Lead optimization of novel p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold
Lead optimization of novel p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold
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DOI：
10.1016/j.bmcl.2012.11.091
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发表时间：
2013-02-01
影响因子：
2.7
通讯作者：
Soga, Tsunehiko
中科院分区：
文献类型：
--
作者：
Miyazaki, Masaki;Naito, Hiroyuki;Soga, Tsunehiko
为了发现p53-MDM2相互作用的有效抑制剂，从而获得有效的抗癌药物，我们通过模仿MDM2与Nutlins的相互作用模式，通过支架跳跃的方式发现了双氢咪唑噻唑衍生物，并对其进行了合成和优化。在发现之后，我们遇到了一个问题，涉及支架的化学不稳定性，即易氧化，导致咪唑噻唑。为了解决这一问题并获得进一步有效的化合物，我们进行了药物研究，从而通过将甲基结合到C-6位置以避免氧化，并通过修饰额外的脯氨酸基序的C-2片段，从而提供了最佳的化合物，从而提供了高效的化合物。吡咯烷在C-2位置的掺入增加了与MDM2蛋白的另一个疏水相互作用位点，这是通过共晶结构分析观察到的诱导拟合产生的。与早期的lead(+)-1或Nutlin-3a相比，这些优化分子的效力有显著提高。(c) 2012 Elsevier Ltd.版权所有。
With the aim of discovering potent inhibitors of the p53-MDM2 interaction and thus obtaining a potent anticancer drug, we have pursued synthesis and optimization of dihydroimidazothiazole derivatives, which have been discovered via scaffold hopping by mimicing the mode of interaction between MDM2 and Nutlins. Upon the discovery we encountered a problem involving the chemical instability of the scaffold, that is, susceptibility to oxidation which led to imidazothiazole. In order to solve this problem and to obtain further potent compounds, we executed medicinal research and thus furnished the optimal compounds by incorporating the methyl group onto the C-6 position to avoid the oxidation, and by modifying the C-2 moiety of the additional proline motif, which furnished high potency. The incorporation of the pyrrolidine moiety at the C-2 position raised another hydrophobic interaction site with MDM2 protein, which was generated by the induced-fitting observed by co-crystal structure analysis. These optimal molecules showed significant improvement in potency when compared with the early lead (+)-1 or Nutlin-3a. (c) 2012 Elsevier Ltd. All rights reserved.