Heavy-atom-free π-twisted photosensitizers for fluorescence bioimaging and photodynamic therapy.

As the field of preclinical research on photosensitizers (PSs) for anticancer photodynamic therapy (PDT) continues to expand, a focused effort is underway to develop agents with innovative molecular structures that offer enhanced targeting, selectivity, activation, and imaging capabilities. In this context, we introduce two new heavy-atom-free PSs, DBXI and DBAI, characterized by a twisted π-conjugation framework. This innovative approach enhances the spin-orbit coupling (SOC) between the singlet excited state (S1) and the triplet state (T1), resulting in improved and efficient intersystem crossing (ISC). Both PSs are highly effective in producing reactive oxygen species (ROS), including singlet oxygen and/or superoxide species. Additionally, they also demonstrate remarkably strong fluorescence emission. Indeed, in addition to providing exceptional photocytotoxicity, this emissive feature, generally lacking in other reported structures, allows for the precise monitoring of the PSs' distribution within specific cellular organelles even at nanomolar concentrations. These findings underscore the dual functionality of these PSs, serving as both fluorescent imaging probes and light-activated therapeutic agents, emphasizing their potential as versatile and multifunctional tools in the field of PDT.

Expanding the Use of Benzothioxanthene Imides to Photochemistry: Eco-Friendly Aerobic Oxidation of Sulfides to Sulfoxides.

The sulfoxide moiety is one of the most commonly utilized groups in pharmaceutical and industrial chemistry. The need for sustainability and easy accessibility to sulfoxide moieties is deemed necessary, due to its ubiquity in natural products and potentially pharmaceutically active compounds. In this context, we report herein a sustainable, aerobic and environmentally friendly photochemical protocol based on the use of a benzothioxathene imide as the photocatalyst to selectively oxidize sulfides under mild irradiation (456 nm), in very low catalyst loading (0.01 mol %) and on water. In addition, to demonstrate the compatibility of our protocol with wide scope of substrates, the latter was successfully applied to the synthesis of the biologically-active Sulforaphane and Modafinil.

A new G-quadruplex-specific photosensitizer inducing genome instability in cancer cells by triggering oxidative DNA damage and impeding replication fork progression.

Photodynamic therapy (PDT) ideally relies on the administration, selective accumulation and photoactivation of a photosensitizer (PS) into diseased tissues. In this context, we report a new heavy-atom-free fluorescent G-quadruplex (G4) DNA-binding PS, named DBI. We reveal by fluorescence microscopy that DBI preferentially localizes in intraluminal vesicles (ILVs), precursors of exosomes, which are key components of cancer cell proliferation. Moreover, purified exosomal DNA was recognized by a G4-specific antibody, thus highlighting the presence of such G4-forming sequences in the vesicles. Despite the absence of fluorescence signal from DBI in nuclei, light-irradiated DBI-treated cells generated reactive oxygen species (ROS), triggering a 3-fold increase of nuclear G4 foci, slowing fork progression and elevated levels of both DNA base damage, 8-oxoguanine, and double-stranded DNA breaks. Consequently, DBI was found to exert significant phototoxic effects (at nanomolar scale) toward cancer cell lines and tumor organoids. Furthermore, in vivo testing reveals that photoactivation of DBI induces not only G4 formation and DNA damage but also apoptosis in zebrafish, specifically in the area where DBI had accumulated. Collectively, this approach shows significant promise for image-guided PDT.