title: Increase in the photoreactivity of uracil derivatives by doubling thionation.
abstract: The ability of 4-thiouracil to strongly absorb UVA radiation and to populate a reactive triplet state in high yield has enabled its use as a versatile photocrosslinker for nearly 50 years. In this contribution, we present a detailed spectroscopic and photochemical investigation of the 2-thiouracil, 4-thiouracil, and 2,4-dithiouracil series in an effort to further advance this chemistry and to scrutinize the photoreactivity of 2,4-dithiouracil. Our results reveal that excitation of 2,4-dithiouracil leads to intersystem crossing to the triplet manifold in 220 ± 40 fs, which enables the population of the reactive triplet state with near unity yield (ΦT = 0.90 ± 0.15) and ultimately leads to a ca. 50% singlet oxygen generation (ΦΔ = 0.49 ± 0.02)-one of the highest singlet oxygen yields reported to date for a photoexcited thiobase. In addition, the long-lived triplet state of 2,4-dithiouracil reacts efficiently with the nucleic acid base adenine 5'-monophosphate through a direct, oxygen-independent photocycloaddition mechanism and at a rate that is at least 3-fold faster than that of 4-thiouracil under equal conditions. The new physico-chemical insights reported for these RNA-thiobase derivatives are compared to those of the DNA and RNA bases and the DNA-thiobase derivatives. Furthermore, the strong near-visible absorption and increased photoreactivity measured for 2,4-dithiouracil lays a solid foundation for developing RNA-targeted photocrosslinking and phototherapeutic agents that are more effective than those currently available.
authors.affiliation: Department of Chemistry and Center for Chemical Dynamics, Case Western Reserve University, Cleveland, OH 44106, USA. carlos.crespo@case.edu.
authors.forename: M
authors.initials: M
authors.lastname: Pollum
authors.forename: S
authors.initials: S
authors.lastname: Jockusch
authors.forename: C E
authors.initials: CE
authors.lastname: Crespo-Hernández
mesh_terms: D015394:Molecular Structure; D055668:Photochemical Processes; D026082:Singlet Oxygen / Q000032:analysis; D013889:Thiouracil / Q000031:analogs & derivatives* / Q000737:chemistry; D014466:Ultraviolet Rays
chemical_list: D026082:Singlet Oxygen; C056582:2,4-dithiouracil; D013889:Thiouracil