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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 EC 50  = 0.064 µM against cancer cells (A549) was found under blue light irradiation (λ exc  = 468 nm, 9.3 J/cm 2 ). 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., (© 2022. The Author(s).)

Photodynamic therapy (PDT) is an alternative approach for the treatment of neoplastic diseases employing photosensitizers activated by light. In order to discover new natural photosensitizers, a convenient workflow was established. To validate the workflow, fungi were selected, because we hypothesized that fruiting bodies and mycelia are an overlooked source. The results proved the hypothesis, as exorbitant high photo-cytotoxicity values were detected. For example, the acetone extract of Cortinarius croceus was characterized by an EC 50, 9.3 J cm -2 of 1 μg mL -1 against cells of a lung cancer cell-line (A549). In sum, a low-cost workflow for the detection and biological evaluation of photosensitizers is presented and discussed. Furthermore, this paper provides the first experimental evidence for phototoxic metabolites in basidiomycetes. This hints towards a new assignable function of fungal pigments, i.e. photochemical defense.