Cyclodextrin-based optosensor for the determination of quinine

 A flow-through optosensor for quinine is described. It has been developed in conjunction with a flow-injection analysis system and uses immobilized β-cyclodextrin as the sensing agent. The detection limit for quinine was 0.20 ng ml^-1 with a relative standard deviation of 2.1% for the determination of 0.05 μg ml^-1 (n=7) of quinine. The method has been successfully tested for the determination of quinine in some pharmaceutical preparations. Received: 4 June 1996 / Revised: 23 August 1996 / Accepted: 24 August 1996     

Cyclodextrin-based optosensor for the determination of quinine

 A flow-through optosensor for quinine is described. It has been developed in conjunction with a flow-injection analysis system and uses immobilized β-cyclodextrin as the sensing agent. The detection limit for quinine was 0.20 ng ml^-1 with a relative standard deviation of 2.1% for the determination of 0.05 μg ml^-1 (n=7) of quinine. The method has been successfully tested for the determination of quinine in some pharmaceutical preparations. Received: 4 June 1996 / Revised: 23 August 1996 / Accepted: 24 August 1996     

Non-aqueous capillary electrophoretic enantioseparation of N-derivatized amino acids using cinchona alkaloids and derivatives as chiral counter-ions

A non-aqueous capillary electrophoretic method developed with quinine and tert.-butyl carbamoylated quinine as chiral selectors for the enantioseparation of N-protected amino acids was applied to the investigation of other quinine derivatives as chiral additives. The optimum composition of the background electrolyte was found to be 12.5 mM ammonia, 100 mM octanoic acid and 10 mM chiral selector in an ethanol-methanol (60:40, v/v) mixture. Under these conditions, a series of chiral acids, as various benzoyl, 3,5-dinitrobenzoyl and 3,5-dinitrobenzyloxycarbonyl amino acid derivatives were investigated with regards to selectand-selector relationships and enantioselectivity employing quinine, quinidine, cinchonine, cinchonidine, tert.-butyl carbamoylated quinine, tert.-butyl carbamoylated quinidine, dinitrophenyl carbamoylated quinine and cyclohexyl carbamoylated quinine as chiral selector.     

Electrochemical Sensor Based on Molecularly Imprinted Polymer Film Prepared with Functional Abietic‐Type Acids as Cross‐Linker for the Determination of Quinine

A novel cross‐linker (functional abietic‐type acids) for preparing highly sensitive, molecularly imprinted sensors was proposed for quinine determination. A MIP film was created on a glassy carbon electrode for determination of quinine using free radical polymerization method. The modification procedure was characterized via electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). The interaction between functional monomer and target molecule was observed by UV spectrometric methods. Under the optimal experimental conditions, the peak currents were proportional to the concentrations of quinine in the range from 8.0×10^?7 to 2.6×10^?4 M with a detection limit of 2.0×10^?8 M. Meanwhile the prepared sensor showed sensitive and selective binding sites for quinine. Determination of quinine in tonic water showed good recovery.     

QUININE SULFATE AS A FLUORESCENCE QUANTUM YIELD STANDARD

Abstract— Samples of quinine sulfate or bisulfate from a number of vendors have been examined. The light absorptivity and fluorescence excitation spectra of quinine bisulfate prepared from six sources of hydrated quinine sulfate had satisfactory agreement with each other. The solid samples of quinine sulfate or bisulfate showed good agreement (2.2 per cent relative difference) in their fluorescence quantum yields but the one commercial solution of quinine sulfate was 20 per cent low. The relative fluorescence quantum yield of quinine sulfate was evaluated with excitation from 240 through 400 nm and was found to have no unexplainable deviations from a constant value. It is suggested that some of the conflicting results in the literature may be due to the common practice of using a different spectral bandwidth for absorbance measurements than that used for excitation.     

奎宁类化合物研究进展

本文介绍了奎宁类化合物的发展历史,并分析了奎宁的化学结构。奎宁类化合物不仅可以作为催化剂,有效催化Michael/Mannich反应、Aza-Henry反应、环加成反应和不对称烯烃异构化反应,并且还可作为其他配体,已经成为不对称合成领域中的不可或缺成员。化学家为了寻找更有效的催化剂及配体,以奎宁类生物碱为前体,对其结构进行改造,改造位点主要集中在C-9位羟基、C-6'位甲氧基、奎宁双环的氮原子和环外烯键上,制备了众多催化剂及配体。此外,奎宁类化合物具有多种独特的生物效应,主要表现在抗疟原虫活性和杀虫活性研究方面。以奎宁为杀虫剂先导结构的优化与杀虫构效关系的系统研究将促进新农药创制学科的发展。     

