The Role of Quinols in Estrogen Neuroprotection

喹啉在雌激素神经保护中的作用

基本信息

批准号：
7012210
负责人：
LASZLO PROKAI
金额：
$ 32.93万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-01-15 至 2007-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7012210
关键词：
Role Quinols Estrogen Neuroprotection

项目摘要

DESCRIPTION (provided by applicant): There has been mounting evidence that estrogens express neuroprotective effects by the suppression of neurotoxic stimuli largely via their direct radical-scavenging activity. The objective of this grant application is to understand this activity by focusing on the underlying chemistry in which the molecular mechanism of the process and the chemical nature and fate of the products derived from the radical-scavenging reaction are considered the key elements. Our hypotheses center on the role of estrogen-derived quinols as specific reaction products whose involvement has been implicated by preliminary data. By systematically varying substituents in the 2- and/or 4-positions of the phenolic A-ring compounds, we should gain insight into the influence of phenoxy-radical (ArO*) stability, electron density of ArO* at the C-1i0 position and, thus, its reactivity towards hydroxyl radical (-0H). The Fenton-reaction, which leads to 0H formation, will be employed as a chemical model. We hypothesize that hydroxylation will be involved upon *0H exposure as an important process that produces non-radical products from estrogens. In the model system that will be used to study the fate of the synthetic estrogens obtained by the systematic modification of the endogenous compounds, only one type of (mono)hydroxylated species, of a quinol structure, is anticipated via a two-step hydroxyl-radical scavenging mechanism. The rate of quinol formation is expected to correlate not only with the steric and electronic elements of the steroidal compounds, but also with their neuroprotective effect. The phenol to quinol pathway may augment the estrogens' free-radical scavenging efficacy, and make a pivotal contribution to neuroprotection. A reductive quinol to phenol transformation (hence, estrogen "recycling") that prevents the depletion of the available neuroprotective estrogens in vivo will also be investigated. This reactivation (in terms of kinetics and influence by the A-ring substituents) will be studied in vitro in cell-free and cellular systems, and by in vivo microdialysis in experimental animals. Support will be sought for the hypothesis that the reduction of quinols is not accompanied by an increased formation of reactive oxygen species. By using glutamate-induced oxidative stress in HT22 cells as an experimental paradigm, we will study the neuroprotective effects of the phenolic A-ring derivatives of estrogens. In addition to structure - activity relationship studies, a correlation between the propensity of the compound to form its quinol product upon -OH exposure and its effective dose in this model system for neuroprotection will be sought. It is anticipated that the new estrogen analogs selected based on mechanistic studies and in vitro screening will show in vivo neuroprotective effects in a transient middle cerebral artery occlusion, a model for cerebral ischemia. Hence, they will serve as new lead compounds for the development of neuroprotective agents with improved efficacy.

描述（由申请人提供）：有越来越多的证据表明，雌激素通过抑制神经毒性刺激在很大程度上通过其直接自由基扫描活性来表达神经保护作用。该赠款应用的目的是通过关注基础化学方法来理解这项活动，在这种化学中，该过程的分子机制以及从自由基消除反应中得出的产物的化学性质和命运被认为是关键要素。我们的假设集中在雌激素衍生的喹诺尔作为特定反应产物的作用，其参与已与初步数据有关。通过在酚类A形化合物的2和/或4位中系统地变化的取代基，我们应该深入了解苯氧基 - 自由基（ARO*）稳定性的影响，ARO*在C-11I0位置的电子密度，从而对其对羟基自由基（-0H）的反应性。导致0H形成的Fenton反应将被用作化学模型。我们假设在暴露 *0H时将涉及羟基化，这是一种重要的过程，该过程会产生来自雌激素的非自由基产物。在模型系统中，将用于研究通过系统修饰的内源性化合物获得的合成雌激素的命运，只有一种（单）羟基化物质是喹诺尔结构的一种类型的（单）羟基化物种，可以通过两步羟基羟基 - 自由基 - 自由基 - 雷神清除机制。喹诺尔形成的速率预计不仅与类固醇化合物的空间和电子元素相关，而且还与它们的神经保护作用相关。苯酚至喹诺尔途径可能会增强雌激素的自由基清除疗效，并对神经保护作用关键贡献。还将研究还研究了可防止苯酚转化的苯酚转化（因此，雌激素“回收”），可防止体内可用的神经保护性雌激素的耗竭。将在无细胞和细胞系统中研究这种重新激活（就A形取代基的动力学和影响而言），以及实验动物中的体内微透析。将寻求支持的假设，即喹诺尔的还原不伴随着活性氧的形成增加。通过在HT22细胞中使用谷氨酸诱导的氧化应激作为实验范式，我们将研究雌激素的酚类A形衍生物的神经保护作用。除了结构 - 活性关系研究外，还将寻求该化合物在-OH暴露后形成其喹诺尔产物的倾向与该神经保护模型系统中的有效剂量之间的相关性。预计基于机械研究和体外筛查选择的新雌激素类似物将在瞬时大脑中动脉闭塞中显示体内神经保护作用，这是脑缺血的模型。因此，它们将作为开发具有提高功效的神经保护剂的新铅化合物。