Excited-State Dynamics of the Thiopurine Prodrug 6-Thioguanine: Can N9-Glycosylation Affect Its Phototoxic Activity?
6-Thioguanine, an immunosuppressant and anticancer prodrug, has been shown to induce DNA damage and cell death following exposure to UVA radiation. Its metabolite, 6-thioguanosine, plays a major role in the prodrug’s overall photoreactivity. However, 6-thioguanine itself has proven to be cytotoxic f...
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| Format: | Article |
| Language: | English |
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MDPI AG
2017-02-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/22/3/379 |
| _version_ | 1818339746274869248 |
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| author | Brennan Ashwood Steffen Jockusch Carlos E. Crespo-Hernández |
| author_facet | Brennan Ashwood Steffen Jockusch Carlos E. Crespo-Hernández |
| author_sort | Brennan Ashwood |
| collection | DOAJ |
| description | 6-Thioguanine, an immunosuppressant and anticancer prodrug, has been shown to induce DNA damage and cell death following exposure to UVA radiation. Its metabolite, 6-thioguanosine, plays a major role in the prodrug’s overall photoreactivity. However, 6-thioguanine itself has proven to be cytotoxic following UVA irradiation, warranting further investigation into its excited-state dynamics. In this contribution, the excited-state dynamics and photochemical properties of 6-thioguanine are studied in aqueous solution following UVA excitation at 345 nm in order to provide mechanistic insight regarding its photochemical reactivity and to scrutinize whether N9-glycosylation modulates its phototoxicity in solution. The experimental results are complemented with time-dependent density functional calculations that include solvent dielectric effects by means of a reaction-field solvation model. UVA excitation results in the initial population of the S2(ππ*) state, which is followed by ultrafast internal conversion to the S1(nπ*) state and then intersystem crossing to the triplet manifold within 560 ± 60 fs. A small fraction (ca. 25%) of the population that reaches the S1(nπ*) state repopulates the ground state. The T1(ππ*) state decays to the ground state in 1.4 ± 0.2 μs under N2-purged conditions, using a 0.2 mM concentration of 6-thioguanine, or it can sensitize singlet oxygen in 0.21 ± 0.02 and 0.23 ± 0.02 yields in air- and O2-saturated solution, respectively. This demonstrates the efficacy of 6-thioguanine to act as a Type II photosensitizer. N9-glycosylation increases the rate of intersystem crossing from the singlet to triplet manifold, as well as from the T1(ππ*) state to the ground state, which lead to a ca. 40% decrease in the singlet oxygen yield under air-saturated conditions. Enhanced vibronic coupling between the singlet and triplet manifolds due to a higher density of vibrational states is proposed to be responsible for the observed increase in the rates of intersystem crossing in 6-thioguanine upon N9-glycosylation. |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-13T15:31:54Z |
| publishDate | 2017-02-01 |
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| spelling | doaj.art-8f4d7f7973cf47b6b2ca9937cb8d0bf42022-12-21T23:40:08ZengMDPI AGMolecules1420-30492017-02-0122337910.3390/molecules22030379molecules22030379Excited-State Dynamics of the Thiopurine Prodrug 6-Thioguanine: Can N9-Glycosylation Affect Its Phototoxic Activity?Brennan Ashwood0Steffen Jockusch1Carlos E. Crespo-Hernández2Department of Chemistry and Center of Chemical Dynamics, Case Western Reserve University, Cleveland, OH 44106, USADepartment of Chemistry, Columbia University, New York, NY 10027, USADepartment of Chemistry and Center of Chemical Dynamics, Case Western Reserve University, Cleveland, OH 44106, USA6-Thioguanine, an immunosuppressant and anticancer prodrug, has been shown to induce DNA damage and cell death following exposure to UVA radiation. Its metabolite, 6-thioguanosine, plays a major role in the prodrug’s overall photoreactivity. However, 6-thioguanine itself has proven to be cytotoxic following UVA irradiation, warranting further investigation into its excited-state dynamics. In this contribution, the excited-state dynamics and photochemical properties of 6-thioguanine are studied in aqueous solution following UVA excitation at 345 nm in order to provide mechanistic insight regarding its photochemical reactivity and to scrutinize whether N9-glycosylation modulates its phototoxicity in solution. The experimental results are complemented with time-dependent density functional calculations that include solvent dielectric effects by means of a reaction-field solvation model. UVA excitation results in the initial population of the S2(ππ*) state, which is followed by ultrafast internal conversion to the S1(nπ*) state and then intersystem crossing to the triplet manifold within 560 ± 60 fs. A small fraction (ca. 25%) of the population that reaches the S1(nπ*) state repopulates the ground state. The T1(ππ*) state decays to the ground state in 1.4 ± 0.2 μs under N2-purged conditions, using a 0.2 mM concentration of 6-thioguanine, or it can sensitize singlet oxygen in 0.21 ± 0.02 and 0.23 ± 0.02 yields in air- and O2-saturated solution, respectively. This demonstrates the efficacy of 6-thioguanine to act as a Type II photosensitizer. N9-glycosylation increases the rate of intersystem crossing from the singlet to triplet manifold, as well as from the T1(ππ*) state to the ground state, which lead to a ca. 40% decrease in the singlet oxygen yield under air-saturated conditions. Enhanced vibronic coupling between the singlet and triplet manifolds due to a higher density of vibrational states is proposed to be responsible for the observed increase in the rates of intersystem crossing in 6-thioguanine upon N9-glycosylation.http://www.mdpi.com/1420-3049/22/3/379sulfur-substituted DNA basesprodrugsphototoxicityexcited-state dynamicssinglet oxygen generationglycosylationlow-temperature emissiontransient absorptionTD-DFT |
| spellingShingle | Brennan Ashwood Steffen Jockusch Carlos E. Crespo-Hernández Excited-State Dynamics of the Thiopurine Prodrug 6-Thioguanine: Can N9-Glycosylation Affect Its Phototoxic Activity? Molecules sulfur-substituted DNA bases prodrugs phototoxicity excited-state dynamics singlet oxygen generation glycosylation low-temperature emission transient absorption TD-DFT |
| title | Excited-State Dynamics of the Thiopurine Prodrug 6-Thioguanine: Can N9-Glycosylation Affect Its Phototoxic Activity? |
| title_full | Excited-State Dynamics of the Thiopurine Prodrug 6-Thioguanine: Can N9-Glycosylation Affect Its Phototoxic Activity? |
| title_fullStr | Excited-State Dynamics of the Thiopurine Prodrug 6-Thioguanine: Can N9-Glycosylation Affect Its Phototoxic Activity? |
| title_full_unstemmed | Excited-State Dynamics of the Thiopurine Prodrug 6-Thioguanine: Can N9-Glycosylation Affect Its Phototoxic Activity? |
| title_short | Excited-State Dynamics of the Thiopurine Prodrug 6-Thioguanine: Can N9-Glycosylation Affect Its Phototoxic Activity? |
| title_sort | excited state dynamics of the thiopurine prodrug 6 thioguanine can n9 glycosylation affect its phototoxic activity |
| topic | sulfur-substituted DNA bases prodrugs phototoxicity excited-state dynamics singlet oxygen generation glycosylation low-temperature emission transient absorption TD-DFT |
| url | http://www.mdpi.com/1420-3049/22/3/379 |
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