Chemical modification of the multitarget neuroprotective compound fisetin.
Chemical modification of the multitarget neuroprotective compound fisetin.
复制标题
DOI：
10.1021/jm2012563
复制
发表时间：
2012-01-12
影响因子：
7.3
通讯作者：
Maher, Pamela
中科院分区：
文献类型：
--
作者：
Chiruta, Chandramouli;Schubert, David;Dargusch, Richard;Maher, Pamela
许多因素与年龄相关的CNS疾病有关，因此仅调节单一因素不太可能提供有效的治疗。也许更好的方法是识别具有与维持大脑功能相关的多种生物活性的小分子。最近，我们确定了一种口服活性，神经保护和认知增强分子，类黄酮非瑟酮，这是有效的几种动物模型的中枢神经系统疾病。非瑟酮具有直接的抗氧化活性，也可以增加细胞内谷胱甘肽（GSH），主要的内源性抗氧化剂的水平。此外，非瑟酮具有神经营养和抗炎活性。然而，其在基于细胞的测定中相对较高的EC50、低亲脂性、高tPSA和差的生物利用度表明存在药用化学改进的空间。在这里，我们描述了一个多层次的方法来筛选，使我们能够确定非瑟酮衍生物在体外神经保护模型中具有显着增强的活性，同时保持其他关键活动。
Many factors are implicated in age-related CNS disorders making it unlikely that modulating only a single factor will provide effective treatment. Perhaps a better approach is to identify small molecules that have multiple biological activities relevant to the maintenance of brain function. Recently, we identified an orally active, neuroprotective and cognition-enhancing molecule, the flavonoid fisetin, that is effective in several animal models of CNS disorders. Fisetin has direct antioxidant activity and can also increase the intracellular levels of glutathione (GSH), the major endogenous antioxidant. In addition, fisetin has both neurotrophic and anti-inflammatory activity. However, its relatively high EC50 in cell based assays, low lipophilicity, high tPSA and poor bioavailability suggest that there is room for medicinal chemical improvement. Here we describe a multi-tiered approach to screening that has allowed us to identify fisetin derivatives with significantly enhanced activity in an in vitro neuroprotection model while at the same time maintaining other key activities.
登录
查看更多内容
影响因子：
4.7
作者：
Sagara，Y;Vanhnasy，J;Maher，P
通讯作者：
Maher，P
影响因子：
2.9
作者：
Maher, Pamela;Salgado, Karmen F.;Lapchak, Paul A.
通讯作者：
Lapchak, Paul A.
影响因子：
8.3
作者：
Gelderblom, Mathias;Leypoldt, Frank;Magnus, Tim
通讯作者：
Magnus, Tim
影响因子：
6.1
作者：
Shia, Chi-Sheng;Tsai, Shang-Yuan;Chao, Pei-Dawn Lee
通讯作者：
Chao, Pei-Dawn Lee
影响因子：
3.7
作者：
Maher P;Dargusch R;Ehren JL;Okada S;Sharma K;Schubert D
通讯作者：
Schubert D