Traditionally, ultraviolet light (100–400 nm) is considered an exogenous carcinogen while visible light (400–780 nm) is deemed harmless. In this work, a LED irradiation system forin vitrophotocytotoxicity testing is described. The LED irradiation system was developed for testing photopharmaceutical drugs, but was used here to determine the basal level response of human cancer cell lines to visible light of different wavelengths, without any photo(chemo)therapeutic. The effects of blue (455 nm, 10.5 mW cm⁻²), green (520 nm, 20.9 mW cm⁻²), and red light (630 nm, 34.4 mW cm⁻²) irradiation was measured for A375 (human malignant melanoma), A431 (human epidermoid carcinoma), A549 (human lung carcinoma), MCF7 (human mammary gland adenocarcinoma), MDA-MB-231 (human mammary gland adenocarcinoma), and U-87 MG (human glioblastoma-grade IV) cell lines. In response to a blue light dose of 19 J cm⁻², three cell lines exhibited a minimal (20%, MDA-MB-231) to moderate (30%, A549 and 60%, A375) reduction in cell viability, compared to dark controls. The other cell lines were not affected. Effective blue light doses that produce a therapeutic response in 50% of the cell population (ED₅₀) compared to dark conditions were found to be 10.9 and 30.5 J cm⁻²for A375 and A549 cells, respectively. No adverse effects were observed in any of the six cell lines irradiated with a 19 J cm⁻²dose of 520 nm (green) or 630 nm (red) light. The results demonstrate that blue light irradiation can have an effect on the viability of certain human cancer cell types and controls should be used in photopharmaceutical testing, which uses high-energy (blue or violet) visible light activation.

Photoactivity, though known for centuries, is only recently shifting back into focus as a treatment option against cancer and microbial infections. The external factor light is the ingenious key-component of this therapy: Since light activates the drug locally, a high level of selectivity is reached and side effects are avoided. The first reported photoactive medicines were plant extracts. Synthetic entities (so-called photosensitizers PSs), however, paved the route towards the clinical approval of the so-called photodynamic therapy (PDT), and thus natural PSs took a backseat in the past. Many isolated bioactive phytochemicals hold a hidden photoactive potential, which is overlooked due to the reduced common awareness of photoactivity. A systematic review of reported natural PSs and their supposed medicinal application was conducted by employing PubMed, Scifinder, and Web of Science. The identified photoactive natural products were compiled including information about their natural sources, their photoyield, and their pharmacological application. Furthermore, the common chemical scaffolds of natural PS are shown to enable the reader to recognize potentially overlooked natural PSs. The literature review revealed over 100 natural PS, excluding porphyrins. The PSs were classified according to their scaffold. Thereby it was shown that some PS-scaffolds were analyzed in a detailed way, while other classes were only scarcely investigated, which leaves space for future discoveries. In addition, the literature revealed that many PSs are phytoalexins, thus the selection of the starting material significantly matters in order to find new PSs. Photoactive principles are ubiquitous and can be found in various plant extracts. With the increasing availability of light-irradiation setups for the identification of photoactive natural products, we anticipate the discovery of many new natural PSs in the near future. With the accumulation of chemically diverse PSs, PDT itself might finally reach its clinical breakthrough as a promising alternative treatment against multi-resistant microbes and cancer types.

Background: With the steady increase of antibiotic resistance, several strategies have been proposed in the scientific community to overcome the crisis. One of many successful strategies is the re-evaluation of known compounds, which have been early discarded out of the pipeline, with state-of-the-art know-how. Xanthoepocin, a polyketide widespread among the genus Penicillium with an interesting bioactivity spectrum against gram-positive bacteria, is such a discarded antibiotic. The purpose of this work was to (i) isolate larger quantities of this metabolite and chemically re-evaluate it with modern technology, (ii) to explore which factors lead to xanthoepocin biosynthesis in P. ochrochloron, and (iii) to test if it is beside its known activity against methicillin-resistant Staphylococcus aureus (MRSA), also active against linezolid and vancomycin-resistant Enterococcus faecium (LVRE)—a very problematic resistant bacterium which is currently on the rise. Results: In this work, we developed several new protocols to isolate, extract, and quantify xanthoepocin out of bioreactor batch and petri dish-grown mycelium of P. ochrochloron. The (photo)chemical re-evaluation with state-of-the-art techniques revealed that xanthoepocin is a photolabile molecule, which produces singlet oxygen under blue light irradiation. The intracellular xanthoepocin content, which was highest under ammonium-limited conditions, varied considerably with the applied irradiation conditions in petri dish and bioreactor batch cultures. Using light-protecting measures, we achieved MIC values against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), which were up to 5 times lower than previously published. In addition, xanthoepocin was highly active against a clinical isolate of linezolid and vancomycin-resistant Enterococcus faecium (LVRE). Conclusions: This interdisciplinary work underlines that the re-evaluation of known compounds with state-of-the-art techniques is an important strategy in the combat against multiresistant bacteria and that light is a crucial factor on many levels that needs to receive more attention. With appropriate light protecting measures in the susceptibility tests, xanthoepocin proved to be a powerful antibiotic against MRSA and LVRE. Exploring the light response of other polyketides may be pivotal for re-introducing previously discarded metabolites into the antibiotic pipeline and to identify photosensitizers which might be used for (antimicrobial) photodynamic therapies.

In this work, two new photopharmacological ruthenium prodrugs are described that can be activated by green light. They are based on the tetrapyridyl biqbpy ligand (6,6′-bis[N-(isoquinolyl)-1-amino]-2,2′-bipyridine), which coordinates to the basal plane of the metal centre and leaves two trans coordination sites for the binding of monodentate sulphur ligands. Due to the distortion of the coordination sphere these trans ligands are photosubstituted by water upon green light irradiation. In vitro cytotoxicity data on A431 and A549 cancer cell lines shows an up to 22-fold increase in cytotoxicity after green light irradiation (520 nm, 75 J cm⁻²), compared to the dark control. Optical microscopy cell imaging and flow cytometry indicate that the cancer cells die via apoptosis. Meanwhile, very low singlet oxygen quantum yields (∼1–2%) and cell-free DNA binding studies conclude that light-induced cell death is not caused by a photodynamic effect, but instead by the changes induced in the coordination sphere of the metal by light, which modifies how the metal complexes bind to biomolecules.