TRANSFER MECHANISM OF QUININE DRUG ACROSS THE OIL/WATER (O/W) INTERFACE

The transfer phenomena of quinine drug at the aqueous 1,2- dichloroethane (DCE)interface have been studied by the current- scanning polarography. The relationships be-tween the wave height and pH of aqueous phase, concentration of quinine as well as therate of water drop are discussed. The effect of supporting electrolyte, buffer solution andthe nature of organic solvent on the polarographic wave is studied. The transfer char-acteristics of quinine in aqueous phase and in organic phase are compared, The mono- pro-tonated and diprotonated quinines can both transfer at the interface so as to produce twopolarographic waves. The transfer process of quinine at the interface is simultaneouslycontrolled by diffusion and reestablishment of the disturbed protonated equilibrium ofquinine. A further investigation is made by chronopotentiometry. On the basis of thetheoretical analysis, the formulae of the limiting current are derived and discussed. Thetheoretical results are in agreement with the experimental ones.     

C−H Activation Enables a Concise Total Synthesis of Quinine and Analogues with Enhanced Antimalarial Activity

We report a novel approach to the classical natural product quinine that is based on two stereoselective key steps, namely a C?H activation and an aldol reaction, to unite the two heterocyclic moieties of the target molecule. This straightforward and flexible strategy enables a concise synthesis of natural (?)‐quinine, the first synthesis of unnatural (+)‐quinine, and also provides access to unprecedented C3‐aryl analogues, which were prepared in only six steps. We additionally demonstrate that these structural analogues exhibit improved antimalarial activity compared with (?)‐quinine both in vitro and in mice infected with Plasmodium berghei.     

Simultaneous separation of the stereoisomers of 1-amino-2-hydroxy and 2-amino-1-hydroxypropane phosphonic acids by stereoselective capillary electrophoresis employing a quinine carbamate type chiral selector

A stereoselective nonaqueous capillary electrophoresis (CE) method utilizing O-(tert-butylcarbamoyl) quinine as chiral ion-pair agent and additive to the non aqueous background electrolyte was evaluated for the simultaneous separation of the enantiomers and diastereomers of 1 -amino-2-hydroxypropane phosphonic acid besides the corresponding beta-aminophosphonic acid analogs, the stereoisomers of 2-amino-1-hydroxypropane phosphonic acid, in a single run. The separations have been carried out using the partial filling technique to avoid strong background signal from the quinine selector. It conveniently allowed the baseline separation of all eight components of interest (alpha- as well as beta-aminophosphonic acids) as N-2,4-dinitrophenyl derivatives in a single run. Moreover, the absolute configurations of all eight peaks were identified. Compared to the quinine carbamate selector, the corresponding 'pseudo-enantiomeric' O-(tert-butylcarbamoyl) quinidine selector exhibited reserved elution order and nearly identical resolutions. The proposed CE method turned out to be advantageous over stereoselective high-performance liquid chromatography (HPLC) with a quinine carbamate type stationary phase, which showed high enantioselectivity, but failed to simultaneously separate all eight components.     

Thermogravimetric determination of ethylenediamine and quinine with dilituric acid: Solubilities of some polymethylenediamine diliturates

The thermolysis curve's of ethylenediamine, trimethylenediamine, tetramethylenediamine pentamethylenediamine, trimethylamine and quinine diliturates were determined. These curves established that (either the hydrated or the anhydrous form of ethylenediamine and quinine diliturate is stable enough for their gravimetric use to be possible. Both ethylenediamine and quinine were determined by precipitation with alcoholic dilituric acid .solution. In addition the solubilities of some polymethylenediamine diliturates were determined.     

