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

• Main Authors: Brennan Ashwood, Steffen Jockusch, Carlos E. Crespo-Hernández
• Format: Article
• Language: English
• Published: MDPI AG 2017-02-01
• Series: Molecules
• Subjects: sulfur-substituted DNA bases; prodrugs; phototoxicity; excited-state dynamics; singlet oxygen generation; glycosylation; low-temperature emission; transient absorption; TD-DFT
• Online Access: http://www.mdpi.com/1420-3049/22/3/379

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.