Bis-naphtho-γ-pyrones from Fungi and Their Bioactivities

Bis-naphtho-γ-pyrones are an important group of aromatic polyketides derived from fungi. They have a variety of biological activities including cytotoxic, antitumor, antimicrobial, tyrosine kinase and HIV-1 integrase inhibition properties, demonstrating their potential applications in medicine and agriculture. At least 59 bis-naphtho-γ-pyrones from fungi have been reported in the past few decades. This mini-review aims to briefly summarize their occurrence, biosynthesis, and structure, as well as their biological activities. Some considerations regarding to synthesis, production, and medicinal and agricultural applications of bis-naphtho-γ-pyrones are also discussed.


Introduction
Bis-naphtho-γ-pyrones (also known as dimeric naphtho-γ-pyrones, bis(naphtho-γ-pyrone)s, or bis-naphthopyran-4-ones) are an important group of fungal polyketides [1]. The interest of many OPEN ACCESS investigators in this class of compounds is due to their broad-range biological activities with potential applications in medicine and agriculture [2][3][4]. Until now, fungal bis-naphtho-γ-pyrones and their biological activities have not been reviewed. This comprehensive mini-review describes the occurrence, biosynthesis, and biological activities of fungal bis-naphtho-γ-pyrones. We also discuss their synthesis, production and applications.

Occurrence
Bis-naphtho-γ-pyrones have a diverse distribution in fungi (Tables 1-3). Their structures are shown in Figures 1-3. Based on the diaryl bond connection, bis-naphtho-γ-pyrones can be divided into three types (or groups), namely chaetochromin-, asperpyrone-, and nigerone-type. The absolute configurations of dimeric naphtho-γ-pyrones have been determined by circular dichroism (CD), 2D-NMR as well as X-ray diffraction analysis of some derivatives [5][6][7]. According to the literature, R-configured dimeric naphtho-γ-pyrones exhibit a first negative Cotton effect in the long-wavelength region, and a positive second one at shorter wavelength. On the contrary, S-configured dimeric naphtho-γ-pyrones exhibit a positive Cotton effect first in the long-wavelength region, and a negative one second at shorter wavelength [6,8].
It is worth mentioning that both asperpyrone and nigerone types of bis-naphtho-γ-pyrones are produced primarily by Aspergillus species where chaetochromin-type bis-naphtho-γ-pyrones do not distribute. This indicates that bis-naphtho-γ-pyrones should have taxonomic significance which needs to be further investigated [41]. Each fungal species also needs to be clearly identified [48][49][50].

Biological Activities
Bis-naphtho-γ-pyrones have a broad-range of biological activities such as cytotoxic, antitumor and antimicrobial properties, which are outlined in Table 5.

Cytotoxic and Antitumor Activity
Chaetochromins A (1) and D (9) from Chaetomium sp. showed strong cytotoxicity with IC 50 values ranging from 0.13 to 0.24 μg/mL in cell cultures of mouse embryo limb bud (LB) and midbrain (MB). Ustilaginoidin A (15) from Ustilaginoidea virens showed relatively weak cytotoxic activity [54]. Chaetochromins A (1), B (4), C (8) and D (9) exhibited strong cytotoxicity on KB cells by inhibiting deoxyribonucleic acid, ribonucleic acid and protein biosynthesis [2]. Further mechanism of action investigations for chaetochromin A (1) revealed that the ATP synthesis in mitochondria was inhibited by uncoupling oxidative phosphorylation and depressing state-3 respiration of mitochondria, which may explain their cytotoxicity and in vivo toxicity to animals [55].
Both ustilaginoidins D (20) and E (21) exhibited strong cytotoxicity on KB cells by inhibiting biosynthesis of nucleic acid and protein [2]. Ustilaginoidin A (15) also inhibited ATP synthesis in mitochondria by uncoupling oxidative phosphorylation and depressing state-3 respiration of mitochondria [55].
Cephalochromin (11) exhibited growth-inhibitory and apoptotic activity against human lung cancer A549 cells in a dose-dependent manner with an IC 50 value of 2.8 μM at 48 h. Cephalochromin induced cell cycle arrest at the G0/G1 phase through down-regulation of cyclin D1, cyclin E, Cdk 2, and Cdk 4 expressions. It markedly increased the hypodiploid sub-G1 phase (apoptosis) of the cell cycle at 48 h as measured by flow cytometric analysis. Reactive oxygen species generation and loss of the mitochondrial membrane potential (MMP) were also markedly induced by cephalochromin [18]. Cephalochromin (11) also inhibited ATP synthesis in mitochondria by uncoupling oxidative phosphorylation and depressing state-3 respiration of mitochondria [55].
Bacterial enoyl-acyl carrier protein reductase (FabI) in bacterial fatty acid synthesis has been demonstrated to be an antibacterial target [56]. Cephalochromin (11) inhibited FabI of Staphylococcus aureus and Escherichia coli with IC 50 values of 1.9 and 1.8 μM, respectively [57].

Conclusions and Future Perspectives
About 59 fungal bis-naphtho-γ-pyrones have been investigated in the past few decades. Some of them display diverse bioactivities, especially cytotoxic, antitumor and antimicrobial activities. The remaining bis-naphtho-γ-pyrones produced by fungi and their bioactivities need to be further studied. In recent years, an increasing number of bis-naphtho-γ-pyrones have been isolated from endophytic fungi [3,10,20] and marine-derived fungi [7,16,23]. These fungi could be the rich sources of biologically active metabolites that are indispensable for medicinal and agricultural applications [1,[63][64][65][66]. In most cases, biological activities, structure-activity relationships, and mode of action of bis-naphtho-γpyrones have been only primarily investigated and need to be studied in detail. The potential applications of bis-naphtho-γ-pyrones as antitumor agents, antimicrobials, and antivirus agents as well as their promising bioactivities have led to considerable interest within the pharmaceutical community. Chemical syntheses have been achieved for a few bioactive bis-naphtho-γ-pyrones such as ustilaginoidin A (15) [67] and nigerone (55) [68,69]. After comprehensive understanding of biosynthetic pathways of some bis-naphtho-γ-pyrones in the next few years, we can effectively not only increase yields of the bioactive bis-naphtho-γ-pyrones (i.e., cephalochromin, isochaetochromins B 1 and B 2 ), but also prevent biosynthesis of some toxic bis-naphtho-γ-pyrones (i.e., ustilaginoidins A-J) [70]. In addition, the physiological and ecological roles of the bis-naphtho-γ-pyrones in fungi need to be clarified in detail [71,72].