New Insights into Chemical and Biological Properties of Funicone-like Compounds.

Funicone-like compounds are a homogeneous group of polyketides that, so far, have only been reported as fungal secondary metabolites. In particular, species in the genus Talaromyces seem to be the most typical producers of this group of secondary metabolites. The molecular structure of funicone, the archetype of these products, is characterized by a γ-pyrone ring linked through a ketone group to a α-resorcylic acid nucleus. This review provides an update on the current knowledge on the chemistry of funicone-like compounds, with special emphasis on their classification, occurrence, and diverse biological activities. In addition, their potential relevance as mycotoxins is discussed.

1. Introduction

Research on fungal secondary metabolites is mainly driven by remarks concerning their bioactive properties, which can either be inherent to their role in biocenotic interrelations or their effects on human health, the latter depending on either their possible accumulation in foodstuffs as mycotoxins, or eventual pharmaceutical relevance.

Funicones and structurally related compounds represent a homogeneous group of fungal polyketides that were initially characterized as determinants of the antagonistic abilities by the producers against other microorganisms, but were later found to possess remarkable biological properties that have promoted their consideration as drug prospects. Considering that these properties are partly based on observations concerning cytostatic and antiproliferative effects on human cells, these products should be also evaluated with reference to toxicological aspects related to possible contamination of foodstuffs by the producing fungi.

In light of the novel knowledge developed in over a decade since the publication of a previous review [1], this paper offers an update on the state of the art concerning occurrence, bioactivities, structural, synthetic, and biosynthetic aspects of funicone-like compounds.

2. Structures and Chemical Properties

Funicone-like compounds include natural products characterized by a molecular structure that is built on a γ-pyrone ring linked through a ketone group to a α-resorcylic acid nucleus. A total of 34 chemically defined compounds, which are referable to this basic structural model, have been identified and characterized so far. Among them, 13 can be considered true funicones because the typical moieties are present without alterations. The other compounds, showing modifications on the α-resorcylic acid nucleus, on the γ-pyrone ring, or on both moieties, are grouped in three subclasses, namely phthalide, furopyrone, and pyridone types, depending on peculiar substructural variations (Table 1).

Table 1

List of funicone-like compounds gathered from the literature.

Code	Name	Formula	Nominal Mass (U)	Source
True Funicones
1	Funicone	C19H18O8	374	[2,3,4,5,6,7,8]
2	Actofunicone	C21H22O9	418	[9]
3	Deoxyfunicone	C19H18O7	358	[5,7,9,10,11,12,13,14]
4	9,14-Epoxy-11-deoxyfunicone	C19H18O8	374	[4]
5	9R,14S-Epoxy-11-deoxyfunicone	C19H18O8	374	[14]
6	9S,14R-Epoxy-11-deoxyfunicone	C19H18O8	374	[14]
7	3-O-Methyl-5,6-epoxyfunicone	C20H20O9	404	[15]
8	6-Hydroxyl-deoxyfunicone	C19H18O8	374	[8]
9	Isofunicone	C19H18O8	374	[16]
10	3-O-Methylfunicone	C20H20O8	388	[5,7,17,18,19,20,21,22,23,24,25,26]
11	Rapicone	C17H16O7	332	[27]
12	Pinophilone A	C19H18O8	374	[28]
13	Pinophilone B	C19H18O8	374	[28]
Furopyrone type
14	Penifupyrone	C19H18O8	374	[5,17,18]
Phthalide type
15	Vermistatin (=fijiensin)	C18H16O6	328	[3,4,6,7,9,12,20,21,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48]
16	Acetoxydihydrovermistatin	C20H20O8	388	[6,33]
17	6-Demethylvermistatin	C17H14O6	314	[8,21,28,40,49]
18	14,15-Dihydrovermistatin	C18H18O6	330	[6,8,12,28,33,36,38,41,44,45,46]
19	2″-epihydroxydihydrovermistatin	C18H18O7	346	[21,28]
20	Hydroxydihydrovermistatin	C18H18O7	346	[6,33]
21	Hydroxyvermistatin	C18H16O7	344	[7,21,28,34]
22	5′-O-methyldihydrovermistatin	C19H20O7	360	[28]
23	Methoxyvermistatin	C19H18O7	358	[6,7,21,28,34,40,42,50]
24	Neosarphenol A	C18H16O6	344	[40]
25	Penisimplicissin	C16H14O6	302	[3,6,20,21,28,33,44,45]
26	6-Demethylpenisimplicissin	C15H12O6	288	[21,28]
27	5′-Hydroxypenisimplicissin	C16H14O7	318	[21]
28	Pinophilone C	C17H16O6	316	[28]
29	Pinophilone D	C18H18O7	346	[28]
Pyridone type
30	Penicidone A	C18H17NO5	327	[51]
31	Penicidone B	C17H15NO5	313	[51]
32	Penicidone C	C19H19NO6	357	[18,21,28,51]
33	Penicidone D	C20H21NO7	387	[17,18,28]
34	Talarodone A	C20H23NO8	405	[18]

