用于抑制PI3激酶的4-亚氨基噻唑烷酮的合成及药理评价
Synthesis and Pharmacological Evaluation of 4-Iminothiazolidinones for Inhibition of PI3 Kinase.
作者信息
Pinson Jo-Anne, Schmidt-Kittler Oleg, Frazzetto Mark, Zheng Zhaohua, Jennings Ian G, Kinzler Kenneth W, Vogelstein Bert, Chalmers David K, Thompson Philip E
机构信息
Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Vic. 3052, Australia.
出版信息
Aust J Chem. 2012 Jan 10;65(10):1396-1404. doi: 10.1071/CH12140.
The thiazolidinedione, compound , has previously shown pan-inhibition of the phosphoinositide 3-kinase (PI3K) class I isoforms. We hypothesized the derivatization of the thiazolidinedione core of compound could introduce isoform selectivity. We report the synthesis, characterization, and inhibitory activity of a novel series of 4-iminothiazolidin-2-ones for inhibition of the class I PI3K isoforms. Their synthesis was successfully achieved by multiple pathways described in this paper. Initial in vitro data of 28 analogues demonstrated poor inhibition of all class I PI3K isoforms. However, we identified an alternate target, the phosphodiesterases, and present preliminary screening results showing improved inhibitory activity.
噻唑烷二酮化合物此前已显示出对I类磷酸肌醇3激酶（PI3K）亚型的全面抑制作用。我们推测化合物噻唑烷二酮核心的衍生化可能会引入亚型选择性。我们报告了一系列新型4-亚氨基噻唑烷-2-酮对I类PI3K亚型抑制作用的合成、表征及抑制活性。本文所述的多种途径成功实现了它们的合成。28种类似物的初步体外数据表明，对所有I类PI3K亚型的抑制作用较差。然而，我们确定了另一个靶点——磷酸二酯酶，并展示了初步筛选结果，显示出改进的抑制活性。
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