Meroterpenoids from Ganoderma Species: A Review of Last Five Years

Abstract Meroterpenoids are hybrid natural products that partially originate from the terpenoid pathway. Ganoderma meroterpenoids (GMs) are a type of meroterpenoids containing a 1,2,4-trisubstituted phenyl and a polyunsaturated terpenoid part. Over last 5 years, great efforts have been made to conduct phytochemistry research on the genus Ganoderma, which have led to the isolation and identification of a number of GMs. These newly reported GMs showed diverse structures and a wide range of biological activities. This review gives an overview of new GMs from genus Ganoderma and their biological activities and biosynthetic pathway, focusing on the period from 2013 until 2018. Graphical Abstract


Introduction
Ganoderma is a ganodermataceae (basidiomycete) white rot fungus, normally growing on woody plants and wood logs [1], and is used for medicinal purposes in China, Japan, and South Korea (Chinese Higher Fungi: 18 volumes). It was first recorded in the Shennong's Classic of Meteria Medica, and classified as an upper-grade medicine in medical books [2]. About 78 species of Ganoderma are recorded in Chinese Higher Fungi, of which, G. lucidum and G. sinense, were found to be edible and medicinallybeneficial fungi, and were registered in Chinese Pharmacopoeia (2010 and 2015 edition). However, other species, such as G. capense, G. cochlear, and G. tsuage, also play an important part in traditional folk medicines. In addition, pharmacological studies have also involved the extract and chemical constituents of other species [3][4][5]. Until now, the chemical constituents and biological activities of 22 species of Ganoderma have been studied.
Ganoderma is rich in novel ''mycochemicals'', including polysaccharide, triterpenoids, steroids, fatty acids, etc. Although polysaccharide is found to be one of the main bioactive constituents, its high molecular weight and complex structure limits its use in the drug market. Meanwhile, the small molecular constituents have played a significant role over the last 200 years in treating and preventing diseases, and are continuing to serve as important leads in modern drug discovery [6][7][8][9][10][11].
Herein, we review the structure, bioactivities, and biosynthesis pathways of GMs from Ganoderma species to lay the foundation for the further research and provide the important sources for the development of lead compounds.

Biosynthetic Pathway of GMs
The prenylation of aromatic compounds plays an important role in the natural product research because it not only gives rise to an astounding diversity of small molecular constituents in plants, fungi and bacteria, but also enhances the bioactivities and bioavailabilities of these compounds [27]. Aromatic prenyltransferase is the key enzyme for the prenylation of aromatic compounds. Meroterpenoids including ubiquinone, plastoquinone, menadione, vitamin E, prenylflavonoids, shikonin and prenylated alkaloids, are formed under prenyltransferase [28]. The analysis of the genome showed that abundant carbohydrate-active enzymes and ligninolytic enzymes were present in the G. lucidum genome [29]. All the meroterpenoids from Ganoderma consist of a 1,2,4-trisubstituted phenyl group and a polyunstaturated terpenoid parts, suggesting that lignin was degraded to phenyl group by the liginolytic enzymes of Ganoderma, and the terpenoid parts were further assembled under prenyltransferase.

Chemical Structures and Bioactivities of GMs
A class of GMs, which had a 1,2,4-trisubtituted phenyl group connecting with C10 or C15 polyunsaturated side chain or polycyclic substructure, widely distributed in genus Ganoderma. According to the difference in their terpenoid parts, these GMs can be divided into three types.
An a,b-unsaturated c-lactone fraction can be formed through a nucleophilic reaction from the carboxyl at C-10 0 or C-14 0 to the ketone carbonyl at C-1 0 (Fig. 2, Table 1). Cao et al [37] investigated the fruiting bodies of G. sinense and a series of GMs with an a,b-unsaturated c-lactone fraction, namely (?)-zizhines A-F (17, 20-24), were isolated. All the compounds were evaluated for their inhibition on extracellular matrix component (fibronectin) generation by using TGF-b1 induced rat kidney tubular epithelial cells. However, all of them didn't show any inhibitory activities. (±)-Chizhine E and F (15,19) and (±)-lucidulactone (16) were isolated from G. lucidum and the individual enantiomers of compounds 15 and 19 significantly inhibit monocyte chemotactic protein 1 (MCP-1) and fibronectin production in a dose-dependent manner [31,36]. Fornicin E (25) obtained from G. capense also was a pair of enantiomers, which showed stronger DPPH scavenging activity than vitamin E (positive control) [16]. (±)-Applanatumol U (14) was identified from G. applanatum and showed no inhibition against COX-1 and COX-2 [32].
With the help of oxidases, the ether ring was present in many GMs (Fig. 4, Table 1). For example, compounds 29-35 had different ether ring in the terpenoid part, whereas, the ether rings in compounds 36-40 were formed through a cyclization between the hydroxyl at C-1 and the hydroxyls of the terpenoid part. Compounds 29, 30, and 35-38 displayed significant antioxidant activities in the DPPH scavenging assay [16,30]. Among them, (±)-cochlearin D (30) and (?)-30 exhibited weak inhibitory effects for the proliferation of hepatic stellate cells (HSCs) induced by transforming growth factor-b1 (TGF-b1) [30]. Except for above compounds, the rest of compounds didn't show renoprotective activities [32,33].

Polycyclic GMs
Because of the presence of polyunsaturated terpenoid part, free radical reaction can be occurred in GMs under the conditions of enzyme and light, which led to the formation of polycyclic structures ( Table 2).

Conclusion
In this review, we summarized the chemical structures and biological activities of 135 GMs in the last five years. Although the first GMs have been isolated in 2000, until recent years GMs were studied in-depth. Moreover, except for G. lucidum and G. sinense registered in Chinese Pharmacopoeia (2010 and 2015 edition), GMs were widely present in many other Ganoderma species, such as G. appalantum, G. capense, G. cochlear, and G. petchii. Above information indicated that GMs could play an important role in explaining the efficacy of Ganoderma.
Thus, more bioactive studies should be carried out in the future for finding and developing lead compounds. Furthermore, GMs possessed multiple prenyl groups or complex ring systems, which provided plentiful molecular model for various biological activities. However, we found that the majority of GMs showed racemic nature, which had impact on their bioactivites. Therefore, it is need to be separated using chiral HPLC method or be stereoselectively synthsized.
Addtionally, the formation of racemic GMs also attracted us attention. Analysis of these polycyclic GMs showed that their polycyclic structures are formed based on the polyunsaturated terpenoid fraction. Studies found that the cyclizations, such as cationic cyclization and radical cyclization, are the key factor to generate racemes. And these reactions can be taken place under conditions of acid,    Fig. 6 Structures of GMs with spiro ring light and heating. However, the reactions in the plants mostly involved in enzyme system, which led to the generation of stereoselective compounds. Thus, we deduced that these polycyclic GMs with racemic nature may be formed for defending high temperature, strong light and diseases.
In all, the efforts to discover novel GMs with interesting biological activity and intriguing strutures from Ganoderma species have long been a hot topic in natural products chemistry. Meanwhile, novel GMs will serve as an abundant resource for synthetic chemists.