Department of Biochemistry and Molecular Biology, and Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States.
J Am Chem Soc. 2011 Feb 2;133(4):676-9. doi: 10.1021/ja108230s.
There is considerable interest in developing non-peptidic, small-molecule α-helix mimetics to disrupt α-helix-mediated protein−protein interactions. Herein, we report the design of a novel pyrrolopyrimidine-based scaffold for such α-helix mimetics with increased conformational rigidity. We also developed a facile solid-phase synthetic route that is amenable to divergent synthesis of a large library. Using a fluorescence polarization-based assay, we identified cell-permeable, dual MDMX/MDM2 inhibitors, demonstrating that the designed molecules can act as α-helix mimetics.
人们对于开发非肽类、小分子α-螺旋类似物以破坏α-螺旋介导的蛋白质-蛋白质相互作用非常感兴趣。在此，我们报告了一种新型基于吡咯并嘧啶的骨架的设计，用于此类具有增加的构象刚性的α-螺旋类似物。我们还开发了一种简便的固相合成路线，适用于大量文库的发散合成。使用基于荧光偏振的测定法，我们鉴定了具有细胞通透性的双重 MDMX/MDM2 抑制剂，证明所设计的分子可以作为α-螺旋类似物发挥作用。
