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Molecules 2017, 22(3), 379; doi:10.3390/molecules22030379

Excited-State Dynamics of the Thiopurine Prodrug 6-Thioguanine: Can N9-Glycosylation Affect Its Phototoxic Activity?

1
Department of Chemistry and Center of Chemical Dynamics, Case Western Reserve University, Cleveland, OH 44106, USA
2
Department of Chemistry, Columbia University, New York, NY 10027, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 17 January 2017 / Revised: 15 February 2017 / Accepted: 24 February 2017 / Published: 28 February 2017
(This article belongs to the Special Issue Experimental and Computational Photochemistry of Bioorganic Molecules)
View Full-Text   |   Download PDF [1514 KB, uploaded 28 February 2017]   |  

Abstract

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. View Full-Text
Keywords: sulfur-substituted DNA bases; prodrugs; phototoxicity; excited-state dynamics; singlet oxygen generation; glycosylation; low-temperature emission; transient absorption; TD-DFT sulfur-substituted DNA bases; prodrugs; phototoxicity; excited-state dynamics; singlet oxygen generation; glycosylation; low-temperature emission; transient absorption; TD-DFT
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Ashwood, B.; Jockusch, S.; Crespo-Hernández, C.E. Excited-State Dynamics of the Thiopurine Prodrug 6-Thioguanine: Can N9-Glycosylation Affect Its Phototoxic Activity? Molecules 2017, 22, 379.

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