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.

1. 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 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.

2. Occurrence

Bis-naphtho-γ-pyrones have a diverse distribution in fungi (Table 1, Table 2 and Table 3). Their structures are shown in Figure 1, Figure 2 and Figure 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].

Table 1

Occurrence of chaetochromin-type bis-naphtho-γ-pyrones 1–26 in fungi.

Bis-naphtho-γ-pyrone	Fungal Species	Reference
Chaetochromin A (1)	Endophytic fungus Chaetomium chiversii	[11]
	Chaetomium gracile	[10]
	Chaetomium microcephalum	[12]
	Chaetomium virenscens (C. thielavioideum)	[13]
Isochaetochromin A1 (2)	Penicillium sp. FK I-4942	[14,15]
Isochaetochromin A2 (3)	Chaetomium microcephalum	[12]
Chaetochromin B (4)	Chaetomium gracile	[6,10]
	Chaetomium microcephalum	[12]
Isochaetochromin B1 (5)	Endophytic fungus Fusarium sp.	[3]
	Penicillium sp. FKI-4942	[14]
Isochaetochromin B2 (6)	Endophytic fungus Fusarium sp.	[3]
	Sponge-derived fungus Metarhizium anisopliae	[16]
	Penicillium sp. FKI-4942	[14]
Oxychaetochromin B (7)	Endophytic fungus Fusarium sp.	[3]
Chaetochromin C (8)	Chaetomium gracile	[10]
Chaetochromin D (9)	Chaetomium gracile	[10]
Isochaetochromin D1 (10)	Endophytic fungus Fusarium sp.	[3]
Cephalochromin = Sch 45752 (11)	Cephalosporium sp.	[17]
	Cosmospora vilior YMJ89051501	[18]
	Nectria flavoviridis	[19]
	Nectria viridescens	[19]
	Endophytic fungus Pseudoanguillospora sp.	[20]
	Verticillium sp. K-113	[21]
	Unidentified fungal isolate SCF-125	[22]
Hypochromin A (12)	Marine-derived fungus Hypocrea vinosa	[23]
Hypochromin B (13)	Marine-derived fungus Hypocrea vinosa	[23]
SC2051 (14)	Marine-derived fungus Hypocrea vinosa	[23]
Ustilaginoidin A (15)	Villosiclava virens (Ustilaginoidea virens)	[24]
Isoustilaginoidin A (16)	Verticillium sp. K-113	[21]
Dihydroisoustilaginoidin A (17)	Verticillium sp. K-113	[21]
	Unidentified fungal isolate SCF-125	[22]
Ustilaginoidin B (18)	Villosiclava virens (Ustilaginoidea virens)	[25]
Ustilaginoidin C (19)	Villosiclava virens (Ustilaginoidea virens)	[25]
Ustilaginoidin D (20)	Sponge-derived fungus Metarhizium anisopliae	[16]
	Villosiclava virens (Ustilaginoidea virens)	[26]
Ustilaginoidin E (21)	Villosiclava virens (Ustilaginoidea virens)	[26]
Ustilaginoidin F (22)	Villosiclava virens (Ustilaginoidea virens)	[26]
Ustilaginoidin G (23)	Villosiclava virens (Ustilaginoidea virens)	[26]
Ustilaginoidin H (24)	Villosiclava virens (Ustilaginoidea virens)	[26]
Ustilaginoidin I (25)	Villosiclava virens (Ustilaginoidea virens)	[26]
Ustilaginoidin J (26)	Villosiclava virens (Ustilaginoidea virens)	[26]

Table 2

Occurrence of asperpyrone-type bis-naphtho-γ-pyrones 27–53 in fungi.

