Decoding the Molecular Basis for the Population Mechanism of the Triplet Phototoxic Precursors in UVA Light‐Activated Pyrimidine Anticancer Drugs

Abstract

The photosensitization of DNA by thionucleosides is a promising photo-chemotherapeutic treatment option for a variety of malignancies. DNA metabolization of thionated prodrugs can lead to cell death upon exposure to a low dose of UVA light. The exact mechanisms of thionucleoside phototoxicity are still not fully understood. In this work, we have combined femtosecond broadband transient absorption experiments with state-of-the-art molecular simulations to provide mechanistic insights into the ultrafast and efficient population of the triplet state in the UVA-activated pyrimidine anticancer drug 4-thiothymine. The triplet state is thought to act as a precursor to DNA lesions and the reactive oxygen species responsible for 4-thiothymine photocytotoxicity. The electronic-structure and mechanistic results presented in this contribution reveal key molecular design criteria that can assist in developing alternative chemotherapeutic agents that may overcome some of the primary deficiencies of classical photosensitizers.

Photochemical and Photodynamical Properties of Sulfur‐Substituted Nucleic Acid Bases,

“…30% in aqueous solutions (Table ). The relatively small quantum yield of singlet oxygen generation in the thiopurine derivatives may be due in part to a competitive quenching of the triplet state through electron transfer to 3 O 2 to generate superoxide . Table also shows that the yield of singlet oxygen generation in azathioprine is approximately two orders of magnitude lower than that in 6‐thiopurine , adding further support to the idea that attachment of a nitroimidazole group to the sulfur atom of a thiocarbonyl group significantly affects the photochemistry of the thiobase derivative.…”

“…The long lifetime of the triplet state in 6‐thiopurine, 6‐thioguanine and 6‐thio‐2′‐deoxyguanosine also increases the probability of singlet oxygen generation. These thiobases have been shown to generate singlet oxygen in higher yield than their respective canonical bases . The singlet oxygen quantum yield of these thiopurine derivatives ranges from 24% for 6‐thio‐2′‐deoxyguanosine for 16% for 6‐thiopurine in aqueous solution at pH 7.4 under 3 O 2 ‐saturated conditions , which is more than 50% smaller than the values reported in early investigations using indirect methods .…”

“…The tail redshifts with decreasing solvent polarity, suggesting that it originates from an n S π* transition (B. Ashwood, M. Pollum, C. E. Crespo‐Hernández, unpublished results) . Vertical excitation energies obtained using single‐reference and multiconfigurational computational methods predict that the lowest‐energy absorption maximum is due to a S 2 (π S π*) transition in the thiouracil and thiothymine derivatives , while it has been assigned primarily to a S 4 (π S π*) transition in 2‐thiocytosine . Similarly, the absorption tail has been assigned to a S 1 (n S π*) transition in the thiothymine and thiouracil derivatives, while it has been assigned to a combination of S 2 (π S π*) and S 1 (n S π*) transitions in 2‐thiocytosine .…”

“…Martínez‐Fernández et al . estimated the adiabatic singlet and triplet energies for 4‐thiothymine to be at 430 and 570 nm for the lowest 1 π S π* and 3 π S π* states in water, whereas Reichardt et al . estimated the adiabatic energy for the 3 π S π* state of 4‐thio‐2′‐deoxythymidine to be at 557 nm in the same solvent.…”

Visible‐Light‐Mediated Excited State Relaxation in Semi‐Synthetic Genetic Alphabet: d5SICS and dNaM

“…Indeed, time-resolved emission spectroscopy of d5SICS/dNaMr evealed the generationo fs inglet oxygen through characteristic phosphorescence spectra (ca. [14,[29][30][31][32][33] Multiple investigations have reported that the photoproducts of modified DNA, obtained by UV radiation,a re responsible for phototoxic damage in the human cell. [27] The long-lived triplet state efficientlyg enerates reactive oxygen species ands inglet oxygen ( 1 O 2 ), which cause genetic mutationsa nd photochemical damage to DNA and other bio-molecules.…”