Abstract
Sulfur-substituted DNA and RNA nucleobase derivatives (a.k.a., thiobases) are an important family of biomolecules. They are used as prodrugs and as chemotherapeutic agents in medical settings, and as photocrosslinker molecules in structural-biology applications. Remarkably, excitation of thiobases with ultraviolet to near-visible light results in the population of long-lived and reactive triplet states on a time scale of hundreds of femtoseconds and with near-unity yields. This efficient nonradiative decay pathway explains the vanishingly small fluorescence yields reported for the thiobases and the scarcity of fluorescence lifetimes in the literature. In this study, we report fluorescence lifetimes for twelve thiobase derivatives, both in aqueous solution at physiological pH and in acetonitrile. Excitation is performed at 267 and 362 nm, while fluorescence emission is detected at 380, 425, 450, 525, or 532 nm. All the investigated thiobases reveal fluorescence lifetimes that decay in a few hundreds of femtoseconds and with magnitudes that depend and are sensitive to the position and degree of sulfur-atom substitution and on the solvent environment. Interestingly, however, three thiopyrimidine derivatives (i.e., 2-thiocytidine, 2-thiouridine, and 4-thiothymidine) also exhibit a small amplitude fluorescence component of a few picoseconds in aqueous solution. Furthermore, the N-glycosylation of thiobases to form DNA or RNA nucleoside analogues is demonstrated as affecting their fluorescence lifetimes. In aqueous solution, the fluorescence decay signals exciting at 267 nm are equal or slower than those collected exciting at 362 nm. In acetonitrile, however, the fluorescence decay signals recorded upon 267 nm excitation are, in all cases, faster than those measured exciting at 362 nm. A comparison to the literature values show that, while both the DNA and RNA nucleobase and thiobase derivatives exhibit sub-picosecond fluorescence lifetimes, the 1ππ* excited-state population in the nucleobase monomers primarily decay back to the ground state, whereas it predominantly populates long-lived and reactive triplet states in thiobase monomers.
Highlights
Sulfur-substituted nucleobase monomers (a.k.a., thiobases) belong to a family of molecules known as prodrugs, which are commonly prescribed as immunosuppressants for organ transplant patients [1] and as maintenance therapy compounds for acute lymphoblastic leukemia, inflammatory bowel disease [2], and gliomas [3,4]
Fluorescence decay signals for selected thiobases exciting at 362 nm and detecting the emissions at 425, 450, 525, and 532 nm were collected in phosphate buffer saline (PBS) or in acetonitrile, and are reported in Figures S4 and S5
The fluorescence up-conversion measurements presented in this study provide complementary measurements of the excited state lifetimes of twelve thiobase derivatives shown in Scheme 1
Summary
Sulfur-substituted nucleobase monomers (a.k.a., thiobases) belong to a family of molecules known as prodrugs, which are commonly prescribed as immunosuppressants for organ transplant patients [1] and as maintenance therapy compounds for acute lymphoblastic leukemia, inflammatory bowel disease [2], and gliomas [3,4]. They are widely used as cytotoxic agents of clinical. While damage to DNA is manifested as structural modifications to the DNA itself, a complete understanding of the photochemical pathways leading to DNA damage requires describing both the radiative and nonradiative electronic relaxation pathways of these thiobases upon the absorption of UV radiation
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