(3R,5S,7as)-(3,5-Bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol, a Novel Neuroprotective Agent
(3R,5S,7as)-(3,5-Bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol, a Novel Neuroprotective Agent
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DOI：
10.1021/jm900254k
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发表时间：
2009-12-10
影响因子：
7.3
通讯作者：
Audus, Kenneth L.
中科院分区：
文献类型：
--
作者：
Desino, Kelly E.;Ansar, Sabah;Audus, Kenneth L.
与微管相互作用的化合物，如紫杉醇，已被证明具有针对β-淀粉样蛋白（A β）诱导的与阿尔茨海默病相关的神经变性的保护特性。在这项工作中，新的代理（3R，5S，7as）-（3，5-双（4-氟苯基）四氢-1H-恶唑并[3，4-c]恶唑-7a-基）甲醇的有效性，保护神经元免受几种毒性刺激和其与微管网络的相互作用进行了研究。神经元培养物暴露于存在5 nM的A β肽（3R，5S，7as）-（3，5-双（4-氟苯基）四氢-1H-恶唑并[3，4-c]恶唑-7a-基）甲醇导致存活率增加50%。（3R，5S，7as）-（3，5-双（4-氟苯基）四氢-1H-恶唑并[3，4-c]恶唑-7a-基）甲醇。微管结合和微管蛋白组装研究显示了与紫杉醇相比的差异，但证实了（3 R，5 S，7as）-（3，5-双（4-氟苯基）四氢-1H-恶唑并[3，4-c]恶唑-7a-基）甲醇与微管的相互作用。此外，使用牛脑微血管内皮细胞实验的体外研究表明，（3R，5S，7as）-（3，5-双（4-氟苯基）四氢-1H-恶唑并[3，4-c]恶唑-7a-基）甲醇可以容易地以被动方式穿过血脑屏障。
Compounds that interact with microtubules, such as paclitaxel, have been shown to possess protective properties against beta-amyloid (A beta) induced neurodegeneration associated with Alzheimer's disease. In this work, the novel agent (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol was investigated for effectiveness in protecting neurons against several toxic stimuli and its interaction with the microtubule network. Exposure of neuronal cultures to A beta peptide in the presence of 5 nM (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol resulted in a 50% increase in survival, Neuronal cultures treated with other toxic stimuli such as staurosporine, thapsigargin, paraquat, and H2O2 showed significantly enhanced survival in the presence of (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol. Microtubule binding and tubulin assembly studies revealed differences compared to paclitaxel but confirmed the interaction of (3 R, 5 S, 7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol with microtubules. Furthermore, in vitro studies using bovine brain microvessel endothelial cells experiments suggest that (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol can readily cross the blood-brain barrier in a passive manner.