Characterization of noncovalent complexes of antimalarial agents of the artemisinin-type and Fe(III)-heme by electrospray mass spectrometry and collisional activation tandem mass spectrometry

In this study, we demonstrate, using electrospray ionization mass spectrometry (ESI-MS) and collision-induced dissociation tandem mass spectrometry (ESI-MS/CID/MS), that stable noncovalent complexes can be formed between Fe(III)-heme and antimalarial agents, i.e., quinine, artemisinin, and the artemisinin derivatives, dihydroartemisinin, alpha- and beta-artemether, and beta-arteether. Differences in the binding behavior of the examined drugs with Fe(III)-heme and the stability of the drug-heme complexes are demonstrated. The results show that all tested antimalarial agents form a drug-heme complex with a 1:1 stoichiometry but that quinine also results in a second complex with the heme dimer. ESI-MS performed on mixtures of pairs of various antimalarial agents with heme indicate that quinine binds preferentially to Fe(III)-heme, while ESI-MS/CID/MS shows that the quinine-heme complex is nearly two times more stable than the complexes formed between heme and artemisinin or its derivatives. Moreover, it is found that dihydroartemisinin, the active metabolite of the artemisinin-type drugs in vivo, results in a Na(+)-containing heme-drug complex, which is as stable as the heme-quinine complex. The efficiency of drug-heme binding of artemisinin derivatives is generally lower and the decomposition under CID higher compared with quinine, but these parameters are within the same order of magnitude. These results suggest that the efficiency of antimalarial agents of the artemisinin-type to form noncovalent complexes with Fe(III)-heme is comparable with that of the traditional antimalarial agent, quinine. Our study illustrates that electrospray ionization mass spectrometry and collision-induced dissociation tandem mass spectrometry are suitable tools to probe noncovalent interactions between heme and antimalarial agents. The results obtained provide insights into the underlying molecular modes of action of the traditional antimalarial agent quinine and of the antimalarials of the artemisinin-type which are currently used to treat severe or multidrug-resistant malaria.     

Intermolecular radical addition to N-acylhydrazones as a stereocontrol strategy for alkaloid synthesis: formal synthesis of quinine

Stereocontrolled Mn-mediated radical addition of alkyl iodides to chiral N-acylhydrazones enables strategic C-C bond disconnection of chiral amines. This strategy was examined in the context of a total synthesis of quinine, generating new findings of functional group compatibility leading to a revised strategy. Completion of a formal synthesis of quinine is presented, validating the application of Mn-mediated radical addition as a useful new C-C bond construction method for alkaloid synthesis. The Mn-mediated addition generates the chiral amine substructure of quinine with complete stereocontrol. Subsequent elaboration includes two successive ring closures to forge the azabicyclo[2.2.2]octane ring system of quincorine, linked to quinine through two known reactions.     

In situ UV resonance Raman micro-spectroscopic localization of the antimalarial quinine in cinchona bark

Deep UV resonance Raman micro-spectroscopy (lambda(exc) = 244 nm) was applied for a highly sensitive, selective, and gentle localization of the antimalarial quinine in situ in cinchona bark. The high potential of the method was demonstrated by the detection of small amounts of the alkaloid in the plant material without any further sample preparation, where conventional (non-resonant) Raman microscopy was unsuccessful due to a strong fluorescence background. The resonance Raman spectrum of cinchona bark corresponds well with that of quinine; it can be distinguished from its diastereomer quinidine via the mode at 831 cm(-1), which is shifted to 843 cm(-1) in the case of quinidine. This vibration involves a bending motion within the side chain around the chiral center of quinine. Vibrations belonging to the quinoline ring (important for its antimalarial activity in forming pi-pi-interactions to hemozoin) and the vinyl group are resonantly enhanced in the UV Raman spectra. A convincing mode assignment is derived by means of a combination of NIR Raman spectroscopy and DFT calculations. The Raman spectra of quinine in cinchona bark are modeled by considering a hydrous environment that causes a shift of the band at 1362 compared with 1371 cm(-1) in anhydrous quinine. This intense vibration is therefore sensitive to the presence of an aqueous environment and is assigned mostly to a stretching motion within the quinoline ring. The presented results nicely show the sensitivity of Raman spectroscopy to monitor subtle differences within the molecular structure and the influence of a biological relevant hydrous environment and trace low concentrated pharmaceutical relevant active agents in plant material.     

Application of multivariate methods to the simultaneous Fourier Transform Infrared (FT-IR) spectrometric determination of stereo-isomers; quinine and quinidine

The two stereo-isomers; quinine and quinidine have been determined in their mixtures in the IR region using chemometric multivariate methods, principal component regression (PCR) and partial least squares (PLS). A training set of thirty synthetic binary mixture solutions in the possible combinations containing 0.0 - 4.0 and 4.0 - 0.0% w/v quinine and quinidine, respectively in chloroform was used to develop the multivariate calibrations. A validation set containing thirty synthetic binary mixtures of variable ratios in the range of 0.2 - 4.0 and 4.0 - 0.2% w/v for quinine and quinidine, respectively in chloroform was used to validate the developed calibrations. The results of analysis of the validation synthetic mixtures were found to be 100.5+/-0.44% (R.S.D.%=0.44) and 100.5+/-0.38% (R.S.D.%=0.38) for quinine and 100.1+/-0.67% (R.S.D.%=0.67) and 100.1+/-0.68% (R.S.D.%=0.68) for quinidine using PCR and PLS models, respectively.     

