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EXCIPLEX PHOTOREACTIVITY IN PHOTOTOXIC COMPOUNDS

光毒性化合物中的 EXCIPLEX 光反应性

基本信息

批准号：
3153269
负责人：
GARY A EPLING
金额：
$ 7.59万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-12-01 至 1987-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3153269
关键词：
DNA antihistamines antimalarial agents cell membrane cytotoxicity drug adverse effect edema erythema light adverse effect neuropharmacologic agent nonvisual photosensitivity phenothiazines photochemistry photostimulus quinine sedative /hypnotic sunburn

项目摘要

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.

摄取许多合成药物(以及许多自然产生的化合物)对人类和动物产生“光毒性”，因此随后暴露在光线下会导致皮肤或视力受损。举例已观察到的具有药理活性的化合物会导致严重的或在人类中频繁的光毒性反应是吩噻嗪(这是抗组胺、镇静剂或抗精神病药物)、喹啉乙醇抗疟疾化合物(奎宁类似物)，以及苯并环庚二烯抗抑郁化合物。综合改装这些药物要避免这种副作用是一项艰巨的挑战，因为造成这种现象的分子和机制原因存在很大的不确定性这些化合物的不受欢迎的光生物活性。我们建议阐明导致这些化合物光毒性的化学机制化合物(代表其他光毒性药物，可能通过类似的机制作出反应)。在我们的研究中，我们将重点放在使用胶束作为模拟药物在体内的实际微环境。活体内环境将通过隔离在胶束中而被仔细地模拟光毒药物和活性底物将紧密平行存在于蛋白质、DNA或细胞膜中的反应功能。因此，我们的胶束模型中发生的化学反应应该是平行的。与蛋白质结合、嵌入的光毒药物发生的情况 DNA，或者埋在细胞膜里。光化学反应的临床表现范围光毒性化合物很棒，不仅包括皮肤反应红斑和浮肿伴随着过度的晒伤反应，但也光致癌和光突变(反映DNA损伤)，光过敏(反映蛋白质损伤)和细胞毒性反应似乎涉及膜的破坏。我们的研究将集中在尝试识别具有光毒性的化合物的共同特征，重点关于可能涉及的激发态，即电荷转移或在自然界中是激动人心的。据认为，这种物种特别有可能在生物聚合物存在的情况下发生不受欢迎的光反应。