2.1. True Funicones

In temporal terms, funicone [benzoic acid, 2-[[5-hydroxy-4-oxo-6-(1E)-1-propenyl-4H-pyran-3-yl]carbonyl]-3,5-dimethoxy, methyl ester] (1) is the founder of this group of compounds, originally characterized from a culture of Penicillium funiculosum [2]. Subsequently, a structural isomer, namely isofunicone (9) [16], and several derivatives, which differ from the parent compound by few substitutions, were identified (Figure 1). This subclass also includes some epoxide derivatives (4–7) on the γ-pyrone ring, two of them (5,6) isolated from co-cultures of a strain of Penicillium sp. with the actinomycete Streptomyces fradiae [14]. Pinophilones A and B (12 and 13) are the only funicone-like compounds presenting a dihydrofuran fragment obtained from the cyclization of the hydroxyl group on the γ-pyrone ring and the double bond on the propenyl chain [28].

Figure 1

Structures of true funicones (1–13): funicone, actofunicone, deoxyfunicone, 9,14-epoxy-11-deoxyfunicone, 9R,14S-epoxy-11-deoxyfunicone, 9S,14R-epoxy-11-deoxyfunicone, 3-O-methyl-5,6-epoxyfunicone, 6-hydroxyl-deoxyfunicone, isofunicone, 3-O-methylfunicone, rapicone, pinophilone A, and pinophilone B.

The rising interest of the scientific community in these substances has led to the development of approaches for their synthesis. In particular, deoxyfunicone (3), 3-O-methylfunicone (10) [52], and rapicone (11) [53] were efficiently prepared by carbonylative Stille cross-coupling reactions between methyl 2-iodo-3,5-dimethoxybenzoate and functionalized γ-pyrone (Figure 2). 5-Stannane derivatives were prepared starting from commercially available kojic acid in four steps [52,53].

Figure 2

General procedures for synthesis of funicones.

2.2. Furopyrone Type

Penifupyrone (14) is the only member of the furopyrone type carrying a 5H-furo[3,2-b]pyran-7(6H)-one moiety instead of a γ-pyrone ring (Figure 3). It was isolated for the first time from an endophytic strain of Talaromyces sp., along with funicone, deoxyfunicone, and 3-O-methylfunicone [5].

Figure 3

Structure of penifupyrone (14).

2.3. Phthalide Type

The molecular structure of compounds in this subclass includes a 4,6-dimethoxyphthalide moiety (Figure 4). Vermistatin (15) is the reference compound of this group, deriving its name from a strain of Talaromyces flavus identified in anamorphic-stage Penicillium vermiculatum [47]. This metabolite was later isolated as a product of Pseudocercospora (=Mycosphaerella) fijiensis and wrongly reported as a new compound with the name fijiensin [30]. This is not surprising because the attribution of different names to the same chemical structure represents a recurring nomenclatural issue in natural product research [54].

Figure 4

Structures of compounds from the phthalide type (15–29): vermistatin, acetoxydihydrovermistatin, 6-demethylvermistatin, 14,15-dihydrovermistatin, 2″-epihydroxydihydrovermistatin, hydroxydihydrovermistatin, hydroxyvermistatin, 5′-O-methyldihydrovermistatin, methoxyvermistatin, neosarphenol A, penisimplicissin, 6-demethylpenisimplicissin, 5′-hydroxypenisimplicissin, pinophilone C, and pinophilone D.

Based on the currently available data, vermistatin represents the most frequent funicone-like compound, having been extracted as a product of at least 15 species. It is frequently extracted along with some derivatives, such as hydroxy- (21) and methoxyvermistatin (22), 6-demethylvermistatin (17), 14,15-dihydrovermistatin (18), hydroxy- (20) and acetoxy-dihydrovermistatin (16), and penisimplicissin (25) [6,7,21,28,33,34,45,49].

