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All-organic, heavy-atom-free photosensitizers based on thionation of nucleobases are receiving increased attention because they are easy to make, noncytotoxic, work both in the presence and absence of molecular oxygen and can be readily incorporated into DNA and RNA. In this contribution, the DNA and RNA fluorescent probe, thieno[3,4-d]pyrimidin-4(1H)-one, has been thionated to develop thieno[3,4-d]pyrimidin-4(1H)-thione, which is nonfluorescent and absorbs near-visible radiation with about 60% higher efficiency. Steady-state absorption and emission spectra are combined with transient absorption spectroscopy and CASPT2 calculations to delineate the electronic relaxation mechanisms of both pyrimidine derivatives in aqueous and acetonitrile solutions and to explain the origin of the remarkable fluorescence quenching in the thionated compound. It is demonstrated that thieno[3,4-d]pyrimidin-4(1H)-thione efficiently populates the long-lived and reactive triplet state in hundreds of femtoseconds independent of solvent. Conversely, fluorescence emission in thieno[3,4-d]pyrimidin-4(1H)-one is highly sensitive to solvent, with an order of magnitude decrease in fluorescence yield in going from aqueous to acetonitrile solution. Collectively, the experimental and computational results demonstrate that thieno[3,4-d]pyrimidine-4(1H)-thione stands out as the most promising thiopyrimidine photosensitizer developed to this date, which can be readily incorporated as a photodynamic agent into sequence-specific DNA and RNA sequences for the treatment of skin cancer cells. 

The substitution of an oxygen atom in an exocyclic carbonyl group of the nucleobases by a sulfur atom in a nucleic acid base generates a thiobase. This substitution causes a redshift in the absorption spectrum of the thiobase with respect to the canonical nucleobase, moving the strongly allowed absorption band from the UVC to the UVA region of the electromagnetic spectrum. Due to this redshift and the efficient population of the triplet state, 4-thiothymidine (4tThd) can be selectively excited without exciting canonical DNA, making it a powerful UVA photosensitizer. The synergistic toxicity of 4tThd and UVA radiation allows for the enhanced killing of skin cancer cells. As a result, 4tThd has been proposed for use in conjunction with UVA radiation as potential photodynamic therapy agent, due to its photochemical properties and to a diminished cytotoxicity. Studies of the monomer 4tThd have been performed to explore the prospective use of 4tThd in photochemotherapeutic application with reduced phototoxic side effects. One study of 4tThd in aqueous solution proposed the main kinetic mechanism to consist of intersystem crossing from the S2 state to the triplet manifold. Vertical excitation energies were calculated using the optimized ground state of 4tThd in water and vacuum. These were found to be in good agreement with the values previously reported. After studying the monomer, the next step is to understand what happens when 4tThd interacts with the DNA bases. Therefore, ground state optimizations and vertical excitation energies calculations were performed for a series of 4tThd-containing dinucleotides. These vertical excitation energy calculations predict the order electronic states and likely kinetic mechanisms when 4tThd is incorporated into DNA, which will greatly assist in the interpretation of planned time-resolved experiments.