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Tandem Mass Spectrometry Approaches for Differentiation and Quantification Pidotimod and Its Three Isomers in the Gas Phase 用于区分和定量气相中匹多莫德及其三种异构体的串联质谱方法。
IF 2.8 4区 化学 Q2 CHEMISTRY, ANALYTICAL Pub Date : 2024-07-21 DOI: 10.1002/chir.23699
Caiyu Zhang, Yang Liu, Lan He, Wei Li

Pidotimod is a chiral drug that possesses two chiral centers, resulting in three isomeric impurities (analytes, A). This study employs electrospray ionization ion trap mass spectrometry (ESI-MS) through collision-induced dissociation (CID) to investigate the chiral recognition of pidotimod and its three isomers to eliminate chromatographic separation. Three approaches were explored: (1) Protonated molecules in CID exhibited discriminative potential for diastereomers, with the ability to distinguish between S,S and R,R configurations, albeit with an Rchiral value of ~1.8. However, differentiation between R,S and S,R configurations was not achievable. (2) Alkali adductions (lithium and sodium) only discerned diastereomers. The Rchiral values of the diastereomers obtained from alkali adduct ions were significantly lower than those obtained from protonated ions. (3) Therefore, a third approach was used to address the challenge of distinguishing between R,S and S,R configurations, including the introduction of chiral references (ref) and transition metals (MII) to form metal-bound complexes [MII(A)(ref)-H]+. Additionally, we synthesized a novel ligand, 4-(N-tert-butoxycarbonyl [Boc]-L-prolinamido)phenol (denoted as ligand A), by modifying N-t-Boc-L-Pro with 2-aminophenol, which, in combination with CuII and NiII, enabled simultaneous differentiation of all four isomers. CuII complexes exhibited significant chiral selectivity between R,S and S,R configurations. Density functional theory calculations were performed to further elucidate the stereodynamic behavior and stoichiometry of these ions in the gas phase. These calculations revealed the interaction energy and coordination sites of the precursor ions in the gas phase, correlating well with MS/MS experiment results. Additionally, the logarithm of the CuII complexes' characteristic fragment ion abundance ratio demonstrated a strong linear relationship with enantiomeric excess (ee). This study presents a novel strategy for chiral drug quality control that eliminates chromatographic separation.

匹多莫德是一种手性药物,具有两个手性中心,从而产生了三种异构体杂质(分析物,A)。本研究采用电喷雾离子阱质谱法(ESI-MS),通过碰撞诱导解离(CID)研究匹多莫德及其三种异构体的手性识别,以消除色谱分离。研究人员探索了三种方法:(1) CID 中的质子化分子表现出对非对映异构体的鉴别潜力,能够区分 S,S 和 R,R 构型,尽管 Rchiral 值约为 1.8。然而,R,S 和 S,R 构型之间却无法区分。(2) 碱加成(锂和钠)只能分辨非对映异构体。从碱加成离子中得到的非对映体的 R 手性值明显低于从质子化离子中得到的非对映体的 R 手性值。(3) 因此,我们采用了第三种方法来解决区分 R,S 和 S,R 构型的难题,包括引入手性参照物(ref)和过渡金属(MII)以形成金属结合复合物 [MII(A)(ref)-H]+。此外,我们还通过用 2-aminophenol 对 N-t-Boc-L-Pro 进行改性,合成了一种新型配体,4-(N-叔丁氧羰基 [Boc]-L-prolinamido)phenol (记为配体 A),这种配体与 CuII 和 NiII 结合使用,可以同时分化所有四种异构体。CuII 复合物在 R、S 和 S、R 构型之间表现出显著的手性选择性。为了进一步阐明这些离子在气相中的立体动力学行为和化学计量,我们进行了密度泛函理论计算。这些计算揭示了前体离子在气相中的相互作用能和配位位点,与 MS/MS 实验结果密切相关。此外,CuII 复合物特征碎片离子丰度比的对数与对映体过量(ee)呈很强的线性关系。这项研究提出了一种无需色谱分离的手性药物质量控制新策略。
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引用次数: 0
The Development of One New Normal Phase Liquid Chromatography Method and Thermodynamic Investigation of Olodaterol Hydrochloride Enantiomer 一种新型正相液相色谱法的开发及盐酸奥洛他特罗对映体的热力学研究
IF 2.8 4区 化学 Q2 CHEMISTRY, ANALYTICAL Pub Date : 2024-07-21 DOI: 10.1002/chir.23704
Wanbing Rao, Chenxia Zhang, Baolei Luan, Zhongqing Wang, Meiyan Qiu, Shaoyu Cai

