Structures and Biological Activities of Secondary Metabolites from Xylaria spp.

The fungus genus Xylaria is an important source of drug discoveries in scientific fields and in the pharmaceutical industry due to its potential to produce a variety of structured novel and bioactive secondary metabolites. This review prioritizes the structures of the secondary metabolites of Xylaria spp. from 1994 to January 2024 and their relevant biological activities. A total of 445 new compounds, including terpenoids, nitrogen-containing compounds, polyketides, lactones, and other classes, are presented in this review. Remarkably, among these compounds, 177 compounds show various biological activities, including cytotoxic, antimicrobial, anti-inflammatory, antifungal, immunosuppressive, and enzyme-inhibitory activities. This paper will guide further investigations into the structures of novel and potent active natural products derived from Xylaria and their potential contributions to the future development of new natural drug products in the agricultural and medicinal fields.


Introduction
The fungus genus Xylaria, belonging to the family Xylariaceae, is a fungus widely distributed in both marine and terrestrial environments.Most of the genus Xylaria is saprophytic, digesting rotten wood, bark, feces, and other organic matter; similar to most saprophytic fungi, it can produce a variety of species.Xylaria species are famous for producing structured novel and potent bioactive secondary metabolites.The secondary metabolites obtained from the fungus genus Xylaria have high biological activity, including antibacterial, antioxidant, and cytotoxic activities [1][2][3][4].The fungus genus Xylaria also has the potential to be used as a bioremediation agent and enzymatic degradation agent in industrial and agricultural fields [5][6][7].
The Xylaria fungi are producers of structurally diverse and biologically active compounds.As of 2020, 245 bioactive compounds (118 new compounds), including sesquiterpenoids, terpenoids, cytochalasins, alkaloids, polyketides, and aromatic compounds, have been isolated from the genus Xylaria.These compounds displayed a wide range of biological activities, comprising antibacterial, antifungal, anticancer, antimalarial, antiinflammatory, and α-glucosidase inhibitory activities.Many of these compounds exhibit a strong potential to be expanded into novel drugs [8,9].The secondary metabolites with novel structures and diverse bioactivities from Xylaria have continued to attract great attention from chemists, agricultural chemists, and pharmacologists.

Nitrogen-Containing Compounds
Nitrogen-containing compounds, including cytochalasan alkaloids and other nitrogencontaining metabolites, are notable for their exceptionally diverse class of secondary metabolites and potent bioactivities.A total of 112 new nitrogen-containing compounds were discovered from the genus Xylaria sp., including 67 cytochalasan alkaloids, and 45 other nitrogen-containing metabolites.Among them, 41 compounds showed cytotoxic activities, antibacterial activities, anti-inflammatory activities, enzyme-inhibitory activities, and other activities.

Polyketides
Polyketides are a class of compounds characterized by their exceptionally diverse structures and bioactivities.Polyketides are generated through a series of Claisen condensation reactions involving acetyl-CoA, malonyl-CoA, and so on.A total of 70 new polyketides were discovered from the genus of Xylaria sp., and 23 of them had cytotoxic activities, antibacterial activities, anti-inflammatory activities, enzyme-inhibitory activities, and so on.

Lactones
Lactones represent a class of compounds that contain lactone rings within their molecular structure.A total of 76 new lactones were discovered from the genus Xylaria sp.Remarkably, 32 compounds had cytotoxic activities, antioxidant activities, antibacterial activities, anti-inflammatory activities, enzyme-inhibitory activities, and so on.

Lactones
Lactones represent a class of compounds that contain lactone rings within their molecular structure.A total of 76 new lactones were discovered from the genus Xylaria sp.Remarkably, 32 compounds had cytotoxic activities, antioxidant activities, antibacterial activities, anti-inflammatory activities, enzyme-inhibitory activities, and so on.

Other Classes
There were also some other classes of secondary metabolites isolated from Xylaria spp., such as fatty acids, steroids, and benzene derivatives.A total of 54 new compounds were isolated from the genus of Xylaria sp., and 26 of them showed cytotoxic activities, antibacterial activities, anti-inflammatory activities, enzyme-inhibitory activities, and so on.

Other Classes
There were also some other classes of secondary metabolites isolated from Xylaria spp., such as fatty acids, steroids, and benzene derivatives.A total of 54 new compounds were isolated from the genus of Xylaria sp., and 26 of them showed cytotoxic activities, antibacterial activities, anti-inflammatory activities, enzyme-inhibitory activities, and so on.

Comprehensive Overview and Conclusions
In this review, the sources, structural diversity, and biological activity of secondary metabolites from Xylaria fungi are summarized, covering the period from 1994 to January 2024.A total of 445 new compounds were obtained from the genus Xylaria.A sample of 177 notable compounds and their biological activities are summarized in Table 1.The structural diversities and bioactivities of the new secondary metabolites discovered from Xylaria spp.are also shown in Figure 9.

Comprehensive Overview and Conclusions
In this review, the sources, structural diversity, and biological activity of secondary metabolites from Xylaria fungi are summarized, covering the period from 1994 to January 2024.A total of 445 new compounds were obtained from the genus Xylaria.A sample of 177 notable compounds and their biological activities are summarized in Table 1.The structural diversities and bioactivities of the new secondary metabolites discovered from Xylaria spp.are also shown in Figure 9.The chemical structures of the 445 new secondary metabolites from Xylaria fungi can mainly be classified into five types, including 133 terpenoids, 112 nitrogen-containing compounds, 70 polyketones, 76 lactones, and 54 other compounds consisting of steroids, fatty acids, and benzene derivatives (Figure 9).However, among these 445 new compounds, terpenoids predominantly accounted for 29.89%, while nitrogen-containing compounds, polyketides, lactones, and other types accounted for 25.18%, 15.73%, 17.07%, and 12.13, respectively.Moreover, it is worth noting that nearly 39.8% (177 compounds) showed broadspectrum biological activities, including cytotoxic (52 compounds), antimicrobial (38 compounds), antifungal (30 compounds), anti-inflammatory (18 compounds), enzyme inhibition (12 compounds), immunosuppressive (10 compounds), and other activities (17 compounds).Notably, cytotoxic (29.37%), antibacterial (21.46%), and antifungal (16.95%) activities represent the top three bioactivities (Figure 9).It is important to highlight that many compounds exhibit multiple activities.For example, xyloketal B (271) is able to act in a number of different disease models in the underlying pathological mechanisms, including oxidative stress, NO disturbance, intracellular Ca 2+ imbalance, and protein aggregation.
In summary, Xylaria fungi have been proven to be an important source of structured novel and diverse secondary metabolites with a broad range of biological activities, revealing their great untapped potential in medicinal and agrochemical applications.However, for most of these discovered compounds, the lack of deep pharmacological mechanisms and comprehensive pharmacokinetic evaluation limits their applications.Overall, this review shed light on the new secondary metabolites from the Xylaria fungi for their potential contributions to the future development of new natural product drugs in the agricultural and medicinal fields.

Figure 9 .
Figure 9. Structural diversity (left) and bioactivities (right) of secondary metabolites in the genus of Xylaria that were discovered from 1994 to January 2023.

Figure 9 .
Figure 9. Structural diversity (left) and bioactivities (right) of secondary metabolites in the genus of Xylaria that were discovered from 1994 to January 2023.