Neosarphenol (24) is an isomer of hydroxyvermistatin, which was named on the basis of the producing fungus, Neosartorya glabra (currently reclassified as Aspergillus neoglaber), rather than with reference to its chemical structure [40].

2.4. Pyridone Type

This series includes compounds containing a γ-pyridone moiety. The molecular structures of penicidone A and B (30,31) are characterized by the presence of an α-resorcylic acid moiety linked through a ketone group to a γ-pyridone, whereas penicidone C, D and talarodone A (32–34) contain the typical 4,6-dimethoxyphthalide moiety of vermistatin replacing the α-resorcylic acid nucleus (Figure 5). Nevertheless, Murakami et al. [18] represented penicidone D (33) in γ-pyridol form, instead of γ-pyridone form.

Figure 5

Structures of compounds from the pyridone type (30–34): penicidone A–D and talarodone A.

3. Fungal Sources

The data summarized in Table 2 show that the fungi reported as funicone producers have been recovered from various substrates, often in association with plants or other organisms, and in diverse environments, both terrestrial and marine. They are also quite heterogeneous in taxonomic terms, as they belong to two Ascomycetes classes: the Dothideomycetes and Eurotiomycetes. Members in the first class are sparse, being ascribed to five orders, with each of them represented by a single strain. Even considering the approximate taxonomic identification of three strains, which were only identified at the genus level, it is clear that funicone biosynthetic aptitudes occur among Dothideomycetes, and might be more widespread than currently known. Conversely, the Eurotiomycetes look to be much more abiding producers and taxonomically homogeneous, with about 31 strains belonging to three genera in two families. Again, some uncertainty in identification is to be noted, deriving from the absence of adequate support by sequencing of valid DNA markers, and by the provisional ascription to Penicillium sp. of some strains prior to the formal separation of the biverticillate Penicillium species and their assignment to the genus Talaromyces [55]. In this respect, the identification of strain IFM53375 as Penicillium simplicissimum was considered unreliable by leading taxonomists of these fungi based on a secondary metabolite profile more respondent to Talaromyces [55]. In another case, the producing strain (AF1-2) was not identified at all [26]; however, the image provided by the authors showing its bright yellow mycelium and the overlying green sporulation in culture on agar medium unequivocally allows its ascription to Talaromyces. In any case, species in the genus Talaromyces are the most typical producers of funicone-like compounds; with reference to the recent affirmation of the horizontal gene transfer concept [56,57], it cannot be excluded that the other fungal species may have occasionally acquired their funicone-biosynthetic abilities through this intriguing biological mechanism.

Table 2

Fungal species/strains reported as producers of funicone-like compounds.