In order to improve and replace the enantiomer method outlined in the olodaterol hydrochloride draft monograph (From the European Pharmacopoeia forum), one new, simple, and fast enantioselective normal phase high-performance liquid chromatography chiral method was developed on polysaccharide-based Chiral MX (2) (4.6 × 250 mm, 5 μm) column. n-Hexane, ethanol, and diethylamine in the ratio of 40:60:0.1 (V/V/V) were selected as mobile phase at a flow rate of 0.8 mL/min, and the detection was performed on a photodiode array detector at 225 nm with 5 μL injection volume. The column temperature was set at 40°C for better peak shape and sensitivity. The analysis time can be shortened to 15 min, whereas the resolution between enantiomer and olodaterol was found to be even more than 10.0, which was far better than that obtained with the reported method in this draft monograph. The developed chiral method was validated in accordance with ICH Q2 (R1), including specificity, LOD&LOQ, precision, linearity, accuracy, and robustness. Thereby, the proposed method was demonstrated to be suitable for the determination of enantiomer in olodaterol hydrochloride bulk drug and drug product. Besides, the thermodynamic parameters were evaluated on the basis of Van't Hoff plots that was used to explain correlative chiral recognition mechanisms with the chiral stationary phase.

为了改进并取代盐酸奥洛他特罗专著草案(来自欧洲药典论坛)中的对映体方法,本研究在多糖基手性 MX (2) (4. 6 × 250 mm, 5 μm)色谱柱上建立了一种新的、简单而快速的对映体选择性正相高效液相色谱手性方法。流动相为正己烷、乙醇和二乙胺,比例为 40:60:0.1(V/V/V),流速为 0.8 mL/min,检测波长为 225 nm,进样量为 5 μL。色谱柱温度设定为 40°C,以获得更好的峰形和灵敏度。分析时间可缩短至 15 分钟,而对映体和奥洛他特罗之间的分辨率甚至超过了 10.0,远远优于本专著草案中报告的方法。所建立的手性方法按照 ICH Q2 (R1) 进行了验证,包括特异性、LOD&LOQ、精密度、线性、准确度和稳健性。结果表明,该方法适用于盐酸奥洛他特罗原药和药品中对映体的测定。此外,还根据 Van't Hoff 图对热力学参数进行了评估,以解释手性固定相的相关手性识别机制。
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引用次数: 0
Study of the Enantioselectivity and Recognition Mechanism of Allyl-β-CD Modified Organic Polymer Monolithic Capillary Column 烯丙基-β-CD改性有机聚合物整体毛细管柱的对映体选择性和识别机理研究
IF 2.8 4区 化学 Q2 CHEMISTRY, ANALYTICAL Pub Date : 2024-07-09 DOI: 10.1002/chir.23697
Chaoheng Jia, Futao Li, Anqi Li, Qiwen Li, Lu Huang

Allyl-β-CD was synthesized and used as the chiral functional monomer to prepare chiral organic polymer monolithic columns in capillary HPLC. First, the enantioselectivity of the prepared allyl-β-CD modified organic polymer monolithic capillary columns was investigated. Then, the influences of enantioseparation conditions of chiral drugs were further explored. Finally, the recognition mechanism was studied by molecular docking with AutoDock. Complete enantioseparations of four chiral drugs as well as partial enantioseparations of eight chiral drugs have been achieved. Results showed that the RSD values for run-to-run, day-to-day, and column-to-column variations ranged from 1.2% to 4.6%, 1.4% to 4.7%, and 2.0% to 6.1%, respectively. The enantioselectivity factor rather than resolution is correlated with the binding free energy difference between enantiomers with allyl-β-CD. Furthermore, the abundant ether bonds, hydroxyl groups, and hydrophobic cavities in cyclodextrin are responsible for the enantioseparation ability of the chiral monolithic capillary columns.

