EXCIPLEX PHOTOREACTIVITY IN PHOTOTOXIC COMPOUNDS

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Ingestion of many synthetic drugs (as well as many naturally-occurring compounds) produces 'phototoxicity" in humans and animals, so that subsequent exposure to light causes skin or vision damage. Examples of pharmacologically active compounds which have been observed to cause severe or frequent phototoxic reactions in humans are phenothiazines (which are antihistamines, sedatives, or antipsychotic drugs), quinolinemethanol antimalarial compounds (which are quinine analogs), and the benzo-cycloheptadiene antidepressant compounds. To synthetically modify these drugs to avoid this side effect is a difficult challenge because of great uncertainty about the molecular and mechanistic cause of this undesired photobiological activity of these compounds. We propose to clarify the chemical mechanisms which cause phototoxicity in these compounds (which are representative of other phototoxic drugs which may react by similar mechanisms). For our study we will focus on in vitro studies which use micelles as models for the actual microenvironment of the drugs in vivo. The in vivo environment will be carefully modeled by sequestering within a micelle both the phototoxic drug and reactive substrates which would closely parallel the reactive functionalities present in proteins, DNA, or a cell membrane. Thus, a chemical reaction occurring in our micelle models should parallel that which occur with a phototoxic drug that is protein-bound, intercalated with DNA, or buried within a cell membrane. The range of clinical manifestations of photochemical reactivity of phototoxic compounds is great, including not only skin reactions of erythema and edema which parallel an exaggerated sunburn response, but also photocarcinogenesis and photomutagenesis (reflecting DNA damage), photoallergy (reflecting protein damage), and cytotoxic reactions which seem to involve membrane destruction. Our study will focus on attempting to recognize common features among compounds that are phototoxic, focusing on the likely involvement of excited states which are charge transfer or exciplex in nature. It is felt that such species are particularly likely to undergo undesired photoreactivity in the presence of biopolymers.