An expedient approach to spot natural photosensitizers was established and with it were – for the first time – photosensitizers in mushrooms identified.

<p><a>Pigments of mushrooms are a fertile ground of inspiration: they spread across various chemical backbones, absorption ranges, and bioactivities. While looking from a photochemical perspective, we discovered a new bioactivity, i.e., photoactivity. We revealed that singlet oxygen production is a common theme in one group of webcaps (i.e., dermocyboid Cortinarii, formerly called Dermocybe). This photoactivity was explored by bioactivity-based molecular networking and photo-activity guided isolation. As a result, three photosensitizers based on anthraquinone structures were isolated. All three were photochemically characterized and (photo)cytotoxically tested. For one of the three, i.e. (-)-7,7’-biphyscion (<b>1</b>), a promising photoyield of </a>f_D= 20 % (l_exc = 455 nm) and an excellent photocytotoxicity of approx. 64 nM against A549 lung cancer cell lines (l_exc = 468 nm, 9.3 J/cm²) was found, while no effect was observed in the dark. Several molecular biological methods proved the harmlessness of <b>1</b> in the dark while showing that apoptosis is dose-dependent induced by <b>1</b> under irradiation. Therewith, <b>1</b> is a promising candidate for photodynamic therapy, while the photoactivity theme in the subgenus hints towards a yet unthought bioactivity in fungi: photoactivated defense.</p>

Pigments of fungi are a fertile ground of inspiration: they spread across various chemical backbones, absorption ranges, and bioactivities. However, basidiomycetes with strikingly colored fruiting bodies have never been explored as agents for photodynamic therapy (PDT), even though known photoactive compound classes (e.g., anthraquinones or alkaloids) are used as chemotaxonomic markers. In this study, we tested the hypothesis that the dyes of skin-heads (dermocyboid Cortinarii) can produce singlet oxygen under irradiation and thus are natural photosensitizers. Three photosensitizers based on anthraquinone structures were isolated and photopharmaceutical tests were conducted. For one of the three, i.e., (–)-7,7′-biphyscion (1), a promising photoyield and photocytotoxicity of EC50 = 0.064 µM against cancer cells (A549) was found under blue light irradiation (λexc = 468 nm, 9.3 J/cm2). The results of molecular biological methods, e.g., a viability assay and a cell cycle analysis, demonstrated the harmlessness of 1 in the dark and highlighted the apoptosis-inducing PDT potential under blue light irradiation. These results demonstrate for the first time that pigments of dermocyboid Cortinarii possess a so far undescribed activity, i.e., photoactivity, with significant potential for the field of PDT. The dimeric anthraquinone (–)-7,7′-biphyscion (1) was identified as a promising natural photosensitizer.

<p><a>Pigments of mushrooms are a fertile ground of inspiration: they spread across various chemical backbones, absorption ranges, and bioactivities. While looking from a photochemical perspective, we discovered a new bioactivity, i.e., photoactivity. We revealed that singlet oxygen production is a common theme in one group of webcaps (i.e., dermocyboid Cortinarii, formerly called Dermocybe). This photoactivity was explored by bioactivity-based molecular networking and photo-activity guided isolation. As a result, three photosensitizers based on anthraquinone structures were isolated. All three were photochemically characterized and (photo)cytotoxically tested. For one of the three, i.e. (-)-7,7’-biphyscion (<b>1</b>), a promising photoyield of </a>f_D= 20 % (l_exc = 455 nm) and an excellent photocytotoxicity of approx. 64 nM against A549 lung cancer cell lines (l_exc = 468 nm, 9.3 J/cm²) was found, while no effect was observed in the dark. Several molecular biological methods proved the harmlessness of <b>1</b> in the dark while showing that apoptosis is dose-dependent induced by <b>1</b> under irradiation. Therewith, <b>1</b> is a promising candidate for photodynamic therapy, while the photoactivity theme in the subgenus hints towards a yet unthought bioactivity in fungi: photoactivated defense.</p>