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通过环糊精-毛细管区带电泳法对N-咪唑衍生物(芳香酶抑制剂)进行手性拆分。对映体选择性识别机制。

Chiral separation of N-imidazole derivatives, aromatase inhibitors, by cyclodextrin-capillary zone electrophoresis. Mechanism of enantioselective recognition.

作者信息

Foulon Catherine, Danel Cécile, Vaccher Marie-Pierre, Bonte Jean-Paul, Vaccher Claude, Goossens Jean-François

机构信息

Laboratoire de Chimie Analytique, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Lille, Lille, France.

出版信息

Electrophoresis. 2004 Aug;25(16):2735-44. doi: 10.1002/elps.200405903.

Abstract

Baseline separation of ten new, substituted [1-(imidazo-1-yl)-1-phenylmethyl)] benzothiazolinone and benzoxazolinone derivatives with one chiral center was achieved using cyclodextrin-capillary zone electrophoresis (CD-CZE). A method for the enantiomeric resolution of these compounds was developed using neutral CDs (native alpha-, beta-, gamma-CDs or alpha-, beta-, gamma-hydroxypropyl (HP)-CDs) as chiral selectors. Operational parameters including the nature and concentration of the chiral selectors, pH, ionic strength, organic modifiers, temperature, and applied voltage were investigated. The use of neutral CDs provides enantiomeric resolution by inclusion of compounds in the CD cavity. The HP-alpha-CD and HP-beta-CD were found to be the most effective complexing agents and allowed efficient enantiomeric resolutions. Optimal separation of N-imidazole derivatives was obtained using 50 mM phosphate buffer at pH 2.5 containing either HP-alpha-CD or HP-beta-CD (7.5-12.5 mM) at 25 degrees C, with an applied field of 0.50 kV.cm(-1) giving resolution factors Rs superior to 1.70 with migration times of the second enantiomer less than 13 min. The same enantiomer migration order observed for all molecules can be related to a close interaction mechanism with CDs. The influence of structural features of the solutes on Rs and tm was studied. The lipophilic character (log kw) of the solutes and the apparent and averaged association constants of inclusion complexes for four compounds with the six different CDs led us to rationalize the enantioseparation mechanisms. The conclusions were corroborated with reversed-phase high-performance liquid chromatography (HPLC) on chiral stationary phases (CSPs) based on CDs.

摘要

使用环糊精-毛细管区带电泳(CD-CZE)实现了十种具有一个手性中心的新型取代[1-(咪唑-1-基)-1-苯基甲基]苯并噻唑啉酮和苯并恶唑啉酮衍生物的基线分离。以中性环糊精(天然α-、β-、γ-环糊精或α-、β-、γ-羟丙基(HP)-环糊精)作为手性选择剂,开发了这些化合物的对映体拆分方法。研究了包括手性选择剂的性质和浓度、pH值、离子强度、有机改性剂、温度和施加电压在内的操作参数。中性环糊精的使用通过将化合物包合在环糊精腔内来实现对映体拆分。发现HP-α-环糊精和HP-β-环糊精是最有效的络合剂,并能实现高效的对映体拆分。在25℃下,使用pH 2.5的50 mM磷酸盐缓冲液,其中含有7.5-12.5 mM的HP-α-环糊精或HP-β-环糊精,施加电场为0.50 kV·cm⁻¹,得到的分离因子Rs优于1.70,第二种对映体的迁移时间小于13分钟,从而实现了N-咪唑衍生物的最佳分离。所有分子观察到的相同对映体迁移顺序可能与与环糊精的紧密相互作用机制有关。研究了溶质结构特征对Rs和tm的影响。溶质的亲脂性特征(log kw)以及四种化合物与六种不同环糊精形成的包合物的表观和平均缔合常数,使我们能够合理化对映体拆分机制。基于环糊精的手性固定相(CSPs)的反相高效液相色谱(HPLC)证实了这些结论。

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