Tricyclic Analogs of Thioguanine as Photosensitizers of Reactive Oxygen Species-Induced DNA and RNA Damage.

Analogs of tricyclic thiopurine nucleosides combine structural features of endogenous DNA adducts with efficient photosensitizing chromophores, making them valuable models for studying nucleic acid damage induced by reactive oxygen species (ROS). In this work, we investigate the photochemical properties of two tricyclic guanosine derivatives, 9-thio-1,N2-ethenoguanosine and 6-methyl-9-thio-1,N2-ethenoguanosine, under UVA irradiation. We characterize their excited-state behavior, their ability to generate singlet oxygen (1O2) and superoxide radicals (O2●-), and the resulting oxidative transformation pathways. Both compounds are photochemically stable under anaerobic conditions but undergo efficient oxygen-dependent phototransformation, yielding a diverse set of oxidative and dimeric photoproducts. Product analysis reveals that singlet oxygen mediates desulfurization, ring opening, and extensive sulfur oxidation, whereas radical pathways involving superoxide lead exclusively to dimer formation. Importantly, the triplet excited states of these tricyclic thiopurines are not quenched by natural nucleosides, allowing both Type I and Type II photosensitizing pathways to operate in nucleic-acid-like environments. These results provide molecular-level insight into ROS-induced purine damage and highlight tricyclic thiopurines as effective photosensitizers of oxidative DNA and RNA damage.