B. mediterranea (DCM)
B. capnodes (EtOAc)
B. whalleyi (EtOAc)		C11H12O3192.21[16]
[16]
[12]
[11]
22.(3R)-5-methylmelleinB. rosacearum (EtOAc)C11H12O3193[14]
23.(3R)-5-methyl-6-methoxymelleinB. rosacearum (EtOAc)C12H14O4223[14]
24.(3R)-4-methoxymelleinB. rosacearum (EtOAc)C11H12O4208.21[14]
25.6-methoxy-5-methylmelleinB. mediterranea (MeOH)C12H14O4222.24[17]
Fatty acids
26.Linoleic acidB. cylindrospora (EtOH)C18H32O2280.44[3]
Flavonoids
27.5-hydroxy-3,7,4′-trimethoxyflavoneB. formosana (EtOH)C19H18O7358.3[10]
Furan
28.(3aS,4aR,8aS,9aR)-3a-hydroxy-8a-methyl-3,5-dimethylenedecahydronaphto [2,3-b]furan-2(3H)-one (HDFO)Biscogniauxia sp. (EtOAc)C15H20O3248.31[18]
Hydroxycinnamic acids and derivatives
29.N-trans-feruloy-3-O-methyl-dopamineB. formosana (EtOH)C19H21NO5343.4[10]
Lignans
30.Methyl 3,4-methylenedioxycinnamateB. formosana (EtOH)C12H14O4222.24[10]
31.3,4-methylenedioxycinnamic acidB. formosana (EtOH)C10H8O4192.17[10]
32.3,4-methylenedioxybenzoic acidB. formosana (EtOH)C8H6O4166.13[10]
Napthoquinone
33.Naphtho [2,3-c]furandione (isofuranonephthoquinone)B. mediterranea (MeOH)C12H6O3198.17[17]
Peptides
(a) 
Cyclic dipeptides
34.cyclo (ʟ -Pro-Gly)B. whalleyi (EtOAc)C7H10N2O2154.16[11]
35.cyclo (ʟ-Pro-ʟ-Leu)B. whalleyi (EtOAc)C11H18N2O2210.27[11]
36.cyclo (ʟ-Pro-ʟ-Phe)B. whalleyi (EtOAc)C14H16N2O2244.29[11]
37.cyclo (ʟ-Pro-ʟ-Val)B. whalleyi (EtOAc)C10H16N2O2196.25[11]
(b) 
Cyclopeptide
38.cyclo-(ʟ-Phe-ʟ-Leu-ʟ-Val-ʟ-Leu-ʟ-Leu)B. mediterranea (MeOH)C32H51N5O5585.8[17]
Phenyl and Phenol Derivatives
39.4-hydroxybenzaldehydeB. formosana (EtOH)C7H6O2122.12[10]
40.5-hydroxy-2-prenylhydroquinoneB. whalleyi (EtOAc)C11H14O3194.09[11]
41.4-(3-methylbut-2-enyloxy)benzoic acidB. formosana (EtOH)C13H16O3220.26[10]
42.4- methoxycinnamaldehydeB. formosana (EtOH)C10H10O2162.18[10]
43.4-methoxy-trans-cinnamic acidB. formosana (EtOH)C10H10O3178.18[10]
44.MethylparabenB. cylindrospora (70% EtOH)C8H8O3152.15[15]
45.Phenylacetic AcidB. mediterranea (EtOAc)C8H8O2136.15[8]
46.SyringaldehydeB. cylindrospora (EtOH 70%)C9H10O4182.17[15]
47.TyrosolB. whalleyi (EtOAc)
B. rosacearum (EtOAc)		C9H13NO2167.09[11,14]
48.Vanillic acidB. cylindrospora (EtOH 70%)C8H8O4168.14[15]
Phthalides
49.[4-[(acetyloxy)methyl]-7-methoxy-6-methyl-1(3H)-isobenzofuranoneBiscogniauxia sp. (EtOAc)C13H14O5209.08[9]
50.Biscogniphthalides ABiscogniauxia sp. (EtOAc)C18H23O7351.14[9]
51.Biscogniphthalides BBiscogniauxia sp. (EtOAc)C17H21O7337.12[9]
52.Biscogniphthalides CBiscogniauxia sp. (EtOAc)C12H13O6253.07[9]
53.Biscogniphthalides DBiscogniauxia sp. (EtOAc)C11H13O4209.08[9]
54.7-hydroxy-5-methoxy-4,6-dimethylphthalideB. whalleyi (EtOAc)C11H12O3208.07[11]
Pyranopyran
55.(Z)-2-methoxy-1-[7-((Z)-2-methoxybut-2-enoyl)-3,4,5,6-tetramethyl-2H,7H-pyrano [2,3-b]pyran-2-yl]but-2-en-1-one (Biscopyran)B. mediterranea (EtOAc)C22H28O6388.18[8]
α-pyrones
56.6-(1′, 2′-dimethyloxiran-1′-yl)-4-methoxy-3-methyl-2H-pyran-2-oneB. whalleyi (EtOAc)C11H14O4233.07[11]
57.Gulypyrone BB. whalleyi (EtOAc)C11H14O4210.09[11]
58.6-[(1R)-1-hydroxy-1-methyl-2-propenyl]-4-methoxy-3-methyl-2H-pyran-2-oneB. whalleyi (EtOAc)C11H14O4210.23[11]
59.NectriapyroneB. whalleyi (EtOAc)
B. rosacearum (EtOAc)		C11H14O3194.23[11]
[14]
60.Phomopyrone AB. whalleyi (EtOAc)C11H14O4210.22[11]
61.VermopyroneB. whalleyi (EtOAc)C9H10O4182.17[11]