合成了烯丙基-β-CD,并将其作为手性功能单体用于制备毛细管高效液相色谱中的手性有机聚合物整体柱。首先考察了所制备的烯丙基-β-CD修饰有机聚合物整体柱的对映体选择性。然后,进一步探讨了手性药物对映体分离条件的影响。最后,利用 AutoDock 进行了分子对接研究。实现了四种手性药物的完全对映体分离和八种手性药物的部分对映体分离。结果表明,运行间差异、日间差异和柱间差异的 RSD 值分别为 1.2% 至 4.6%、1.4% 至 4.7% 和 2.0% 至 6.1%。对映体选择性因子而非分辨率与对映体与烯丙基-β-CD 的结合自由能差有关。此外,环糊精中丰富的醚键、羟基和疏水腔也是手性整体毛细管柱具有对映体分离能力的原因。
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引用次数: 0
Expanding the Role of Chiral Drugs and Chiral Nanomaterials as a Potential Therapeutic Tool 扩大手性药物和手性纳米材料作为潜在治疗工具的作用。
IF 2.8 4区 化学 Q2 CHEMISTRY, ANALYTICAL Pub Date : 2024-07-04 DOI: 10.1002/chir.23698
Sourabh Satapathy, Shivam Kumar, Balak Das Kurmi, Ghanshyam Das Gupta, Preeti Patel

Chirality, the property of molecules having mirror-image forms, plays a crucial role in pharmaceutical and biomedical research. This review highlights its growing importance, emphasizing how chiral drugs and nanomaterials impact drug effectiveness, safety, and diagnostics. Chiral molecules serve as precise diagnostic tools, aiding in accurate disease detection through unique biomolecule interactions. The article extensively covers chiral drug applications in treating cardiovascular diseases, CNS disorders, local anesthesia, anti-inflammatories, antimicrobials, and anticancer drugs. Additionally, it explores the emerging field of chiral nanomaterials, highlighting their suitability for biomedical applications in diagnostics and therapeutics, enhancing medical treatments.

手性是分子具有镜像形式的特性,在制药和生物医学研究中发挥着至关重要的作用。本综述突出了手性日益增长的重要性,强调了手性药物和纳米材料如何影响药物的有效性、安全性和诊断。手性分子可作为精确的诊断工具,通过独特的生物分子相互作用帮助准确检测疾病。文章广泛介绍了手性药物在治疗心血管疾病、中枢神经系统疾病、局部麻醉、消炎药、抗菌药和抗癌药方面的应用。此外,文章还探讨了新兴的手性纳米材料领域,重点介绍了它们在诊断和治疗方面的生物医学应用,从而提高了医疗效果。
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引用次数: 0
Induced Chirality in Sulfasalazine by Complexation With Albumins: Theoretical and Experimental Study 通过与白蛋白络合诱导磺胺沙拉嗪的手性:理论与实验研究
IF 2.8 4区 化学 Q2 CHEMISTRY, ANALYTICAL Pub Date : 2024-07-04 DOI: 10.1002/chir.23696
Giulia Saneti Grandini, Valdecir Farias Ximenes, Nelson Henrique Morgon, Aguinaldo Robinson de Souza

Through molecular recognition, drugs can interact and complex with macromolecules circulating in the body. The serum albumin transport protein, found in several mammals, has several interaction sites where these molecules can be located. The drug sulfasalazine (SSZ) is known in the literature to complex at drug site 1 (DS1) in human serum (HSA) and bovine serum (BSA) proteins. This complexation can be studied using various spectroscopic techniques. With the techniques used in this work, absorption in the ultraviolet and visible regions (UV–Vis) and electronic circular dichroism (ECD), a significant difference was observed in the results involving HSA and BSA. The application of theoretical methodologies, such as TD-DFT and molecular docking, suggests that the conformation that SSZ assumes in DS1 of the two proteins is different, which exposes it to different amino acid residues and different hydrophobicities. This difference in conformation may be related to the location of DS1 where the drug interacts or to the possibility of SSZ moving in the BSA site, due to its larger size, and moving less freely in HSA.

