In Depth Natural Product Discovery from the Basidiomycetes Stereum Species

Natural metabolites from microorganisms play significant roles in the discovery of drugs, both for disease treatments in humans, and applications in agriculture. The Basidiomycetes Stereum genus has been a source of such bioactive compounds. Here we report on the structures and activities of secondary metabolites from Stereum. Their structural types include sesquiterpenoids, polyketides, vibralactones, triterpenoids, sterols, carboxylic acids and saccharides. Most of them showed biological activities including cytotoxic, antibacterial, antifungal, antiviral, radical scavenging activity, autophagy inducing activity, inhibiting pancreatic lipase against malarial parasite, nematocidal and so on. The syntheses of some metabolites have been studied. In this review, 238 secondary metabolites from 10 known species and various unidentified species of Stereum were summarized over the last seven decades.


Introduction
Natural products deriving from microorganisms are one of the most valuable sources for medicinal and agricultural applications [1][2][3]. Basidiomycetes, as producers of bioactive secondary metabolites, provide an exciting opportunity to obtain new natural products with high application potential [4]. The increasing number of new and active compounds recently discovered in Basidiomycetes have demonstrated their capacity for producing many more unknown natural products, most of which are still unexploited for their applications.
Stereum belongs to the family of Stereaceae (Basidiomycetes), which is mainly distributed in tropical and subtropical areas, and it often lives in woody debris, rotting trunks and sometimes on buried dead wood [5]. There are 27 species in Stereum, according to the Dictionary of Fungi (http://www.speciesfungorum.org/Names/Fundic.asp, January, 2020). Stereum spp. are known to be producers of biologically active secondary metabolites. Previous investigations recorded a number of interesting new compounds isolated from Stereum, especially sesquiterpenoids, and about ten types of sesquiterpenoids were obtained from the genus, so it is one of the major sources of structurally diverse sesquiterpenes. Secondary metabolites from Stereum had diversiform biological activities, such as cytotoxic, antimicrobial, inhibit pancreatic lipase, nematocidal and so on. Some of them showed promising activities, for example, vibralactone, isolated from Stereum vibrans, is a lead compound with a novel skeleton structure and strong inhibitory activity (IC 50 0.4 µg/mL) against pancreatic lipase, which is a potential candidate for a new antiobesity therapeutic [6,7]. Up to now, there are 10 known species and various unidentified species of Stereum have been investigated for their metabolites. This review presents 238 secondary metabolites isolated from the Stereum spp., including their structures and biological activities reported over the last seven decades. exploitation of cis-1,2-dihydrocatechol in the development of total syntheses of hirsutic acid C (7) and complicatic acid (27) [26,27]. In addition to chemical syntheses, scientists are also working on biosynthetic approaches. The biosynthesis of hirsutic acid C (7) and complicatic acid (27) was carried out using 13 C-stable isotope feeding [24]. Recently, Flynn et al. described the cloning and functional characterization of a hirsutene synthase, which combined a sesquiterpene synthase (STS) with a C-terminal 3-hydroxy-3-methylglutaryl-coenzyme A (3-hydroxy-3-methylglutaryl-CoA) synthase (HMGS) domain [28]. Their structures are shown in Figure 1.

Drimane
Methoxylaricinolic acid (90) and laricinolic acid (91) ( Figure 5), two sesquiterpenes with a drimane skeleton were isolated from the fruit bodies of S. ostrea [52]. The two compounds exhibited marginal inhibition against lipid peroxidation in rat liver microsomes with the same IC 50 values of 50 µg mL −1 .

Phenol Derivatives and Other Aromatic Compounds
Phenol is an important part of a large variety of natural products, and presents high antimicrobial potential [71].

Sterols
Sterols have long been regarded as important compounds in drug discovery because of their varied biological activities, such as cytotoxicity, neurite outgrowth-promoting activity, anti-NO production and acetylcholinesterase inhibition [103]. Steroids are predominant secondary metabolites with various structural features, both their isolation and synthesis have gained attention in recent years [104,105].

Carboxylic Acids and Saccharides
Three carboxylic acids with two primary alcohols, sterepinic acids A-C (233-235), have been isolated from Stereum sp.

Conclusions
Over the past 70 years, 238 compounds have been discovered from the genus of Stereum, nearly half of which were sesquiterpenoids, and some of them were only found in Stereum. The results have shown that the production of secondary metabolites by organisms is not random, but related to their ecological niches [114]. We speculate that the production of sesquiterpenoids may be a characteristic of Stereum, especially since the bioactive ones may help Stereum to defend their habitat or to suppress the growth of competitors to maintain its own abundance.
According to the studies, we found that some bioactivities of metabolites may be related to critical bonds or groups of structure. For example, sterhirsutins E (15) and G (17) (Figure 1), the immunosuppressant bioactivity depends on the ether bond between C-15 and C-16 . When sterenins E-G (107-109) are compared with sterenins H (110) and I (111) (Figure 6), the strength of inhibitory activity against α-glucosidase is related to the carbonyl and isoprenyl groups. When we compare dankasterone A (217) with dankasterone B (218) (Figure 11), it seems that the carbonyl groups in the structure are essential for its cytotoxicity. Therefore, we may get more bioactive compounds by changing specific bonds and groups through chemical processes.
The discovery of novel and bioactive secondary metabolites is a target of drug and natural product chemists. Microorganisms are dominant sources for such substances. The metabolites of Stereum have been a potential drug repository for antiobesity therapeutics, cancer, inflammation, and other diseases, but it is difficult to obtain large quantities of active compounds because only minor amounts can be obtained from natural sources. As a result, we should do more research into the synthesis of such compounds. Recently, SteTC1, a type I cembrane diterpene synthetase from S. histurum, was characterized via genomic data analysis, phylogenetic method, protein sequence alignment and products detection with GC-MS [115]. This is instructive for scientists to do research using integrated approaches. There are 27 species in Stereum, but only 10 known species have been studied for their metabolites, so more new and active compounds are likely to be discovered from Stereum in the future.

Conflicts of Interest:
The authors declare no conflict of interest.