Direct Enantiomer Differentiation of Drugs and Drug-Like Compounds via Noncovalent Copper–Amino Acid Complexation and Ion Mobility-Mass Spectrometry,Analytical Chemistry

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Direct Enantiomer Differentiation of Drugs and Drug-Like Compounds via Noncovalent Copper–Amino Acid Complexation and Ion Mobility-Mass Spectrometry
Analytical Chemistry ( IF 6.7 ) Pub Date : 2024-07-25 , DOI: 10.1021/acs.analchem.4c02710
Benjamin K Blakley ₁ , Emanuel Zlibut ₁ , Rashi M Gupta ₁ , Jody C May ₁ , John A McLean ₁

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Drug enantiomers can possess vastly different pharmacological properties, yet they are identical in their chemical composition and structural connectivity. Thus, resolving enantiomers poses a great challenge in the field of separation science. Enantiomer separations necessitate interaction of the analyte with a chiral environment─in mass spectrometry-based analysis, a common approach is through a three-point interaction with a chiral selector commonly introduced during sample preparation. In select cases, the structural difference imparted through noncovalent complexation results in enantiomer-specific structural differences, facilitating measurement using a structurally selective analytical technique such as ion mobility-mass spectrometry (IM-MS). In this work, we investigate the direct IM-MS differentiation of chiral drug compounds using mononuclear copper complexes incorporating an amino acid chiral selector. A panel of 20 chiral drugs and drug-like compounds were investigated for separation, and four l-amino acids (l-histidine, l-tryptophan, l-proline, and l-tyrosine) were evaluated as chiral selectors (CS) to provide the chiral environment necessary for differentiation. Enantiomer differentiation was achieved for four chiral molecule pairs (R/S-thalidomide, R/S-baclofen, R/S-metoprolol, and d/l-panthenol) with two-peak resolution (R_p–p) values ranging from 0.7 (>10% valley) to 1.5 (baseline separation). Calibration curves relating IM peak areas to enantiomeric concentrations enabled enantiomeric excess quantitation of racemic thalidomide and metoprolol with residuals of 5.7 and 2.5%, respectively. Theoretical models suggest that Cu^II and l-histidine complexation around the analyte chiral center is important for gas-phase stereoselectivity. This study demonstrates the potential of combining enantioselective noncovalent copper complexation with structurally selective IM-MS for differentiating chiral drugs and drug-like compounds.

中文翻译：

通过非共价铜-氨基酸络合和离子淌度质谱法直接区分药物和类药物化合物

药物对映体可能具有截然不同的药理学特性，但它们的化学组成和结构连接性是相同的。因此，解析对映体对分离科学领域提出了巨大的挑战。对映体分离需要分析物与手性环境相互作用，在基于质谱的分析中，一种常见的方法是通过与样品制备过程中通常引入的手性选择器进行三点相互作用。在某些情况下，通过非共价络合产生的结构差异会导致对映体特异性的结构差异，从而有助于使用离子淌度质谱 (IM-MS) 等结构选择性分析技术进行测量。在这项工作中，我们研究了使用结合氨基酸手性选择器的单核铜配合物对手性药物化合物的直接 IM-MS 区分。研究了一组 20 种手性药物和药物样化合物的分离情况，并评估了四种L-氨基酸（ L-组氨酸、 L-色氨酸、 L-脯氨酸和L-酪氨酸）作为手性选择剂 (CS)，以提供分化所需的手性环境。四个手性分子对（ R / S -沙利度胺、 R / S -巴氯芬、 R / S -美托洛尔和d / l -泛醇）实现了对映体区分，双峰分辨率 ( R _p–p ) 值范围为 0.7 （>10% 谷值）至 1.5（基线分离）。将 IM 峰面积与对映体浓度相关联的校准曲线能够对外消旋沙利度胺和美托洛尔进行对映体过量定量，残差分别为 5.7% 和 2.5%。理论模型表明，分析物手性中心周围的 Cu ^II和l-组氨酸络合对于气相立体选择性非常重要。这项研究证明了将对映选择性非共价铜络合与结构选择性 IM-MS 相结合来区分手性药物和药物样化合物的潜力。

更新日期：2024-07-25

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