通过分子识别,药物可以与体内循环的大分子发生相互作用和复合。在几种哺乳动物体内发现的血清白蛋白转运蛋白有几个相互作用位点,这些分子可以位于其中。据文献记载,药物磺胺沙拉嗪(SSZ)可与人血清(HSA)和牛血清(BSA)蛋白中的药物位点 1(DS1)发生复合物作用。这种络合作用可通过各种光谱技术进行研究。本研究中使用的紫外和可见光区吸收(UV-Vis)和电子圆二色性(ECD)技术,在涉及 HSA 和 BSA 的结果中观察到了显著的差异。理论方法(如 TD-DFT 和分子对接)的应用表明,SSZ 在两种蛋白质的 DS1 中的构象不同,这使其暴露于不同的氨基酸残基和不同的疏水性。这种构象上的差异可能与药物相互作用的 DS1 位置有关,也可能与 SSZ 在 BSA 位点移动的可能性有关,因为 SSZ 的体积较大,而在 HSA 中移动的自由度较低。
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引用次数: 0
Self-Assembled Chiral Film Based on Melanin Polymers 基于黑色素聚合物的自组装手性薄膜。
IF 2 4区 化学 Q2 CHEMISTRY, ANALYTICAL Pub Date : 2024-06-18 DOI: 10.1002/chir.23695
Massimiliano Gaeta, Gabriele Travagliante, Matteo Barcellona, Maria Elena Fragalà, Roberto Purrello, Alessandro D'Urso

Chirality plays a fundamental role in natural phenomena, yet its manifestation on solid surfaces remains relatively unexplored. In this study, we investigate the formation of chiroptical melanin-based self-assembled films on quartz substrates, leveraging mussel-inspired surface chemistry. Water-soluble porphyrins serve as molecular synthons, facilitating the spontaneous formation of hetero-aggregates in phosphate-buffered saline containing L- or D-DOPA. Spectroscopic analysis reveals chiral transfer from DOPA enantiomers to porphyrin hetero-aggregates, followed by the disruption of these latter and subsequent generation of chiral melanin structures in solution. Quartz substrates inserted into these solutions spontaneously accumulate homogeneous melanin-like films over days, demonstrating the feasibility of self-assembly. The resulting films exhibit characteristic UV/Vis and CD spectra, with distinct signals indicating successful chiral induction. Interestingly, the AFM characterizations reveal a distinct surface morphology, and in addition, some thermal and mechanical properties have been taken into account. Overall, this study sheds light on the formation, stability, and chiroptical properties of melanin-based films, paving the way for their application in various fields.

手性在自然现象中扮演着重要角色,但其在固体表面上的表现形式却相对欠缺研究。在这项研究中,我们利用贻贝启发的表面化学,研究了在石英基底上形成基于黑色素的手性自组装薄膜。水溶性卟啉可作为分子合成物,在含有 L- 或 D-DOPA 的磷酸盐缓冲盐水中促进异质聚集体的自发形成。光谱分析揭示了 DOPA 对映体向卟啉杂聚物的手性转移,随后这些杂聚物被破坏,进而在溶液中生成手性黑色素结构。插入这些溶液中的石英基底会在数天内自发地积聚成类似黑色素的均匀薄膜,这证明了自组装的可行性。生成的薄膜显示出特征性的 UV/Vis 和 CD 光谱,其独特的信号表明成功地进行了手性诱导。有趣的是,原子力显微镜(AFM)表征显示了独特的表面形态,此外,一些热和机械特性也被考虑在内。总之,这项研究揭示了基于黑色素的薄膜的形成、稳定性和手电特性,为它们在各个领域的应用铺平了道路。
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引用次数: 0
Graph-theoretical chirality measure and chirality–property relations for chemical structures with multiscale mirror asymmetries 具有多尺度镜像不对称的化学结构的图论手性度量和手性-属性关系。
IF 2 4区 化学 Q2 CHEMISTRY, ANALYTICAL Pub Date : 2024-06-10 DOI: 10.1002/chir.23678
Minjeong Cha, Jessica Ma, Ji-Young Kim, Emine Sumeyra Turali Emre, Nicholas A. Kotov