Species	Source/Lifestyle/Substrate	Location	Compounds	Ref.
Dothideomycetes, Pleosporales, Didymellaceae
Phoma sp. nov. LG0217	Endophytic in Parkinsonia microphylla	Tucson(Arizona, USA)	15, 18	[36]
Dothideomycetes, Botryosphaeriales, Phyllostictaceae
Guignardia sp. No. 4382	Endophytic in Kandelia candel	Hong Kong (China)	17	[49]
Dothideomycetes, Mycosphaerellales, Mycosphaerellaceae
Pseudocercospora (=Mycosphaerella) fijiensis	Banana plant	Honduras	15	[30]
Dothideomycetes, Capnodiales, Dissoconaceae
Ramichloridium apiculatum NHL2956	Air in bakery	Nagoya (Japan)	11	[27]
Dothideomycetes, Cladosporiales, Cladosporiaceae
Cladosporium sp. JS1-2	endophytic in Ceriops tagal	Hainan (China)	15	[35]
Eurotiomycetes, Eurotiales, Aspergillaceae
Aspergillus neoglaber (identified as Neosartorya glabra) CGMCC 32286	Unknown	China	24	[40]
Aspergillus ruber(identified as Eurotium rubrum) SH-823	Soft coral (Sarcophyton sp.)	Xuwen (China)	15, 23	[42]
Penicillium citreonigrum PAI 1/1 C	Sponge(Pseudoceratina purpurea)	Bali (Indonesia)	3, 15, 18	[12]
Penicillium glabrum SF-7123	Sediment	Ross Sea(Antarctica)	3	[13]
Penicillium simplicissimum IFM53375	Unknown	Japan	1, 15, 16, 18, 20, 25	[6]
Penicillium sp.	Endophytic in Riccardia multifida	Maoer Mountain (China)	8, 17, 1	[8]
Penicillium sp.	Unknown	Japan	3	[10]
Penicillium sp.	Unknown	Japan	9	[16]
Penicillium sp.	Ash	Mount Pinotubo (Philippines)	3	[11]
Eurotiomycetes, Eurotiales, Trichocomaceae
Talaromyces flavus			15	[29]
Talaromyces flavus CCM-F748		Slovakia	15	[47]
Talaromyces flavus FKI-0076	Soil	Hiroo (Japan)	2, 3, 15	[9]
Talaromyces flavus IFM52668	Unknown	Japan	1, 4, 15	[4]
Talaromyces pinophilus F36CF	Endophytic in Arbutus unedo	Favignana Isle(Italy)	10	[58]
Talaromyces pinophilus H608	Mangrove sediment	Xiamen (China)	1, 3, 10, 15, 21, 23	[7]
Talaromyces sp. IPV2 (identified as Penicillium funiculosum)	Apple root	Sondrio Province (Italy)	1	[2,59]
Talaromyces pinophilus LT4, LT6	Soil from rhizosphere of Nicotiana tabacum	Lecce Province(Italy)	7, 10	[15,19]
Talaromyces pinophilus SCAU037	Soil from rhizosphere of Rhizophora stylosa	Techeng Isle (China)	10, 12, 13, 15, 17, 18, 19, 21, 22, 23, 25, 26, 28, 29, 32, 33	[28]
Talaromyces pinophilus ST2	Soil from rhizosphere of Nicotiana tabacum	Scafati (Italy)	10	[25]
Talaromyces purpureogenus MHZ 111	Soil	Mohe (China)	15, 18	[46]
Talaromyces ruber (identified as Penicillium rubrum)	Water	Berkeley Pit lake (USA)	15, 18, 25	[45]
Talaromyces sp. ZHS32	Marine sediment	Zhejiang (China)	15	[39]
Talaromyces sp. AF1-2(unidentified in original report)	Salt pan	Australia	10	[26]
Talaromyces sp. HM6-1-1	Seawater	Dongshan Isle (China)	15, 18	[38]
Talaromyces sp. HN29-3B1(identified as Penicillium sp.)	Endophytic in Cerbera manghas	Hainan (China)	15, 17, 19, 21 23, 25, 26, 27	[21]
Talaromyces sp. HSZ-43(identified as Penicillium sp.)	Endophytic in Trypterigium wilfordii	Shanxi (China)	1, 3, 10, 14	[5]
Talaromyces sp. IFB-E022(identified as Penicillium sp.)	Endophytic in Quercus variabilis	Zijin Mountain (China)	30, 31, 32	[51]
Talaromyces sp. XWS02F62(identified as Penicillium sp.)	Sponge (Callyspongia sp.)	Xuwen County (China)	15, 18	[41]
Talaromyces thailandiasis KPFC 3399	Soil	Thailand	15, 20, 25	[33]
Talaromyces verruculosus CMI294548	Unknown	Pakistan	15	[31]

Recently, some independent studies have reported that production of funicone-like compounds may occur in co-cultures of various microbial strains (Table 3). Again, the Eurotiomycetes are more represented in these few studies, and can be thought to provide the genetic base for biosynthesis, which is eventually stimulated by the co-cultured strain in the course of an antibiotic struggle, as clearly demonstrated in the case of the pairing between Talaromyces siamensis and Phomopsis sp. (Sordariomycetes, Diaporthaceae) [43]. In two cases, the partner microbe was represented by Streptomyces strains (Actinomycetota), which are well-known for their capacity to modulate the metabolic potential of fungi [60].

Table 3

Microbial species/strains reported as producers of funicone-like compounds in co-cultures.