Bis-naphtho-γ-pyrone	Fungal Species	Reference
Asperpyrone A (27)	Endophytic fungus Aspergillus sp.	[34]
	Endophytic fungus Aspergillus sp. DCS31	[35]
	Aspergillus niger	[30]
	Endophytic fungus Aspergillus niger	[8]
	Endophytic fungus Aspergillus tubingensis	[36]
Asperpyrone B (28)	Aspergillus niger	[30]
	Aspergillus niger IFB-E003	[31]
	Aspergillus niger ATCC 11414	[33]
Asperpyrone C (29)	Aspergillus niger	[30]
Asperpyrone D (30)	Endophytic fungus Aspergillus sp. DCS31	[35]
	Endophytic fungus Aspergillus niger	[8]
	Endophytic fungus Aspergillus tubingensis	[36]
Asperpyrone E (31)	Endophytic fungus Aspergillus niger	[8]
Aurasperone A (32)	Alternaria alternata	[27]
	Aspergillus sp. FKI-3451	[4]
	Aspergillus awamori	[28,37]
	Endophytic fungus Aspergillus auleatus	[32]
	Aspergillus fonsecaeus	[29]
	Aspergillus niger	[28,37]
	Aspergillus niger	[38]
	Aspergillus niger	[30]
	Aspergillus niger IFB-E003	[31]
	Aspergillus niger ATCC 11414	[33]
	Endophytic fungus Aspergillus tubingensis	[36]
Isoaurasperone A (33)	Endophytic fungus Aspergillus sp.	[34]
	Aspergillus niger	[38]
	Endophytic fungus Aspergillus niger	[8]
Aurasperone B (34)	Alternaria alternata	[27]
	Aspergillus sp. FKI-3451	[4]
	Aspergillus awamori	[28,39]
	Aspergillus fonsecaeus	[29]
	Aspergillus niger	[28,39]
	Aspergillus niger	[38]
	Aspergillus niger ATCC 11414	[33]
	Aspergillus niger C-433	[40]
Aurasperone B (34)	Aspergillus niger ATCC 11414	[33]
	Aspergillus vadensis	[41]
Aurasperone C (35)	Alternaria alternata	[27]
	Aspergillus awamori	[28,39]
	Aspergillus niger	[28,39]
	Aspergillus niger	[38]
	Aspergillus niger C-433	[40]
	Aspergillus niger ATCC 11414	[33]
Dianhydro-aurasperone C (36)	Endophytic fungus Aspergillus sp.	[34]
	Aspergillus niger	[38]
	Endophytic fungus Aspergillus niger	[8]
	Endophytic fungus Aspergillus tubingensis	[36]
Aurasperone D (37)	Aspergillus niger	[42]
	Aspergillus niger	[38]
	Endophytic fungus Aspergillus niger	[8]
	Aspergillus niger C-433	[40]
Aurasperone E (38)	Aspergillus niger	[38]
	Aspergillus niger C-433	[40]
	Endophytic fungus Aspergillus tubingensis	[36]
Aurasperone F (39)	Alternaria alternata	[27]
	Aspergillus niger C-433	[40,43]
Isoaurasperone F (40)	Endophytic fungus Aspergillus niger	[8]
Aurasperone G (41)	Aspergillus niger C-433	[43]
Fonsecinone A (42)	Endophytic fungus Aspergillus sp.	[34]
	Endophytic fungus Aspergillus auleatus	[32]
	Aspergillus fonsecaeus	[29]
	Aspergillus niger	[30]
	Aspergillus niger IFB-E003	[31]
	Aspergillus niger ATCC 11414	[33]
	Endophytic fungus Aspergillus tubingensis	[36]
	Endophytic fungus Cladosporium herbarum IFB-E002	[44]
Fonsecinone B (43)	Aspergillus fonsecaeus	[29]
	Aspergillus niger ATCC 11414	[33]
Fonsecinone C (44)	Aspergillus fonsecaeus	[29]
	Aspergillus niger ATCC 11414	[33]
Fonsecinone D (45)	Aspergillus fonsecaeus	[29]
Nigerasperone B (46)	Aspergillus niger EN-13	[45]
Nigerasperone C (47)	Aspergillus niger EN-13	[45]
Rubasperone A (48)	Endophytic fungus Aspergillus tubingensis	[46]
Rubasperone B (49)	Endophytic fungus Aspergillus tubingensis	[46]
Rubasperone C (50)	Endophytic fungus Aspergillus tubingensis	[46]
Rubasperone D (51)	Endophytic fungus Aspergillus tubingensis (GX1-5E)	[47]
Rubasperone E (52)	Endophytic fungus Aspergillus tubingensis (GX1-5E)	[47]
Rubasperone F (53)	Endophytic fungus Aspergillus tubingensis (GX1-5E)	[47]

Table 3

Occurrence of nigerone-type bis-naphtho-γ-pyrones 54–59 in fungi.

Bis-naphtho-γ-pyrone	Fungal Species	Reference
10,10'-Bifonsecin B (54)	Marine-derived fungus Aspergillus carbonarius	[7]
Nigerone (55)	Marine-derived fungus Aspergillus carbonarius	[7]
	Aspergillus niger	[5]
6'-O-Demethylnigerone (56)	Marine-derived fungus Aspergillus carbonarius	[7]
	Aspergillus niger	[5]
8'-O-Demethylnigerone (57)	Marine-derived fungus Aspergillus carbonarius	[7]
8'-O-Demethylisonigerone (58)	Marine-derived fungus Aspergillus carbonarius	[7]
Isonigerone (59)	Marine-derived fungus Aspergillus carbonarius	[7]
	Aspergillus niger	[5]

Figure 1

Structures of chaetochromin-type bis-naphtho-γ-pyrones (1–26) from fungi.

