Triplet stabilization for enhanced drug photorelease from sunscreen-based photocages.

Recently, sunscreen-based drug photocages have been introduced to provide UV protection to photoactive drugs, thus increasing their photosafety. Here, combined experimental and theoretical studies performed on a photocage based on the commercial UVA filter avobenzone (AB) and on the photosensitizing non-steroidal anti-inflammatory drug ketoprofen (KP) are presented unveiling the photophysical processes responsible for the light-triggered release. Particular attention is paid to solvent stabilization of the drug and UV filter excited states, respectively, which leads to a switching between the triplet excited state energies of the AB and KP units. Most notably, we show that the stabilization of the AB triplet excited state in ethanol solution is the key requirement for an efficient photouncaging. By contrast, in apolar solvents, in particular hexane, KP has the lowest triplet excited state, hence acting as an energy acceptor quenching the AB triplet manifold, thus inhibiting the desired photoreaction.

Spectroscopic characterization of dipicolinic acid and its photoproducts as thymine photosensitizers.

Dipicolinic acid (DPA), present in large amount in bacterial spores, has been proposed to act as an endogenous photosensitizer in spore photoproduct formation. The proposed mechanism involves a triplet-triplet energy transfer from DPA to thymine. However, up to now, no spectroscopic studies have been performed to determine the interaction between the endogenous compound and the nucleobase, probably due to its photolability in aqueous solutions. Here, triplet excited state properties of DPA are reported together with its bimolecular quenching rate constant by thymidine, kq of ca. 5.3 × 109 M-1 s-1. To run more reliable studies, a stable methyl ester derivative of DPA, which exhibits the same spectroscopic properties as the parent compound, is also described. Finally, DPA photoproducts are characterized. Studies of their triplet excited state properties have demonstrated that, interestingly, one of them is able to photosensitize thymidine triplet excited state formation.

Experimental and theoretical studies on thymine photodimerization mediated by oxidatively generated DNA lesions and epigenetic intermediates.

Interaction of nucleic acids with light is a scientific question of paramount relevance not only in the understanding of life functioning and evolution, but also in the insurgence of diseases such as malignant skin cancer and in the development of biomarkers and novel light-assisted therapeutic tools. This work shows that the UVA portion of sunlight, not absorbed by canonical DNA nucleobases, can be absorbed by 5-formyluracil (ForU) and 5-formylcytosine (ForC), two ubiquitous oxidatively generated lesions and epigenetic intermediates present in living beings in natural conditions. We measure the strong propensity of these molecules to populate triplet excited states able to transfer the excitation energy to thymine-thymine dyads, inducing the formation of cyclobutane pyrimidine dimers (CPDs). By using steady-state and transient absorption spectroscopy, NMR, HPLC, and theoretical calculations, we quantify the differences in the triplet-triplet energy transfer mediated by ForU and ForC, revealing that the former is much more efficient in delivering the excitation energy and producing the CPD photoproduct. Although significantly slower than ForU, ForC is also able to harm DNA nucleobases and therefore this process has to be taken into account as a viable photosensitization mechanism. The present findings evidence a rich photochemistry crucial to understand DNA damage photobehavior.

Photoinduced intersystem crossing in DNA oxidative lesions and epigenetic intermediates.

The propensity of 5-formyluracil and 5-formylcytosine, i.e. oxidative lesions and epigenetic intermediates, in acting as intrinsic DNA photosensitizers is unraveled by using a combination of molecular modeling, simulation and spectroscopy. Exploration of potential energy surfaces and non-adiabatic dynamics confirm a higher intersystem crossing rate for 5-formyluracil, whereas the kinetic models evidence different equilibria in the excited states for both compounds.

A Sunscreen-Based Photocage for Carbonyl Groups.

Photolabile protecting groups (PPGs) have been exploited in a wide range of chemical and biological applications, due to their ability to provide spatial and temporal control over light-triggered activation. In this work, we explore the concept of a new photocage compound based on the commercial UVA/UVB filter oxybenzone (OB; 2-hydroxy-4-methoxybenzophenone) for photoprotection and controlled release of carbonyl groups. The point here is that oxybenzone not only acts as a mere PPG, but also provides, once released, UV photoprotection to the carbonyl derivative. This design points to a possible therapeutic approach to reduce the severe photoadverse effects of drugs containing a carbonyl chromophore.