Species 1	Species 2	Source/Substrate	Location	Compounds	Ref.
Alternaria alternataYX-25	Streptomyces exfoliatusYX-32	mangrove mud	Yunxiao (China)	15	[37]
Penicillium sp.WC-29-5	Streptomyces fradiae007	rhizosphere of Aegiceras corniculatum/sediment	Hainan (China)Jiaozhou Bay (China)	3, 5, 6, 15	[14]
Talaromyces pinophilus17F4103	Paraphaeosphaeria sp.17F4110	soil	Miyazaki (Japan)	10, 14, 32, 33, 34	[18]
Talaromyces siamensisFKA-61	Phomopsis sp.FKA-62	soil	Japan	15	[43]

4. Biosynthesis

The potential biosynthetic pathways of funicone-like compounds have been investigated by two independent research groups [21,28]. Figure 6 shows a possible scheme for each type of compound proposed in the previous section. Funicone-like compounds are epta and octaketides, originating from units of acetate-mevalonate. The main structural differences can be caused by the folding of the eptaketidic and octaketidic chains, which produce structures with a methyl or a propenyl group, respectively, on the γ-pyrone ring. The presence of an amino group in compounds belonging to the pyridone type suggests a possible transamination process during the biosynthesis of γ-pyridone. The origin of the phthalide type can be attributed to the lactonization of the carboxylic group in the α-resorcylic ring, with the hydroxyl group produced through the reduction of the exocyclic ketone group.

Figure 6

Proposed biosynthetic schemes of funicone-like compounds.

Subsequent functional modifications (e.g., reduction, epoxydation, hydroxylation, methylation, and acetylation) are responsible for the ample structural variability observed in the group of funicone-like compounds.

5. Bioactivities

As previously introduced, the biological activity of funicones was initially evaluated with reference to antibiotic properties, generally evidencing poor effects against bacteria and yeasts, and more relevant activities against filamentous fungi. Subsequent investigations on antiproliferative properties against human cells line have become prevalent, underlining the potential of these compounds as antitumor drugs. Additional data have been gathered on the antiviral and the insecticidal properties, and the inhibitory effects toward several enzymes; moreover, some minor bioactivities have been described. The outcomes of this wide-ranging investigational work, as assessed in quantitative terms, are summarized in Table 4.

Table 4

Main bioactivities of funicone-like compounds.