Figure 2

Structures of asperpyrone-type bis-naphtho-γ-pyrones (27–53) from fungi.

Figure 3

Structures of nigerone-type bis-naphtho-γ-pyrones (54–59) from fungi.

To date, twenty-six chaetochromin-type bis-naphtho-γ-pyrones (Table 1 and Figure 1) with C-9-C-9' linkages have been isolated from the genera Chaetomium, Hypocrea, Nectria, Penicillium, Verticillium, and Villosiclava (Ustilaginoidea). The absolute configurations of ustilaginoidin A (15) and the congeners from Ustilaginoidea virens were proved to be R, and the congeners of chaetochromin A (1) from Chaetomium spp. were S [9]. Both isochaetochromins B1 (5) and B2 (6) from Fusarium sp., Penicillium sp. and Metarhizium anisopliae were considered as the diastereomers of chaetochromin B (4) [10].

Twenty-seven asperpyrone-type bis-naphtho-γ-pyrones (Table 2 and Figure 2) with C-10-C-7' or C-10-C-9' or C-6-C-7' or C-6-C-9' linkages have been isolated from the genera Alternaria and Aspergillus.

Aurasperone A (32) is a 10,7'-bisnaphtho-γ-pyrone from Alternaria alternata [27] and a few Aspergillus species [4,28,29,30,31,32,33]. This compound clearly has a positive Cotton effect first in the long wavelength region, and a negative one second at shorter wavelength, indicating positive chirality of the chromophores and the S-configuration of the compound [6]. The absolute configurations for some asperpyrone-type bis-naphtho-γ-pyrones remain to be determined.

Six nigerone-type bis-naphtho-γ-pyrones (54–59) with C-10-C-10' or C-10-C-6' linkages have been isolated from the genus Aspergillus [5,7]. All these bis-naphtho-γ-pyrones have R-configurations of the 10-10' or 10-6' bonds.

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].

3. Biosynthesis

Chaetochromin A (1) was the first bis-naphtho-γ-pyrone whose biosynthesis was studied by employing the fungus Chaetomium gracile. Both acetate and malonate were confirmed as the precursors in the biosynthesis of chaetochromin A (1) by employing Chaetomium gracile and addition of the carbon-13 labelled precussors [51]. The proposed biosynthetic pathway (Scheme 1) of asperpyrone-type bis-naphtho-γ-pyrones in the fungus Aspergillus niger was outlined by Chiang et al. [33]. The aromatic structure of naphtho-γ-pyrones suggests that a non-reducing polyketide synthase (NR-PKS) gene with the following domain organization is likely responsible for their biosynthesis: starter unit ACP transacylase (SAT), β-ketoacyl synthase (KS), acyl transferase (AT), product template (PT), acyl carrier protein (ACP), and thiolesterase/Claisen-cyclase (TE/CLC) [33]. Linear naphtho-γ-pyrone YWA1 (61) was known in equilibrium with the side-chain open form (60). After recyclization, angular naphtho-γ-pyrone 62 could be formed in the presence of C-14 phenol group (Scheme 1). The irreversible dehydration of hemiketal from aurasperone B (34) produced stable dimeric naphtho-γ-pyrones fonsecinone B (43) and aurasperone A (32). Table 4 shows some monomeric naphtho-γ-pyrones such as rubrofusarin B (65), fonsecin (67), fonsecin B (68) and flavasperone (72) which were considered as the intermediates in the biosynthesis of bis-naphtho-γ-pyrones in fungi [38]. Accordingly, the structures of these proposed intermediates are shown in Figure 4.

Scheme 1

Proposed biosynthetic pathway of asperpyrone-type bis-naphtho-γ-pyrones in Aspergillus niger [33].

Table 4

Some monomeric naphtho-γ-pyrones 63–76 from fungi.

