2'-methoxyacetopenone as dna photosensitiser for mono and biphotonic processes

Resumen

Solar light is necessary for life on Earth and its beneficial effects are beyond any doubt. However, ultraviolet radiation (UV), which is part of the solar spectrum, can be harmful to living beings, as it is capable of generating mutations in DNA, which are closely related to the appearance of skin cancer. DNA damage can be produced both by direct absorption of UV radiation by this biomolecule and through photosensitised processes. Specially important in the case of the UVA range, which represents 90% of the solar UV radiation that reaches the Earth's surface. Although this light is barely absorbed by DNA, it is able to produce damage to the genetic material due to the presence of UVA-absorbing photosensitising compounds in its vicinity. This Doctoral Thesis is focused on photosensitised DNA damage, more concretely, on the mechanistic understanding of the processes involved in the formation of pyrimidine dimers through the triplet excited state. For this purpose, the photochemistry of DNA models of increasing complexity has been studied, using 2'-methoxyacetophenone as photosensitiser. Initially, the complete characterisation of this photosensitiser has been carried out in Chapter 3 by means of UV-Vis transient absorption spectroscopy. Its triplet excited state has been investigated in-depth, determining its spectrum, lifetime, rate constant for quenching by a thymine model, and capability to produce 1O2. The aim was to demonstrate its potential as a DNA photosensitiser, not only for cyclobutane pyrimidine dimer (CPD) formation, but also for oxidative damage. From the obtained results, the suitability of 2¿-methoxyacetophenone as a DNA photosensitiser for mechanistic studies has been confirmed. Hence, it has been used in Chapter 4 to determine the nature of the rate controlling reaction step in the photosensitised cyclodimerisation of homo and heterobipyrimidine models, where the nucleobases are linked by polymethylene bridges of different length and present different substitution patterns at the C5 position. In all cases, selective irradiation of 2¿methoxyacetophenone in the presence of the bipyrimidine models results in the formation of the corresponding CPD, demonstrating the efficiency of the photosensitised process. Analysis of the reaction kinetics for all compounds has allowed establishing the reactivity order, which is rationalised on the basis of a thorough photophysical study. Thus, it has been found that upon variation of the substitution pattern and the length of the linking bridge it is possible to switch from a process governed by the intrinsic excited state cyclodimerisation to a process controlled by the energy transfer from the photosensitiser to the base. Finally, the biphotonic photosensitisation of pyrimidine derivatives has been explored in Chapter 5, following a new and more general approach than the one recently reported in the literature. This approach does not require the synthetic effort associated with the preparation of covalently linked photosensitiser and pyrimidine units. It is based on the absorption of a first photon by 2¿methoxyacetophenone, followed by triplet energy transfer to the pyrimidine, which then receives a second photon to reach a higher triplet state that gives rise to new chemistry. The feasibility of this approach has been demonstrated through the study of two model reactions, namely the Norrish-Yang photoreaction and the photohydration of uracil derivatives.