Steroids
62.CerevisterolB. whalleyi (EtOAc)C28H46O3430.34[11]
63.ErgoneB. whalleyi (EtOAc)C28H40O392.6[11]
64.Ergosta-4,6,8(14), 22-tetraen-3-oneB. formosana (EtOH)C28H40O392.6[10]
65.ErgosterolB. whalleyi (EtOAc)C28H44O396.34[11]
66.Ergosterol peroxideB. whalleyi (EtOAc)C28H44O3428.6[11]
67.3β-hydroxystigmast-5-en-7-oneB. cylindrospora (EtOH 70%)C29H48O2428.7[15]
68.β-cytostenoneB. cylindrospora (EtOH)C29H48O412.7[4]
69.β-sitosterolB. cylindrospora (EtOH)C29H50O414.7[4]
Terpenoids and the Derivatives
(a) 
Diterpenoids
70.Biscognisecoisopimarate ABiscogniauxia sp. (EtOAc)C23H38O6433.25[19]
71.3β-Hydroxyrickitin ABiscogniauxia sp. (EtOAc)C20H27O4331.19[19]
(b) 
Meroterpenoids
72.Biscogniacid BBiscogniauxia sp. (EtOAc)C12H15O5239.09[20]
73.Biscogniacid CBiscogniauxia sp. (EtOAc)C12H15O5239.09[20]
74.Biscognienyne DBiscogniauxia sp. (EtOAc)C16H20O4299.12[20]
75.Biscognienyne FBiscogniauxia sp. (EtOAc)C17H20O6343.11[20]
76.Biscognin ABiscogniauxia sp. (EtOAc)C16H23O5295.15[20]
77.Biscognin BBiscogniauxia sp. (EtOAc)C1 6H23O4279.16[20]
78.Biscognin CBiscogniauxia sp. (EtOAc)C15H21O4265.14[20]
79.Biscognin DBiscogniauxia sp. (EtOAc)C16H21O4277.14[20]
80.Biscognin EBiscogniauxia sp. (EtOAc)C16H21O4277.14[20]
81.Biscognin FBiscogniauxia sp. (EtOAc)C16H22O4301.214[20]
82.Biscogniacid ABiscogniauxia sp. (EtOAc)C12H13O4221.08[21]
83.Biscognienyne ABiscogniauxia sp. (EtOAc)C16H22O3285.14[21]
84.Biscognienyne BBiscogniauxia sp. (EtOAc)C16H20O3283.13[21]
85.Biscognienyne CBiscogniauxia sp. (EtOAc)C15H20O4287.12[21]
86.Biscognienyne EBiscogniauxia sp. (EtOAc)C16H20O4283.13[20]
87.Dimericbiscognienynes ABiscogniauxia sp. (EtOAc)C32H40O6545.28[21]
88.Dimericbiscognienynes BBiscogniauxia sp. (EtOAc)C32H42O6545.28[22]
89.Dimericbiscognienynes CBiscogniauxia sp. (EtOAc)C32H41O6521.29[22]
(c) 
Sesquiterpenoids
90.Biscogniauxiaol AB. petrensis (MeOH)C15H23O3251.1644[23]
91.Biscogniauxiaol BB. petrensis (MeOH)C15H28O3279.1927[23]
92.Biscogniauxiaol CB. petrensis (MeOH)C15H28O4295.1882[23]
93.Biscogniauxiaol DB. petrensis (MeOH)C15H28O4295.187[23]
94.Biscogniauxiaol EB. petrensis (MeOH)C15H28O4295.1878[23]
95.Biscogniauxiaol FB. petrensis (MeOH)C16H28O4307.1873[23]
96.Biscogniauxiaol GB. petrensis (MeOH)C15H28O3277.1764[23]
97.Epiguaidiol AB. whalleyi (EtOAc)C15H26O2238.37[11]
98.Graphostromane EB. whalleyi (EtOAc)C15H26O2261.18[11]
99.(1R*,4S*,5S*,7S*,10R*)-guaia-11(12)-en-7,10-diolB. whalleyi (EtOAc)C15H26O2261.18[11]
100.(1R,4S,5S,7R,10R,11R)-guaiane-10,11,12-triolB. whalleyi (EtOAc)C15H27O3255.37[11]
101.(1R,4S,5S,7R,10R,11S)-guaiane-10,11,12-triolB. whalleyi (EtOAc)C15H27O3255.37[11]
102.Patchouliguaiol AB. whalleyi (EtOAc)C15H24O2236.34[11]
103.PogostolB. whalleyi (EtOAc)C15H26O222.37[11]
104.XyralanoneB. whalleyi (EtOAc)
B. nummularia (EtOAc)		C15H27O3255.37[11,13]
105.Xylaranol AB. whalleyi (EtOAc)C8H10O4170.16[11]
106.Xylaranol BB. nummularia (EtOAc)C15H28O3257.29[13]
107.Xylariterpenoids AB. whalleyi (EtOAc)C15H25O3253.36[11]
108.Xylariterpenoids BB. whalleyi (EtOAc)C15H25O3253.36[11]
109.Xylariterpenoid LB. whalleyi (EtOAc)C15H22O2257.15[11]
110.Xylariterpenoid MB. whalleyi (EtOAc)C15H24O4291.15[11]
111.Xylariterpenoid NB. whalleyi (EtOAc)C15H23O219.17[11]
112.(1R,2S,6R,7S)-1,2-dihydroxy-α-bisabololB. whalleyi (EtOAc)C15H22O277.17[11]