	Monomeric Naphtho-γ-pyrone	Fungal Species	Reference
	Nigerasperone A (63)	Aspergillus niger EN-13	[45]
	Rubrofusarin (64)	Aspergillus niger	[38]
		Endophytic fungus Aspergillus tubingensis GX1-5E	[46]
	Rubrofusarin B = Heminigerone (65)	Alternaria alternata	[27]
		Endophytic fungus Aspergillus sp.	[34]
		Endophytic fungus Aspergillus niger IFB-E003	[31]
		Marine-derived fungus Aspergillus carbonarius	[7]
		Aspergillus niger var. niger TC 1629	[52]
		Endophytic fungus Aspergillus tubingensis GX1-5E	[46]
		Endophytic fungus Aspergillus tubingensis NRRC 4700	[36]
		Endophytic fungus Cladosporium herbarum IFB-E002	[44]
	Rubrofusarin-6-O-α-D-ribofuranoside (66)	Endophytic fungus Aspergillus niger	[8]
	Fonsecin (67)	Alternaria alternata	[27]
		Marine-derived fungus Aspergillus carbonarius	[7]
		Aspergillus niger	[38]
		Aspergillus niger C-433	[40]
		Aspergillus niger var.niger TC 1629	[52]
		Endophytic fungus Aspergillus tubingensis GX1-5E	[47]
		Endophytic fungus Aspergillus tubingensis NRRC 4700	[36]
	Fonsecin B = Fonsecin monomethyl ether (68)	Alternaria alternata	[27]
		Aspergillus niger	[38]
		Aspergillus niger var. niger TC 1629	[52]
		Endophytic fungus Aspergillus tubingensis NRRC 4700	[36]
	TMC-256A1 (69)	Marine-derived fungus Aspergillus carbonarius	[7]
		Aspergillus niger var. niger TC 1629	[52]
		Endophytic fungus Aspergillus tubingensis GX1-5E	[46]
		Endophytic fungus Aspergillus tubingensis NRRC 4700	[36]
	(R)-10-(3-succinimidyl)-TMC-256A1 (70)	Endophytic fungus Aspergillus niger	[8]
	TMC-256C1 (71)	Aspergillus niger var. niger TC 1629	[52]
	Flavasperone = Asperxanthon = TMC-256C2 (72)	Endophytic fungus Aspergillus sp. DCS31	[35]
		Aspergillus sp. FKI-3451	[4]
		Marine-derived fungus Aspergillus carbonarius	[7]
		Aspergillus niger	[38]
		Aspergillus niger var. niger TC 1629	[52]
		Endophytic fungus Aspergillus tubingensis	[47]
	Indigotide B (73)	Entomopathogenic fungus Cordyceps indigotica	[53]
		Sponge-derived fungus Metarhizium anisopliae mxh-99	[16]
	8-O-Methylindigotide B (74)	Entomopathogenic fungus Cordyceps indigotica	[53]
	Indigotide G (75)	Sponge-derived fungus Metarhizium anisopliae mxh-99	[16]
	Indigotide H (76)	Sponge-derived fungus Metarhizium anisopliae mxh-99	[16]

Figure 4

Structures of some monomeric naphtho-γ-pyrones 63–76 from fungi.

4. 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.

Table 5

Biological activities of bis-naphtho-γ-pyrones from fungi.

Bis-naphtho-γ-pyrone	Biological Activity	Reference
Chaetochromin A (1)	Cytotoxic and antitumor activity	[2,54,55]
	Teratogenicity to mice embryo	[59]
	Inhibitory effects on nitric oxide (NO) production by activated macrophages	[60]
	Antibacterial activity	[12]
	Immunological activity	[12]
	Inhibitory activity on botulinum neurotoxin serotype A	[58]
Isochaetochromin A1 (2)	Inhibitory activity on triacylglycerol synthesis	[14]
Isochaetochromin A2 (3)	Antibacterial activity	[12]
	Immunological activity	[12]
Chaetochromin B (4)	Cytotoxic and antitumor activity	[2,54]
	Antibacterial activity	[12]
	Immunological activity	[12]
Isochaetochromin B1 (5)	HIV-1 integrase inhibitory activity	[3]
	Inhibitory activity on triacylglycerol synthesis	[14]
Isochaetochromin B2 (6)	Anti-tubercular activity	[16]
	HIV-1 integrase inhibitory activity	[3]
	Inhibitory activity on triacylglycerol synthesis	[14]
Oxychaetochromin B (7)	HIV-1 integrase inhibitory activity	[3]
Chaetochromin C (8)	Cytotoxic and antitumor activity	[2,54]
Chaetochromin D (9)	Cytotoxic and antitumor activity	[2,54]
	Impairing effects on mitochondrial respiration and structure	[61]
Chaetochromin D1 (10)	HIV-1 integrase inhibitory activity	[3]
Cephalochromin (11)	Cytotoxic and antitumor activity	[18,55]
	Inhibitory effects on nitric oxide (NO) production by activated macrophages	[57]
	Antimicrobial activity	[21,57]
	Inhibitory activity on calmodulin-sensitive cyclic nucleotide phosphodiestease	[22]
	Inhibitory activity on botulinum neurotoxin serotype A	[58]
Hypochromin A (12)	Tyrosine kinase inhibitory activity	[23]
Hypochromin B (13)	Tyrosine kinase inhibitory activity	[23]
SC2051 (14)	Tyrosine kinase inhibitory activity	[23]
Ustilaginoidin A (15)	Cytotoxic and antitumor activity	[54,55]
Isoustilaginoidin A (16)	Antimicrobial activity	[21]
Dihydroisoustilaginoidin A (17)	Antimicrobial activity	[21]
	Inhibitory effects on nitric oxide (NO) production by activated macrophages	[62]
Ustilaginoidin D (20)	Cytotoxic and antitumor activity	[2]
	Anti-tubercular activity	[16]
Ustilaginoidin E (21)	Cytotoxic and antitumor activity	[2]
Asperpyrone A (27)	Antimicrobial activity	[34]
	Inhibitory activity on Taq DNA polymerase	[30]
Asperpyrone B (28)	Antimicrobial activity	[31]
Aurasperone A (32)	Antimicrobial activity	[31]
	Inhibitory activity on xanthine oxidase	[31]
	Inhibitory activity on acyl-CoA:cholesterol acyltransferase	[4]
	Inhibitory activity on Taq DNA polymerase	[30]
Isoaurasperone A (33)	Antimicrobial activity	[34]
Dianhydro-aurasperone C (36)	Antibacterial activity	[34]
	Drug resistance-reversing activity	[59]
Aurasperone D (37)	Central nervous system depressant effects	[42]
	Inhibitory activity on acyl-CoA:cholesterol acyltransferase	[4]
Fonscinone A (42)	Antimicrobial activity	[31,34]
	Inhibitory activity on Taq DNA polymerase	[30]
8'-O-Demethylnigerone (57)	Anti-tubercular activity	[7]
8'-O-Demethylisonigerone (58)	Anti-tubercular activity	[7]

