title: 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.
authors.affiliation: Departamento de Química, Universidad Autónoma de Madrid, 28049, Cantoblanco, Madrid, Spain.|Current address: Istituto di Biostrutture e Bioimmagini, Consiglio delle Ricerche, 80134, Napoli, Italy.
authors.forename: Lara
authors.identifier: http://orcid.org/0000-0001-5361-9390
authors.initials: L
authors.lastname: Martínez-Fernández
authors.affiliation: Dipartimento di Chimica e Chimica Industriale, Università di Pisa, v. G. Moruzzi 3, 56124, Pisa, Italy.
authors.forename: Giovanni
authors.identifier: http://orcid.org/0000-0002-4753-6318
authors.initials: G
authors.lastname: Granucci
authors.affiliation: Department of Chemistry and Center for Chemical Dynamics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
authors.forename: Marvin
authors.initials: M
authors.lastname: Pollum
authors.affiliation: Department of Chemistry and Center for Chemical Dynamics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Crespo-Hernández
authors.affiliation: Dipartimento di Chimica e Chimica Industriale, Università di Pisa, v. G. Moruzzi 3, 56124, Pisa, Italy.
authors.forename: Maurizio
authors.identifier: http://orcid.org/0000-0002-3594-0890
authors.initials: M
authors.lastname: Persico
authors.affiliation: Departamento de Química, Universidad Autónoma de Madrid, 28049, Cantoblanco, Madrid, Spain.
authors.forename: Inés
authors.identifier: http://orcid.org/0000-0002-9455-4906
authors.initials: I
authors.lastname: Corral
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D004579:Electron Transport; D004735:Energy Transfer; D056004:Molecular Dynamics Simulation; D017319:Photosensitizing Agents / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D011789:Quantum Theory; D012997:Solvents; D013053:Spectrophotometry; D013816:Thermodynamics; D013936:Thymidine / Q000031:analogs & derivatives / Q000737:chemistry; D014466:Ultraviolet Rays
chemical_list: C414668:4-thiothymidine; D000970:Antineoplastic Agents; D017319:Photosensitizing Agents; D011355:Prodrugs; D011743:Pyrimidines; D012997:Solvents; D013936:Thymidine
keywords: DNA damage; molecular dynamics; sensitizers; singlet oxygen; time-resolved spectroscopy