Chirality is an essential geometric property unifying small molecules, biological macromolecules, inorganic nanomaterials, biological microparticles, and many other chemical structures. Numerous chirality measures have attempted to quantify this geometric property of mirror asymmetry and to correlate these measures with physical and chemical properties. However, their utility has been widely limited because these correlations have been largely notional. Furthermore, chirality measures also require prohibitively demanding computations, especially for chiral structures comprised of thousands of atoms. Acknowledging the fundamental problems with quantification of mirror asymmetry, including the ambiguity of sign-variable pseudoscalar chirality measures, we revisit this subject because of the significance of quantifying chirality for quantitative biomimetics and describing the chirality of nanoscale materials that display chirality continuum and scale-dependent mirror asymmetry. We apply the concept of torsion within the framework of differential geometry to the graph theoretical representation of chiral molecules and nanostructures to address some of the fundamental problems and practical limitations of other chirality measures. Chiral gold clusters and other chiral structures are used as models to elaborate a graph-theoretical chirality (GTC) measure, demonstrating its applicability to chiral materials with different degrees of chirality at different scales. For specific cases, we show that GTC provides an adequate description of both the sign and magnitude of mirror asymmetry. The direct correlations with macroscopic properties, such as chiroptical spectra, are enhanced by using the hybrid chirality measures combining parameters from discrete mathematics and physics. Taking molecular helices as an example, we established a direct relation between GTC and optical activity, indicating that this chirality measure can be applied to chiral metamaterials and complex chiral constructs.

手性是统一小分子、生物大分子、无机纳米材料、生物微粒和许多其他化学结构的基本几何特性。许多手性测量方法都试图量化这种镜像不对称的几何特性,并将这些测量方法与物理和化学特性联系起来。然而,由于这些相关性在很大程度上是名义上的,因此其实用性受到了广泛限制。此外,手性测量还需要进行高得令人望而却步的计算,特别是对于由数千个原子组成的手性结构。我们认识到镜像不对称性量化的基本问题,包括符号可变伪标量手性测量的模糊性,因此我们重新探讨了这一主题,因为量化手性对于定量生物仿生学和描述显示手性连续性和尺度依赖性镜像不对称性的纳米材料的手性具有重要意义。我们将微分几何框架内的扭转概念应用于手性分子和纳米结构的图论表示,以解决其他手性度量方法的一些基本问题和实际限制。我们以手性金簇和其他手性结构为模型,阐述了图论手性(GTC)度量,证明它适用于不同尺度、不同手性程度的手性材料。在特定情况下,我们证明 GTC 能够充分描述镜像不对称的符号和大小。通过使用结合离散数学和物理学参数的混合手性度量,增强了与宏观特性(如自旋光谱)的直接相关性。以分子螺旋为例,我们建立了 GTC 与光学活性之间的直接关系,表明这种手性度量可用于手性超材料和复杂的手性结构。
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引用次数: 0
Determination of N-centered stereochemistry in N22-methylated chlorophyll-a derivatives and their epimer-dependent optical spectra 确定 N22-甲基化叶绿素-a 衍生物中的 N 中心立体化学及其表聚体依赖性光学光谱。
IF 2 4区 化学 Q2 CHEMISTRY, ANALYTICAL Pub Date : 2024-06-05 DOI: 10.1002/chir.23681
Riko Ataka, Tohru Taniguchi, Kenji Monde, Hitoshi Tamiaki

An N-centered epimeric mixture of chlorophyll-a derivatives methylated at the inner nitrogen atom was separated by reverse-phase high-performance liquid chromatography. Circular dichroism (CD) spectroscopic analyses of the epimerically pure N22-methyl-chlorins revealed that the minor first-eluted and major second-eluted stereoisomers were (22S)- and (22R)-configurations, respectively. Their visible absorption and CD spectra in solution were dependent on the N22-stereochemistry. The epimer-dependent spectral changes were independent of the substituents at the peripheral 3-position of the core chlorin chromophore.

