Circular dichroism detection in high-performance liquid chromatography: Evaluation of the anisotropy factor

The application of a circular dichroism (c.d.) detection system in HPLC using a chiral stationary phase is presented. The simultaneous measurement of the absorbance and c.d. signal allows the evaluation of the anisotropy factor (g = Δ/) and thus the determination of the enantiomeric excess (e.e.) of the eluates. When this detection system is used in preparative chiral chromatography the collection of the enantiomeric fractions can be readily optimized.     

使用手性冠醚的高效毛细管电泳法研究伯胺类药物的手性分离

目的　采用HPCE法拆分伯胺类药物对映异构体。方法　缓冲液 2 0mmol/LTris 0 .1%H3 PO4(v/v)(pH 2 .0 6 ) +18 冠 6 四甲酸 (18C6H4) ;检测波长 2 10nm。结果　 8种伯胺类药物得以拆分。结论　缓冲液中添加手性冠醚的HPCE法能较好地拆分伯胺类药物。     

手性液晶的研究——Ⅸ．联苯羧酸酯类

合成了文题所述的十三个手性液晶化合物。经元素分析和红外光谱分析确证了其结构，并进行了相态、相变温度和电滞回线的测定，证实其为铁电液晶。     

Enantiomeric Resolution of Drug Compounds by Liquid Chromatography

Novel techniques have recently emerged to separate chiral drug compounds into pure enantiomers. The mechanism, experimental difficulties, and applicability of these methods can vary greatly, and the choices involved are not straightforward. The most significant new advances in the field of chiral separations have come from work done with liquid chromatographic systems and chiral stationary-phase columns. This review describes several commonly used approaches to chiral separation, diastereomeric derivatization, chiral mobile-phase additives, and three major types of chiral stationary phases. Although no single method can be judged superior for every drug application, it appears that chiral stationary phases have received the most attention recently and they are emphasized here.     

Stereoselective distribution of tiaprofenic acid in synovium and cartilage in osteoarthritic patients

Objective: In order to document the stereoselective distribution in joints of a chiral nonsteroidal anti-inflammatory drug, the relative affinities of the enantiomers of tiaprofenic acid in synovium and for cartilage were compared. Methods: The distribution of tiaprofenic acid in synovium and in cartilage was studied 25 h after administering the racemic drug for 2 days (600 mg of a sustained-release preparation, once daily), in 12 inpatients with osteoarthritis of the hip requiring arthroplasty. Enantiomers were quantified in plasma and freeze-ground tissues by a chiral HPLC assay. Results: Plasma concentrations of the dextrorotatory (R) enantiomer (0.40 μg/ml) were higher than those of its antipode. The concentration of racemate in synovium (in dried and fresh tissues, 150% and 40%, respectively, of the concentration in plasma) was much higher than that in cartilage (in dried tissues 32% of the plasma concentration). The ratio of the active, dextrorotatory (R) enantiomer to its antipode was higher in synovial tissue than in plasma. Conclusion: Tiaprofenic acid is distributed stereoselectively in plasma and synovium, which contain a higher concentration of the active, dextrorotatory (R) enantiomer. In cartilage, it reaches only a very low concentration. Received: 26 June 1995/Accepted in revised form: 7 November 1995     

聚合物负载的手性催化剂和手性试剂和合成及应用

近年来,用聚合物负载的手性催化剂和手性试剂完成的不对称合成反应主要集中在潜手性酮的不对称还原反应;烯烃的不对称双羟基化反应;烯烃的不对称环氧化反应;不对称Ｄｉｅｌｓ－Ａｌｄｅｒ反应和饱和碳原子上的不对称取代反应。就近十年来聚合物负载手性催化剂和手性试剂的合成及应用进行了讨论。     

包甲素类似物的绝对构型研究

目的　建立手性包甲素类似物绝对构型的简便方法。方法　以外消旋６β－羟基莨菪烷－３－酮为原料,通过拆分、酰化和还原制备手性包甲素类似物。结果　合成了手性包甲素类似物,通过物理常数、光谱数据鉴定其结构并与已知构型的化合物Ｉｓ进行化学关联确定其绝对构型。结论　本文建立的方法可用于确定某些活性手性包甲素类似物的绝对构型,从而有助于此类化合物构效关系的进一步研究。     

Effects of ibuprofen enantiomers and its coenzyme A thioesters on human prostaglandin endoperoxide synthases