Tyramines
113.N-trans-feruloyltyramineB. cylindrospora (EtOH 70%)C18H19NO4313.35[15]
114.N-cis-feruloyltyramineB. cylindrospora (EtOH 70%)C18H19NO4313.3[15]
Other
115.Meso-2,3-butanediolB. rosacearum (EtOAc)C4H10O290.07[14]
Table 2. Occurrence of secondary metabolites in Biscogniauxia strain and biological activities studied.
Table 2. Occurrence of secondary metabolites in Biscogniauxia strain and biological activities studied.
StrainsThe Part Where the Mushroom GrowsGrowing ConditionsIdentified CompoundsBiological ActivityRef.
B. mediterranea Ohu 19BOpuntia humifusa plantPotato dextrose agar (PDA) medium20Antifungal (C. fragariae, C. gloeosporioide C. acutatum)[16]
B. petrensis MFLUCC14-0151Dendrobium orchidsMartin modified (MM) medium90–96Antifungal (C. albicans)[23]
B. formosana BCRC 33718Cinnamomum spPotato dextrose agar (PDA) medium1, 2, 26, 28–31, 38, 40–42, 63Antimycobacterial (M. tuberculosis)[10]
B. whalleyi SWUF13-085Corticated woodPotato dextrose agar (PDA) medium3, 4, 53, 57, 58, 82–90, 107–112Cytotoxic activity (HeLa cells, HT29, HT116 cells, MCF-7 cells, Vero cells) and
NO production inhibition		[11]
B. capnodes
TAC-2014		Averrhoa carambolaPotato dextrose broth (PDB) medium7, 8, 15, 21Antioxidant activity[12]
B. rosacearum IRAN 4194C and IRAN 4287CVitis vinifera L.Potato dextrose broth (PDB) medium12–14, 20, 22–24, 46, 58, 115Phytotoxic activity[14]
B. nummularia LCP 05669Cephalotaxus harringtoniaPotato dextrose agar containing V8 medium10, 11, 104, 106Antigerminative activity[13]
B. mediterranea LF657Deep-sea sedimentsFive different agar media (Cytophaga-Flavobacterium-Bacteroides medium, tryptone, yeast extract, Bacto™ agar)24, 32, 37Activity against the enzyme GSK-3β[17]
Biscogniauxia sp. No. 71-10-1-1Usnea mutabilis Stirt.-82–95, 87
82, 87		Cytotoxic activity (HeLa, SW480, PANC-1)
Anti-AD activities		[21]
Biscogniauxia sp. No. 69-8-7-1Rimelia reticulataPotato dextrose agar (PDA) medium49–52AChE activity[9]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Purbaya, S.; Harneti, D.; Safriansyah, W.; Rahmawati; Wulandari, A.P.; Mulyani, Y.; Supratman, U. Secondary Metabolites of Biscogniauxia: Distribution, Chemical Diversity, Bioactivity, and Implications of the Occurrence. Toxins 2023, 15, 686. https://doi.org/10.3390/toxins15120686

AMA Style

Purbaya S, Harneti D, Safriansyah W, Rahmawati, Wulandari AP, Mulyani Y, Supratman U. Secondary Metabolites of Biscogniauxia: Distribution, Chemical Diversity, Bioactivity, and Implications of the Occurrence. Toxins. 2023; 15(12):686. https://doi.org/10.3390/toxins15120686

Chicago/Turabian Style

Purbaya, Sari, Desi Harneti, Wahyu Safriansyah, Rahmawati, Asri Peni Wulandari, Yeni Mulyani, and Unang Supratman. 2023. "Secondary Metabolites of Biscogniauxia: Distribution, Chemical Diversity, Bioactivity, and Implications of the Occurrence" Toxins 15, no. 12: 686. https://doi.org/10.3390/toxins15120686

APA Style

Purbaya, S., Harneti, D., Safriansyah, W., Rahmawati, Wulandari, A. P., Mulyani, Y., & Supratman, U. (2023). Secondary Metabolites of Biscogniauxia: Distribution, Chemical Diversity, Bioactivity, and Implications of the Occurrence. Toxins, 15(12), 686. https://doi.org/10.3390/toxins15120686

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop