Computational studies of photodynamic drugs, phototoxic reactions and drug design

Sammanfattning: The most important criterion when designing new drugs or improving old ones in order to prevent side effects or at least diminish them is drug safety. Treatment of all diseases generally needs use of either topical application or systemic medications (transported in the blood) during a certain period of time. These treatments are associated with a number of adverse effects. Photosensitivity is one of those side effects, with phototoxicity as one of the photosensitivity disorders. This adverse side effect arises because of a reaction between UV or visible-light and the drug molecule, its active form or photoproduct(s). Due to phototoxic side effect, unexpected symptoms varying from just a simple rash to severe cutaneous affectations can appear. Furthermore, biomolecular damage occurs once the drug-light interaction takes place persistently and ends with cell death.Several drug families, such as over-the-counter drugs in the non-steroidal anti-inflammatory drug family of 2-arylpropionic acid derivatives, or prescription required fluoroquinolone drugs, have the capability to absorb mainly UV light radiation which in turn causes different phototoxic reactions by forming radical derivatives, reactive oxygen species or both. These may effect DNA, protein and lipid cell components leading to photogenotoxicity, photoallergy and lipid peroxidation, respectively. The photodegradation mechanisms of drugs belonging to the above mentioned families including ketoprofen, ibuprofen, flurbiprofen, naproxen, the active form of nabumetone, diclofenac and its main photoproduct, suprofen, tiaprofenic acid, naphazoline, norfloxacin and lomefloxacin are investigated in more detail in this thesis.The results obtained by computational density functional theory (DFT) and time-dependent-DFT (TD-DFT) are in line with experimental data available to date. The studies provide detailed insight into the molecular basis and understanding of the full photodegradation mechanisms of drugs mentioned above. This also plays an important role in preventing or at least reducing the phototoxic adverse effects by enabling the development of safe drugs in this area. Hence, new modified non-steroid anti-inflammatory molecules were designed by computational techniques. Obtained results suggest possibility of their future usage as pharmaceuticals with reduced photodegradation and cyclooxygenase 1 induced adverse side effects compared to the parent compounds.