Name (Code)	Bioactivity	Concentration	Bioassay	Ref.
Actofunicone (2)	Reinforcement of miconazole	3.7 µM	Candida albicans (IC50)	[9]
6-Demethylpenisimplicissin (26)	Enzyme inhibitory	9.5 µM	α-glucosidase (IC50)	[21]
Deoxyfunicone (3)	Anticholesterol	10 µM	Efflux from RAW264.7	[7]
	Antiviral	4.6 µM	HCV (IC50 on Huh-7.5.1)	[61]
	Cytotoxic	22.6 µM	KB (IC50)	[5]
	Enzyme inhibitory	24.3 µM	Protein tyrosine phosphate 1B (IC50)	[13]
		1.1–4.4 µM	HIV-1-integrase (IC50)	[11]
	Lipid inhibitory	10 µM	Accumulation in HepG2	[7]
			Downregulation of FAS, ACC, HMGR
			Decrease in oxLDL in RAW264.7
	NO inhibitory	10.6 µM40.1 µM	LPS-stimulated BV2 (IC50)LPS-stimulated RAW264.7 (IC50)	[13]
	PGE2 inhibitory	32.3 µM	LPS-stimulated BV2 (IC50)	[13]
	Reinforcement of miconazole	1.6 µM	C. albicans (IC50)	[9]
2″-epiHydroxydihydrovermistatin (19)	Enzyme inhibitory	8 µM	α-glucosidase (IC50)	[21]
9,14-Epoxy-11-deoxyfunicone (4)	Antifungal	0.53 µmol/disc	Aspergillus niger	[4]
9R,14S-Epoxy-11-deoxyfunicone (5)	Cytotoxic	3.97 µM	H1975 (IC50)	[14]
9S,14R-Epoxy-11-deoxyfunicone (6)	Cytotoxic	3.73 µM5.73 µM	HL-60 (IC50)H1975 (IC50)	[14]
Funicone (1)	Anticholesterol	10 µM	Efflux from RAW264.7	[7]
	Antifungal	0.27 µmol/disc	Aspergillus fumigatus	[4]
	Cytotoxic	13.2 µM	KB (IC50)	[5]
	Lipid inhibitory	10 µM	Accumulation in HepG2	[7]
			Downregulation of FAS, ACC, HMGR
Isofunicone (9)	Pollen growth inhibitory	8.02 mM	Camellia sinensis (84%)	[16]
Hydroxyvermistatin (21)	Anticholesterol	10 µM	Efflux from RAW264.7	[7]
			Upregulation of PPARγ, LXRα, ABCG1
			Decrease scavenger receptors CD36, SR-1
	Enzyme inhibitory	20.3 µM	α-glucosidase (IC50)	[21]
	Lipid inhibitory	10 µM	Accumulation in HepG2	[7]
			Decrease in FAS, ACC, HMGR
			Decrease in oxLDL in RAW264.7
Methoxyvermistatin (23)	Anticholesterol	10 µM	Decrease scavenger receptors CD36, SR-1	[7]
	Cytotoxic	0.056 mM0.042 mM	KB (IC50)KBv200 (IC50)	[34]
	Enzymatic inhibitory	236 µM	α-glucosidase (IC50)	[42]
	Lipid inhibitory	10 µM	Decrease in oxLDL in RAW264.7	[7]
3-O-Methylfunicone (10)	Anticholesterol	10 µM	Efflux from RAW264.7	[7]
	Antifungal	0.27 mM	Rhizoctonia solani, Fusarium solani,Cylindrocladium scoparium, Alternaria alternata (IC100)	[19]
	Antiviral	5 µM	decreased mortality of MDBK infected by BoHV-1	[62]
		6.2 µM	HCV (IC50 on Huh-7.5.1)	[61]
	Cytotoxic/antiproliferative/proapoptotic	35.3 µM	KB (IC50)	[5]
		10 µM	MDBK (IC50)	[62]
		63.8 µM63.3 µM	HCT116 (LD50)HeLa (LD50)	[26]
		0.16 mM	HEp-2; inhibition colony formation, decrease neutral red uptake, inhibition O2 consumption (IC50)	[24]
		0.07 mM	HeLa (44%); promotion p21; downregulation cyclin D1/Cdk4 complex	[63]
		0.21 mM	MCF-7; downregulates αvβ5 integrin, MMP-9 inhibitor, impairs microtubule assemblage, inhibitor of survivin, hTERT and Nanog-1 expression, reduces mammospheres	[64,65]
		0.21 mM	A375M (IC85, 48 h)	[66]
		0.14 mM	NCI-H2452; decreases αvβ5 integrin, MMP-2, VEGF, ERK1/2; synergism with cisplatin	[67,68]
	Enzyme Inhibitory	12.5 µM50.1 µM34.3 µM	DNA polymerase κDNA polymerase ηDNA polymerase ι	[26]
		5 mM	DNA polymerase κ and η	[52]
	Insecticidal	0.14 mM	Acyrthosiphon pisum (26.2%)	[23]
	Lipid inhibitory	10 µM	Accumulation in HepG2	[7]
			Decrease in FAS, ACC, HMGR
			Decrease in oxLDL in RAW264.7
Penicidone A (30)	Cytotoxic	60.1 µM54 µM46.5 µM41.5 µM	SW116 (IC50)K562 (IC50)KB (IC50)HeLa (IC50)	[51]
Penicidone B (31)	Cytotoxic	54.2 µM21.1 µM29.6 µM35.1 µM	SW116 (IC50)K562 (IC50)KB (IC50)HeLa (IC50)	[51]
Penicidone C (32)	Cytotoxic	80.8 µM54.3 µM44.3 µM54.7 µM	SW116 (IC50)K562 (IC50)KB (IC50)HeLa (IC50)	[51]
	Enzyme inhibitory	51.9 µM	α-glucosidase (IC50)	[28]
Penifupyrone (14)	Cytotoxic	4.7 µM	KB (IC50)	[5]
Penisimplicissin (25)	Cytotoxic	−6.70−5.83	CCRF-CEM (log10 GI50)HL-60 (log10 GI50)	[45]
	Enzyme inhibitory	0.66 mM0.33 mM	IL-1β (IC100)caspase 1 (IC100)	[44]
Rapicone (11)	Enzyme inhibitory	5 mM	DNA polymerase κ	[52]
Vermistatin (15)	Antibacterial	0.076 mM	Staphylococcus aureus, Bacillus cereus (MIC)	[35]
	Anticholesterol	10 µM	Efflux from RAW264.7	[7]
			Decrease scavenger receptors CD36, SR-1
	Cytotoxic	0.28 mM	KB (IC50)	[34]
		33.9 µM	B16 (IC50)	[39]
	Enzyme inhibitory	29.2 µM	α-glucosidase (IC50)	[21]
		107.1 µM	α-glucosidase (IC50)	[42]
	Insecticidal	0.46 mM	Helicoverpa armigera (IC50)	[35]
	Lipid inhibitory	10 µM	accumulation in HepG2	[7]
			Decrease in FAS, ACC, HMGR
			Decrease in oxLDL in RAW264.7
	NO inhibitory	52.7 µM	LPS-stimulated BV2 (IC50)	[46]
	Phytotoxic	3.1–6.1 mM	Banana leaves	[30]
	Reinforcement of miconazole	2.1 µM	C. albicans (IC50)	[9]

