新型对映体纯西格玛受体调节剂：通过高效液相色谱法进行快速（半）制备型手性拆分及绝对构型确定

Novel Enantiopure Sigma Receptor Modulators: Quick (Semi-)Preparative Chiral Resolution via HPLC and Absolute Configuration Assignment.

作者信息

Rui Marta, Marra Annamaria, Pace Vittorio, Juza Markus, Rossi Daniela, Collina Simona

机构信息

Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Viale Taramelli 12, Pavia 27100, Italy.

Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, Vienna 1090, Austria.

出版信息

Molecules. 2016 Sep 10;21(9):1210. doi: 10.3390/molecules21091210.

The identification of novel pan-sigma receptor (SR) modulators, potentially useful in cancer treatment, represents a new goal of our research. Here, we report on the preparation of novel chiral compounds characterized by a 3-C alkyl chain bridging an aromatic portion to a 4-benzyl-piperidine moiety. All of the studied compounds have been prepared both in racemic and enantiomerically-pure form, with the final aim to address the role of chirality in the SR interaction. To isolate and characterize enantiomeric compounds, high-performance liquid chromatography (HPLC) procedures were set up. A systematic analytical screening, involving several combinations of chiral stationary and mobile phases, allowed us to optimize the analytical resolution and to set up the (semi-)preparative chromatographic conditions. Applying the optimized procedure, the enantiomeric resolution of the studied compounds was successfully achieved, obtaining all of the compounds with an enantiomeric excess higher than 95%. Lastly, the absolute configuration has been empirically assigned to enantiopure compounds, combining the electronic circular dichroism (ECD) technique to the elution order study.

鉴定新型泛西格玛受体（SR）调节剂（可能对癌症治疗有用）是我们研究的新目标。在此，我们报告了新型手性化合物的制备，其特征在于通过3-C烷基链将芳族部分与4-苄基-哌啶部分桥接。所有研究的化合物均以消旋体和对映体纯形式制备，最终目的是研究手性在SR相互作用中的作用。为了分离和表征对映体化合物，建立了高效液相色谱（HPLC）方法。通过系统的分析筛选，涉及手性固定相和流动相的多种组合，我们能够优化分析分辨率并建立（半）制备色谱条件。应用优化后的方法，成功实现了所研究化合物的对映体拆分，获得了所有对映体过量高于95%的化合物。最后，结合电子圆二色性（ECD）技术和洗脱顺序研究，凭经验确定了对映体纯化合物的绝对构型。