4.1. Cytotoxic and Antitumor Activity

Chaetochromins A (1) and D (9) from Chaetomium sp. showed strong cytotoxicity with IC50 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 IC50 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].

4.2. Antimicrobial Activity

Isochaetochromin B2 (6) and ustilaginoidin D (20) isolated from the sponge-derived fungus Metarhizium anisopliae mxh-99 exhibited anti-tubercular activity with MIC values of 50.0 μg/mL [16]. 8'-O-Demethylnigerone (57) and 8'-O-demethylisonigerone (58) from the marine-derived Aspergillus carbonarius also showed weak anti-tubercular activity against Mycobacterium tuberculosis H37Rv with MIC values of 43.0 and 21.5 μM, respectively [7].

Cephalochromin (11), isoustilaginoidin A (16), and dihydroisoustilaginoidin A (17) isolated from Verticillium sp. K-113 were active against Gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus, and Streptococcus pyogenes) with MIC values ranging from 3 to 10 μg/mL, but not against Gram-negative bacteria and fungi [21]. Chaetochromin A (1), isochaetochromin A2 (3), and chaetochromin B (4) possessed significant antibacterial activity against Escherichia coli, Staphylococcus aureus and Bacillus subtilis [12]. Asperpyrone B (28), aurasperone A (32) and fonscinone A (42) isolated from the endophytic fungus Aspergillus niger IFB-E003 exhibited growth inhibition against bacteria (Bacilllus subtilis, Escherichia coli and Pseudomonas fluorescence) and fungi (Trichophyton rubrum and Candida albicans) with MIC values ranging from 1.9 to 31.2 μg/mL [31].

Asperpyrone A (27), isoaurasperone A (33), dianhydroaurasperone C (36), and fonsecinone A (42) from an endophytic Aspergillus species showed antimicrobial activities. Among them, fonsecinone A (42) exhibited the strongest antifungal and antibacterial activity, with MIC values of 12.5 and 25 μM, respectively [34].

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 IC50 values of 1.9 and 1.8 μM, respectively [57].

4.3. Other Biological Activities

In addition to the cytotoxic, antitumor and antimicrobial activities of bis-nathphtho-γ-pyrones mentioned above, other biological activities include tyrosine kinase inhibition [23], HIV-1 integrase inhibition [3], calmodulin-sensitive cycle nucleotide phosphodiestease inhibition [22], triacylglycerol synthesis inhibition [14], xanthine oxidase inhibition [31], acyl-CoA:cholesterol acyltransferase inhibition [4], central nerveous system depressant effects [42], immunological activity [12], botulinum neutotoxin serotype A inhibition [57], drug resistance-reversing activity [58], and Taq DNA polymerase inhibition [30], which are outlined in Table 5.

5. 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-γ-pyrones 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 B1 and B2), 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].