Wang Zhenyu, Jonca Malgorzata, Lambros Ted, Ferguson Stephen, Goodnow Robert
Discovery Chemistry, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.
J Pharm Biomed Anal. 2007 Dec 21;45(5):720-9. doi: 10.1016/j.jpba.2007.08.013. Epub 2007 Aug 17.
Inhibition of the MDM2-p53 interaction can stabilize the p53 protein and offer a novel strategy for cancer therapy. The imidazoline compound (Nutlin-3) is a promising small molecule antagonist of the MDM2-p53 interaction. This compound was synthesized as a racemic mixture, and one enantiomer is 100-200-fold more active than the other enantiomer. In this study, various enantiomeric separation approaches were explored to resolve the Nutlin-3 enantiomers using chiral supercritical fluid chromatography (SFC) as well as chiral liquid chromatography (LC) under normal phase mode, reversed phase mode and polar organic phase mode. The chiral SFC method based on Chiralcel OD column showed superior separation in terms of selectivity and efficiency. Optimization of the chiral separation method enabled high throughput preparative scale purification. Ultimately, 5 g of racemic mixture were purified on Prep-SFC in 75 min with the recovery rate above 92%.
抑制MDM2-p53相互作用可使p53蛋白稳定，并为癌症治疗提供一种新策略。咪唑啉化合物（Nutlin-3）是一种有前景的MDM2-p53相互作用小分子拮抗剂。该化合物以消旋混合物形式合成，其中一种对映体的活性比另一种对映体高100 - 200倍。在本研究中，探索了各种对映体分离方法，以使用手性超临界流体色谱（SFC）以及正相模式、反相模式和极性有机相模式下的手性液相色谱（LC）来拆分Nutlin-3对映体。基于Chiralcel OD柱的手性SFC方法在选择性和效率方面表现出卓越的分离效果。手性分离方法的优化实现了高通量制备规模的纯化。最终，5 g消旋混合物在制备型SFC上于75分钟内纯化完成，回收率高于92%。
