EXCIPLEX PHOTOREACTIVITY IN PHOTOTOXIC COMPOUNDS

摄入许多合成药物（以及许多天然药物） 化合物）在人类和动物中产生“光毒性”，因此， 随后暴露于光会导致皮肤或视力损伤。 的实例 已观察到可引起严重 或常见的光毒性反应是吩噻嗪（ 抗组胺药、镇静剂或抗精神病药）、喹啉甲醇 抗疟化合物（奎宁类似物），以及 苯并环庚三烯类抗抑郁化合物。 合成修饰 这些药物避免这种副作用是一个困难的挑战，因为 关于这一现象的分子和机械原因的巨大不确定性 这些化合物的不希望的光生物活性。 我们建议 阐明导致光毒性的化学机制， 化合物（其代表可 类似的机制）。 对于我们的研究，我们将集中在体外研究，使用胶束作为 药物在体内实际微环境的模型。 体内 环境将仔细模拟螯合胶束内， 光毒性药物和反应底物， 存在于蛋白质、DNA或细胞膜中的活性官能团。 因此，在我们的胶束模型中发生的化学反应应该平行于 与蛋白质结合、嵌入 或者被埋在细胞膜里。 光化学反应性的临床表现范围 光毒性化合物是伟大的，不仅包括皮肤反应， 红斑和水肿，与夸张的晒伤反应平行，但也 光致癌和光诱变（反映DNA损伤）， 光过敏（反映蛋白质损伤）和细胞毒性反应， 似乎与细胞膜破坏有关 我们的研究将集中在尝试 为了识别光毒性化合物的共同特征， 可能涉及的激发态是电荷转移或 自然界中的兴奋。 据认为，这类物种特别有可能 在生物聚合物存在下发生不希望的光反应性。

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.