Enhanced Production and Anticancer Properties of Photoactivated Perylenequinones

Abstract

Hypocrellins and hypomycins are naturally occurring fungal perylenequinones with potential photodynamic activity against cancer and microbial diseases. This project pursued three lines of research. First, the production of perylenequinones was enhanced by investigating the effect of culture medium and light exposure on their biosynthesis. Solid-fermentation cultures on rice medium allowed for enhanced production of hypocrellins as compared to Cheerios or oatmeal medium. Alternatively, increased production of hypomycins, which are structurally related to the hypocrellins, was observed on oatmeal medium. In both cases, light exposure was an essential factor for the enhanced biosynthesis. In addition, this led to the discovery of two new perylenequinones, ent-shiraiachrome A (5) and hypomycin E (8), which were elucidated based on spectroscopic data. Finally, the photocytotoxic effects of both classes of compounds were evaluated against human skin melanoma, with EC 50 values at nanomolar levels for hypocrellins and micromolar levels for hypomycins. In contrast, both classes of compounds showed reduced dark toxicity (EC 50 values >100 μM), demonstrating promising phototherapeutic indices.

Phylogenetic Position of Shiraia-Like Endophytes on Bamboos and the Diverse Biosynthesis of Hypocrellin and Hypocrellin Derivatives

“…Other sources of perylenequinone production could be found. For example, strain MSX60519, isolated from dry leaf litter, was also found to produce hypocrellins [ 16 ], and Li et al [ 61 ] explored an endolichenic strain, Phaeosphaeria sp. 20081120, which could produce HA, HB and other perylenequinones.…”

“…The hypocrellin cluster consists of five main compounds—hypocrellin (1), hypocrellin A (2), hypocrellin B (3), shiraiachrome A (4), and hypocrellin D (5), and their structures are shown in Figure 1 . There is some confusion in the literature over the nomenclature of these compounds, and in this paper the names as defined by Al Subeh et al are followed [ 16 ]. Hypocrellin (1), hypocrellin A (2) and hypocrellin B (3) were first isolated from traditional Chinese medicinal products, which were called “Zhuhongjun” or “Zhuxiaorouzuojun” [ 1 , 17 , 18 , 19 ], and were identified as Hypocrella bambusae (Berk.…”

“…Shiraia -like endophytes associated with plants have been identified and shown to produce hypocrellins [ 16 , 26 , 27 , 28 , 29 ]. Based on phylogenetic analysis, these strains generally clustered in the family Shiraiaceae [ 25 , 26 ], but their explicit taxonomic status could not be established due to the lack of morphological characteristics.…”

Thielavins: tuned biosynthesis and LR-HSQMBC for structure elucidation

“…Recently, we evaluated the effect of different fermentation conditions, including varying both culture media and light exposure, on the biosynthesis of perylenequinones, specifically hypocrellins and hypomycins, by the fungus Shiraia -like sp. (strain MSX60519) [ 1 , 2 ]. We showed that the production of these fungal metabolites could be tuned based on media and light exposure.…”

“…We showed that the production of these fungal metabolites could be tuned based on media and light exposure. For instance, continuous LED exposure led to enhanced production of hypocrellins on rice medium vs hypomycins on oatmeal medium [ 1 ]. Previously, those classes of secondary metabolites had not been reported from the same fungus, and it was interesting to see how their biosynthesis could be modulated.…”