6. Potential Role of Funicone-like Compounds as Mycotoxins

The applicative aspects of studies concerning fungal bioactive secondary metabolites involve their accumulation in food products and ensuing possible impact on consumers’ health. Within the multitude of such compounds described so far, a very small number have been considered mycotoxins, based on the results of toxicological studies that noted their noxious effects on humans and animals [69]. This implies that a high number of compounds yet to be examined for these aspects may represent a potentially underestimated concern [70,71].

Funicones are one of the classes of fungal secondary metabolites for which very limited assessments have been carried out in this regard so far. Most of the producing species are not established pathogens of crops, with the exception of Pseudocercospora (=Mycosphaerella) fijiensis, a vermistatin producer that is known as the agent of black sigatoka disease of banana [72]. However, this is a leaf pathogen that is not known to spread to fruit, implying that it is unlikely that bananas can be contaminated with vermistatin. Nevertheless, a search for this compound in some fruit products carried out in Nigeria evidenced its presence at low levels (0.30 µg kg−1) in pineapple and mixed juices [73]. This is not at all surprising, as several Talaromyces spp. are commonly found in association with both healthy and diseased pineapples, including T. purpureogenus, T. funiculosus, and T. flavus, which may even survive pasteurization [74,75,76,77]. Conversely, a preliminary search carried out in Italy on marketed pineapple juices yielded negative results with reference to the eventual presence of 3-O-methylfunicone [78]. Recently, vermistatin was also detected in the analysis of grains used as cattle and poultry feed in Kenya [79], indicating that it may also occur as a cereal contaminant. Moreover, the finding of vermistatin as a product in co-cultures of strains of Alternaria alternata and Streptomyces exfoliatus [37] deserves to be further investigated, particularly in view of verifying the biosynthetic capacities by the first species. It is known as a pathogen of many crops and a saprophyte able to proliferate in several kinds of foodstuffs, with very important implications as a mycotoxin producer [80].

Considering the widespread endophytic occurrence of Talaromyces spp. [23,81], which are the dominant producers of funicones, the possible release of these compounds in plant products may arise during the postharvest phase, where the biosynthetic aptitudes can be boosted along with the saprophytic development. Recent reports of these fungi as postharvest pathogens concern T. albobiverticillius on pomegranate [82], T. rugulosus on grapes [83], T. minioluteus on onion bulbs and quince, orange, and tomato fruit [84], and both of the latter two species on pears [85]. Although none of these species are known to produce funicones, it is quite possible that other Talaromyces spp. producers of these compounds may affect fruit and other crop products, likewise documented for pineapple. This conclusion is supported by the finding of T. funiculosus as an agent of fruit core rot of peach [86].

Among the other funicone sources, Ramichloridium apiculatum, generally recorded as a soil saprophyte and only known as a producer of rapicone [27], was reported as an agent of sooty blotch and flyspeck of apples and pears in China [87], which may represent an indication for possible contamination of these fruits and their derived transformation products.

7. Conclusions

The present review provides an update on the recent developments concerning the distribution, chemical diversity, bioactivity and implications of occurrence of funicone-like compounds. The structures and properties of 34 funicone-like compounds extracted from different fungal species were reviewed. In particular, species in the genus Talaromyces seem to be the most typical producers of this group of secondary metabolites, soliciting consideration in view of possible chemotaxonomic implications.

In addition to outlining the general anti-inflammatory, antifungal, antiviral, and cytotoxic activities of these compounds, the available data indicate vermistatin as the most credited candidate to be added to the list of mycotoxins currently considered as food contaminants, with reference to its more common occurrence amongst the known funicone producers. The majority of these taxonomically heterogeneous fungi can perform its biosynthesis, implying that its presence in crop products may be more than just occasional. Whether this represents a threat or, conversely, can eventually be beneficial to consumers’ health based on the described bioactivities, deserves thorough further assessments.