1. Ibuprofen enantiomers and their respective coenzyme A thioesters were tested in human platelets and blood monocytes to determine their selectivity and potency as inhibitors of cyclo-oxygenase activity of prostaglandin endoperoxide synthase-1 (PGHS-1) and PGHS-2.
2. Human blood from volunteers was drawn and allowed to clot at 37°C for 1 h in the presence of increasing concentrations of the test compounds (R-ibuprofen, S-ibuprofen, R-ibuprofenoyl-CoA, S-ibuprofenoyl-CoA, NS-398). Immunoreactive (ir) thromboxane B₂ (TXB₂) concentrations in serum were determined by a specific EIA assay as an index of the cyclo-oxygenase activity of platelet PGHS-1.
3. Heparin-treated blood from the same donors was incubated at 37°C for 24 h with the same concentrations of the test compounds in the presence of lipopolysaccharide (LPS, 10 μg ml⁻¹). The contribution of PGHS-1 was suppressed by pretreatment of the volunteers with aspirin (500 mg; 48 h before venepuncture). As a measure of LPS induced PGHS-2 activity immunoreactive prostaglandin E₂ (irPGE₂) plasma concentrations were determined by a specific EIA assay.
4. S-ibuprofen inhibited the activity of PGHS-1 (IC₅₀ 2.1 μM) and PGHS-2 (IC₅₀ 1.6 μM) equally. R-ibuprofen inhibited PGHS-1 (IC₅₀ 34.9) less potently than S-ibuprofen and showed no inhibition of PGHS-2 up to 250 μM. By contrast R-ibuprofenoyl-CoA thioester inhibited PGE₂ production from LPS-stimulated monocytes almost two orders of magnitude more potently than the generation of TXB₂ (IC₅₀ 5.6 vs 219 μM).
5. Western blotting of PGHS-2 after LPS induction of blood monocytes showed a concentration-dependent inhibition of PGHS-2 protein expression by ibuprofenoyl-CoA thioesters.
6. These data confirm that S-ibuprofen represents the active entity in the racemate with respect to cyclo-oxygenase activity. More importantly the data suggest a contribution of the R-enantiomer to therapeutic effects not only by chiral inversion to S-ibuprofen but also via inhibition of induction of PGHS-2 mediated by R-ibuprofenoyl-CoA thioester.
7. The data may explain why racemic ibuprofen is ranked as one of the safest non-steroidal anti-inflammatory drugs (NSAIDs) so far determined in epidemiological studies.

     

Analytical Chiral Separation of the Stereoisomers of a Novel Carbonic Anhydrase Inhibitor and Its Deethylated Metabolite,and the Assignment of Absolute Configuration of the Human Metabolite and Chiral Degradation Products

Several approaches to the separation of four stereoisomers, 1–4, of a novel, topically active, carbonic anhydrase inhibitor, 1, with two chiral centers in the molecule and four isomers, 5–8, of its chiral metabolite, 5, were evaluated. These methods include nonchiral derivatization followed by separation on chiral stationary phases (CSPs) and chiral derivatization and separation on nonchiral columns and on CSPs. Baseline separation of stereoisomers 1–4 was achieved in less than 15 min after chiral derivatization with (S)-(+)-l-(l-naphthyl)ethyl isocyanate (NEIC) and chiral chromatography on a (R)-N-(3,5-dinitrobenzoyl)phenyl glycine (DNBPG) column under normal phase (NP) conditions. Similarly, isomers 5-8 were baseline separated in less than 20 min after derivatization with NEIC and chromatography on nonchiral (nitrophenyl) and chiral [(S)-(3,5-dinitrobenzoyl)leucine; DNBL] columns in series under the same NP chromatographic conditions. Only partial separation of the diastereomeric derivatives was observed on a variety of nonchiral columns. In addition, all other direct and indirect chiral separation approaches gave only partial separation of at least two stereoisomers within the group of 1–4 or 5–8. The details of chiral separations using various methods and separation () and capacity factors (k) of the derivatized isomers 1–8 on a series of chiral and nonchiral columns are presented. Using these methods, the absolute configuration of the human metabolite of 1 was established as S ₁ S ₂ (5), and the heat (HD) and light (LD) degradation products of 1 as R ₁ S ₂ (3) and S₁ S ₂ (5), respectively.     

（S）—（一）—α—苯乙胺萃取过程的研究

提出采用萃取法回收苯乙胺的工艺方案,考察了多种萃取剂的萃取性能,确定了氯仿作萃取剂的操作条件。根据实验和计算表明本方案苯乙胺的萃取收率可达９７％以上,苯乙胺的总回收率可达８７％以上。