通过反相高效液相色谱法分离了内氮原子甲基化的叶绿素-a 衍生物的 N-中心二元混合物。对N22-甲基-氯素的二价纯化物进行的圆二色性(CD)光谱分析显示,第一次洗脱的次要立体异构体和第二次洗脱的主要立体异构体分别为(22S)-和(22R)-构型。它们在溶液中的可见吸收光谱和 CD 光谱取决于 N22 立体化学结构。依赖于外延体的光谱变化与核心氯素发色团外围 3 位的取代基无关。
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引用次数: 0
Enantioselective liquid–liquid extraction of 2-cyclohexylmandelic acid enantiomers using chiral ionic liquids 利用手性离子液体对 2-环己基扁桃酸对映体进行对映选择性液液萃取。
IF 2 4区 化学 Q2 CHEMISTRY, ANALYTICAL Pub Date : 2024-05-28 DOI: 10.1002/chir.23682
Yachun Luo, Xiaoyu Deng, Yan Zhang, Genlin Sun, Zhihong Yan

Obtaining optically pure compounds in an eco-friendly and cost-efficient manner plays an important role in human health and pharmaceutical industry. Racemic separation using multistage stereoselective liquid–liquid extraction has become one of the most practical and effective approach to access homochiral enantiomers. Currently, chiral ionic liquids (CILs) with structural designability have become a promising chiral additive and enable them as adjustable candidates for racemic separation. Herein, a high-effective stereoselective liquid–liquid extraction process composed of imidazolium cations and amino acid-derived anions as the chiral additive was established for racemic 2-cyclohexylmandelic acid (CHMA) separation. We have systematically investigated the choice of organic solvent, concentration of CIL, extraction temperature, and the pH of aqueous phase. For three-stage stereoselective extraction, the maximum enantiomeric excess (e.e.) for CHMA was reached up to 40.6%. Furthermore, the mechanism of steric effect and stereoselective capacity between the CILs and racemic CHMA was discussed and simulated. We envision that the work will facilitate the development of CILs in multistage liquid–liquid extraction and promote the large-scale production of optically pure enantiomers.

以环保、经济的方式获得光学纯化合物在人类健康和制药业中发挥着重要作用。利用多级立体选择性液液萃取进行外消旋分离已成为获得同手性对映体最实用、最有效的方法之一。目前,具有结构可设计性的手性离子液体(CILs)已成为一种前景广阔的手性添加剂,使其成为外消旋分离的可调候选物。在此,我们建立了一种由咪唑阳离子和氨基酸衍生阴离子作为手性添加剂的高效立体选择性液液萃取工艺,用于外消旋 2-环己基扁桃酸(CHMA)的分离。我们系统地研究了有机溶剂的选择、CIL 的浓度、萃取温度和水相的 pH 值。在三级立体选择性萃取中,CHMA 的最大对映体过量(e.e.)达到了 40.6%。此外,我们还讨论并模拟了 CILs 与外消旋 CHMA 之间的立体效应和立体选择能力的机理。我们希望这项工作能促进 CILs 在多级液液萃取中的发展,并推动光学纯对映异构体的大规模生产。
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引用次数: 0
Counting the truxillines—11 or more, the question is now 现在的问题是,如果把 11 条或更多的 "长枕 "算在内的话。
IF 2 4区 化学 Q2 CHEMISTRY, ANALYTICAL Pub Date : 2024-05-21 DOI: 10.1002/chir.23680
Tomislav Portada, Zlatko Brkljača

Truxillines are a group of tropane alkaloids present in coca leaves that are formed by photochemical dimerization of cinnamoylcocaine(s). Proportion of different truxilline forms present in cocaine serves as its geographical, manufacture, and storage “fingerprint”; thus, the quantitative determination of truxilline content represents one of the powerful methods of analysis and characterization of cocaine samples. Contrary to the statements repeatedly presented in the literature, namely, that there exist exactly 11 truxillines and that every single truxilline is diastereomer of any other, here we show that, in fact, a total of 15 truxillines exist, which can be divided in two structurally isomeric groups—five mutually diastereomeric truxillates and 10 mutually diastereomeric truxinates.

曲昔林碱是存在于古柯叶中的一组托烷生物碱,由肉桂酰可卡因(s)光化学二聚形成。可卡因中不同形式的曲昔林比例可作为其地理、制造和储存的 "指纹";因此,定量测定曲昔林含量是分析和鉴定可卡因样本的有效方法之一。与文献中反复出现的说法(即存在 11 种曲西林,每种曲西林都是其他曲西林的非对映异构体)相反,我们在此表明,事实上总共存在 15 种曲西林,它们在结构上可分为两组异构体--5 种相互非对映的曲西林酸盐和 10 种相互非对映的曲西林酸盐。
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引用次数: 0
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Chirality
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