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(3H)-one, has been thionated to develop thieno[3,4-d]pyrimidin-4(3H)-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. It is demonstrated that thieno[3,4-d]pyrimidin-4(3H)-thione efficiently populates the long-lived and reactive triplet state generating singlet oxygen with a quantum yield of about 80% independent of solvent. It is further shown that thieno[3,4-d]pyrimidin-4(3H)-thione exhibits high photodynamic efficacy against mono-layer melanoma cells and cervical cancer cells both under normoxic and hypoxic conditions. Our combined spectroscopic, computational, and in vitro data demonstrate the excellent potential of thieno[3,4-d]pyrimidin-4(3H)-thione as a heavy-atom-free PDT agent and paves the way for further development of photosensitizers based on the thionation of thieno[3,4-d]pyrimidine derivatives. Collectively, the experimental and computational results demonstrate that thieno[3,4-d]pyrimidine-4(3H)-thione stands out as the most promising thiobase photosensitizer developed to this date.
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Thionated organic compounds as emerging heavy-atom-free photodynamic therapy agents
This minireview focuses on recent progress in developing heavy-atom-free photosensitizers based on the thionation of nucleic acid derivatives and other biocompatible organic compounds for prospective applications in photodynamic therapy. Particular attention is given to the use of thionated nucleobase derivatives as “ one-two punch ” photodynamic agents. These versatile photosensitizers can act as “ Trojan horses ” upon metabolization into DNA and exposure to activating light. Their incorporation into cellular DNA increases their selectivity and photodynamic efficacy against highly proliferating skin cancer tumor cells, while simultaneously enabling the use of low irradiation doses both in the presence and in the absence of molecular oxygen. Also reviewed are their primary photochemical reactions, modes of action, and photosensitization mechanisms. New developments of emerging thionated organic photosensitizers absorbing visible and near-infrared radiation are highlighted. Future research directions, as well as, other prospective applications of heavy-atom-free, thionated photosensitizers are discussed.
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- Award ID(s):
- 1800052
- NSF-PAR ID:
- 10249358
- Date Published:
- Journal Name:
- Chemical Science
- Volume:
- 11
- Issue:
- 41
- ISSN:
- 2041-6520
- Page Range / eLocation ID:
- 11113 to 11123
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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null (Ed.)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.more » « less
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Site-selected sulfur-substituted nucleobases are a class of all organic, heavy-atom-free photosensitizers for photodynamic therapy applications that exhibit excellent photophysical properties such as strong absorption in the ultraviolet-A region of the electromagnetic spectrum, near-unity triplet yields, and a high yield of singlet oxygen generation. Recent investigations on doubly thionated nucleobases, 2,4-dithiothymine, 2,4-dithiouracil, and 2,6-dithiopurine, demonstrated that these set of dithionated nucleobases outperform the photodynamic efficacy exhibit by 4-thiothymidine–the most widely studied singly substituted thiobase to date. Out of the three dithionated nucleobases, 2,6-dithiopurine was shown to be the most effective, exhibiting inhibition of cell proliferation of up to 63% when combined with a low UVA dose of 5 J cm −2 . In this study, we elucidated the electronic relaxation pathways leading to the population of the reactive triplet state of 2,6-dithiopurine. 2,6-Dithiopurine populates the triplet manifold in less than 150 fs, reaching the nπ* triplet state minimum within a lifetime of 280 ± 50 fs. Subsequently, the population in the nπ* triplet state minimum internally converts to the long-lived ππ* triplet state within a lifetime of 3 ± 1 ps. The relatively slow internal conversion lifetime is associated with major conformational relaxation in going from the nπ* to ππ* triplet state minimum. A unity triplet yield of 1.0 ± 0.1 is measured.more » « less
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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.more » « less
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/d0sc04747c
