Theoretical study of the phototoxicity of naproxen and the active form of nabumetone.
Density functional theory using the hybrid functional B3LYP has been employed in order to study the mechanisms of photoinduced decomposition of the closely related nonsteroidal anti-inflammatory drugs naproxen (NP) and 6-methoxy-2-naphthylacetic acid (MNAA; the active form of nabumetone). The photochemical properties and computed energies of various species obtained in this study show that both drugs dominate in their deprotonated forms at physiological pH. The deprotonated acids are unable to decarboxylate from their excited singlets; instead, they decarboxylate from their first excited triplet states with high efficiency, overcoming energy barriers less than 3 and 1 kcal/mol for MNAA and NP, respectively. The ultraviolet and visible spectra of the neutral, deprotonated, and decarboxylated moieties of MNAA and NP are more-or-less similar but with higher probabilites (oscillator strength) for the latter. This fact, as well as the higher reactivity of NP, is explained in terms of the electron-donating effect of the additional methyl group present in NP. Singlet oxygen, superoxide radical anion, and corresponding peroxyl radical species are expected to be formed in different steps throughout the proposed photodegradation pathways of both drugs, which give rise to their effects on biomolecules, for example, lipid peroxidation.
Department of Natural Sciences and Orebro Life Science Center, Orebro University, 701 82 Orebro, Sweden.
Klefah A K
KA
Musa
Leif A
LA
Eriksson
D003198:Computer Simulation; D008956:Models, Chemical; D015394:Molecular Structure; D009280:Naphthaleneacetic Acids / Q000737:chemistry*; D009288:Naproxen / Q000737:chemistry*; D010084:Oxidation-Reduction; D010777:Photochemistry; D017319:Photosensitizing Agents / Q000737:chemistry*; D011789:Quantum Theory
D009280:Naphthaleneacetic Acids; D017319:Photosensitizing Agents; D009288:Naproxen; C044612:6-methoxy-2-naphthylacetic acid