Natural Dibenzo-α-Pyrones and Their Bioactivities

Natural dibenzo-α-pyrones are an important group of metabolites derived from fungi, mycobionts, plants and animal feces. They exhibit a variety of biological activities such as toxicity on human and animals, phytotoxicity as well as cytotoxic, antioxidant, antiallergic, antimicrobial, antinematodal, and acetylcholinesterase inhibitory properties. Dibenzo-α-pyrones are biosynthesized via the polyketide pathway in microorganisms or metabolized from plant-derived ellagitannins and ellagic acid by intestinal bacteria. At least 53 dibenzo-α-pyrones have been reported in the past few decades. This mini-review aims to briefly summarize the occurrence, biosynthesis, biotransformation, as well as their biological activities and functions. Some considerations related to synthesis, production and applications of dibenzo-α-pyrones are also discussed.


Dibenzo-α-pyrones from Plants
The dibenzo-α-pyrones from plants are listed in Table 2. One dibenzo-α-pyrone, namely djalonensone (11), was isolated from the roots of Anthocleista djalonensis (Loganiaceae). The authors postulated djalonensone to be a significant taxonomic marker of the plant species [48]. However, djalonensone is identical to alternariol 9-methyl ether (AME) which has been isolated from a series of fungi including pathogenic and endophytic fungi [1]. Thus, the significance of djalonensone (11) as an important taxonomic marker of the plant species should be reconsidered. The possibility that djalonensone (11) was produced by an endophytic fungus residing in the healthy roots of A. djalonensis, needs further investigation [49].

Scheme 3.
Hypothetical biosynthetic pathways of alternariol (10) and its derivatives (11,14) in an endophytic fungus from Datura stramonium [25]. Urolithins include a family of metabolites of dibenzo-α-pyrone structures with different phenolic hydroxylation patterns. They are produced in different animals after the intake of ellagitannins and ellagic acid (EA) [71,72]. Ellagitannins are hydrolyzed to ellagic acid (55) in the acidic environment of the stomach by the action of the intestinal bacteria. The proposed transformation from ellagic acid to urolithins by the intestinal bacteria [6,7,63] is shown in Scheme 1.

Biological Activities and Functions
Dibenzo-α-pyrones and their derivatives with diverse chemical properties have been clarified (Figures 1-5, Tables 1 and 2). Some of them act as mycotoxins to humans and animals or as phytotoxins to plants. They have been examined to have a variety of biological activities and functions, which mainly include the cytotoxic, antioxidant, antiallergic, antimicrobial, antinematodal, and acetylcholinesterase inhibitory activities.

Toxicity on Human and Animals
The association of mycotoxins from Alternaria fungi with human and animal health is not a recent phenomenon. Alternaria toxins have been linked to a variety of adverse effects (i.e., genotoxic, mutagenic, and carcinogenic) on human and animal health [8]. Altenuene (1), alternariol (10), and alternariol 9-methyl ether (11) were studied for their toxicity to chickens. Addition of these compounds in chicken feed from sublethal to lethal levels progressively reduced feed efficiency, suppressed weight gain and increased internal haemorrhaging [27,73].

Cytotoxic Activity
Among Alternaria dibenzo-α-pyrones, alternariol (10) was the most active metabolite to have cytotoxic activity on L5178Y mouse lymphoma cells [9], as well as to have inhibitory activity on protein kinase and xanthine oxidase [28]. Further investigation showed that alternariol (10) was a topoisomerase I and II poison which might contribute to the impairment of DNA integrity in human colon carcinoma cells [73,76]. It induced cell death by activation of the mitochondrial pathway of apoptosis in human colon carcinoma cells [76]. Alternariol (10) and its 9-methyl ether (11) induced cytochrome P450 1A1 and apoptosis in murine heptatoma cells dependent on the aryl hydrocarbon receptor [77]. Other alternariol derivatives such as alternariol 9-methyl ether (11), alternariol 9-Osulfate (13), and altenusin (56) were also screened to be cytotoxic [9].
Dehydroaltenusin (17), isolated from A. tenuis, was found to be a specific inhibitor of eukaryotic DNA polymerase α to show its strong cytotoxic activity on tumor cells [45,78]. This compound also exhibited strong inhibitory activity on mammalian DNA polymerase α in vitro [79]. It was further proved to abrogate cell proliferation of the cultured mammalian cells to show its potential as an effective chemotherapeutic agent against tumors [44].
Urolithins derived from ellagic acid (55) were screened to have cytotoxic and anti-tumor activities. Urolithin A (40) inhibited cell growth of human colon cancer cell lines HT29 by inhibiting the canonical wnt signal pathway and interfere with β-catenin/TCF-dependent transcription [80], and inhibited growth of 22Rv1 prostate cancer cells by interfered with the expression of CYP1B1 protein [81]. Urolithin A (40), urolithin B (42), and 8-O-methylurolithin A (50) also showed antiproliferative effect on human bladder cancer T24 cells [82].

Antioxidant Activity
Urolithin A (40), isourolithin A (41), and urolithin B (42) from the fruits of Trapa natans showed antioxidant activity. Among them, isourolithin A (41) showed the strongest, and urolithin B (42) showed weak antioxidative effect [4]. As ellagic acid and ellagitannins are extremely poorly absorbed in gut, urolithins appear to be responsible for biological activities related to the intake of ellagitannins. Most of urolithins (i.e., urolithins A, C, and D) exhibited antioxidant activity in a cell-based assay [6]. However, there have been contradictory reports on their antioxidant capacity [62,87]. Recently, urolithins were revealed to display both antioxidant and pro-oxidant activities depending on assay system and conditions by using oxygen radical absorbance capacity (ORAC) assay, three cell-based assays, copper-initiated pro-oxidant activity (CIPA) assay, and cyclic voltammetry. Urolithins were screened to be the strong antioxidants in the ORAC assay, but mostly pro-oxidants in cell-based assays [88]. The antioxidant activity of urolithins is very likely mediated exclusively by the hydrogen atom transfer (HAT) mechanism. The hydrogen atom is donated by the phenolic hydroxyl group [88].
Both urolithins A (40) and B (42) from human feces exhibited estrogenic and antiestrogenic activities, which suggested that consumption of ellagitannin-containing foodstuffs such as pomegranate, walnuts, berries, and oak-aged wines may exert some proestrogenic/antiestrogenic effects [91].

Conclusions and Future Perspectives
We have just clarified one part of the dibenzo-α-pyrones from fungi, plants and bacteria. The remaining dibenzo-α-pyrones in bioorganisms need to be further identified. In recent years, more and more dibenzo-α-pyrones have been isolated from plant endophytic fungi. These endophytic fungi could be the rich sources of biologically active compounds that are indispensable for medicinal and agricultural applications [92,93]. In most cases, biological activities, structure-activity relationships, and modes of action of dibenzo-α-pyrones were only primarily investigated.
With comprehensive understanding of the biosynthetic pathways of some dibenzo-α-pyrones in the next few years, we may be able to effectively not only increase the yields of bioactive dibenzo-α-pyrones, but also block the biosynthesis of some toxic dibenzo-α-pyrones (i.e., phytotoxins and mycotoxins) [1].