Flow-injection chemiluminescence determination of quinine using on-line electrogenerated cobalt(III) as oxidant

A novel chemiluminescence (CL) flow system for the determination of quinine is described. It is based on the direct chemiluminescence reaction of quinine and cobalt(III) in sulfuric acid medium. The unstable Co(III) was on-line electrogenerated by constant-current electrolysis. The chemiluminescence intensity was linear with a quinine concentration in the range of 0.1-100 mug ml(-1). The determination limit was 3.3x10(-8) g ml(-1). The whole process could be completed in 1 min. The proposed method is suitable for automatic and continuous analysis, and has been applied successfully to the analysis of quinine in pharmaceutical preparation.     

丙酮酸乙酯多相不对称催化加氢反应的初始过渡期研究

采用奎宁修饰的Pt/Al2O3为催化剂,研究了在常压下,乙酸溶剂中丙酮酸乙酯的不对称加氢反应.考察了奎宁修饰剂浓度、反应温度、预修饰时间、底物起始浓度及氧的加入对内酮酸乙酯不对称氢化反应初始过渡期(ITP)特征的影响.结果表明,在不对称氢化反应的初期,存在对映选择性随底物转化率的增加而不断升高的现象(即ITP现象),反应条件的变化能不同程度地改变ITP特征,在奎宁修饰催化剂时加入O2能明显提高催化剂对产物的对映选择性,改善ITP现象.ITP特征取决于反应起始阶段反应体系中各组分在催化剂表面的相互作用及达到平衡的速度,其实质是手性修饰型催化剂表面的重排过程.     

The Woodward-Doering/Rabe-Kindler total synthesis of quinine: setting the record straight

In 1918, Paul Rabe and Karl Kindler reported the three-step conversion of d-quinotoxine into quinine. In 1944 Robert B. Woodward and William von Eggers Doering reported the total synthesis of homomeroquinene and d-quinotoxine from 7-hydroxyisoquinoline. Based on the transformations by Rabe and Kindler, Woodward and Doering asserted the "Total Synthesis of Quinine" (the title of their 1944 and 1945 papers). In 2000 and 2001, Gilbert Stork concluded that the claim by Woodward and Doering is a "myth" because they had synthesized only homomeroquinene and d-quinotoxine; no synthetic quinine had been made in Cambridge. In fact, Rabe and Kindler never published the experimental details of their conversion of d-quinotoxine into quinine. This Review presents the results of a detailed examination of the synthesis of cinchona alkaloids, and previously unpublished material combined with unpublished material and numerous interviews give insight into the lives of the personalities in this nearly 100-year saga.     

A Local‐Desymmetrization‐Based Divergent Synthesis of Quinine and Quinidine

Herein we report a novel synthetic entry to the legendary quinuclidine natural products quinine and quinidine. The developed strategy is based on the use of a symmetrical and nonstereogenic precursor to access quinine and quinidine through a “local‐desymmetrization” approach, in stark contrast conceptually to the preparation of stereodefined disubstituted piperidines (or their acyclic precursors) as featured in all past syntheses. The developed strategy also provided quinine and quinidine derivatives that could not be readily obtained through previous total syntheses or by modification of the naturally occurring substances.     

Rapid gas chromatography/mass spectrometry quinine determination in plasma after automated solid-phase extraction

The combined use of an automatic solid-phase extraction (SPE) apparatus with Oasis MCX cartridges and gas chromatography/mass spectrometry (GC/MS) to rapidly quantify quinine in biological samples with cyproheptadine as the internal standard is described. The selected ion monitoring mode, with the quantification ions m/z 136 and 287 (qualifier ions: m/z 261, 381 and 215, 96), allows the estimation of quinine levels, respectively. Separation was completed within 12.7 min. Excellent linearity was found up to 10 000 microg/L of plasma. The limit of detection (LOD) was 12.2 microg/L and the limit of quantification (LOQ) was 40.6 microg/L. High reproducibility (intra-assay CV range 1.9-4.3%, inter-assay CV range 2.2-11.3%) and accuracy values (intra-assay range 83.2-103.7%, inter-assay range 86.8-103.7%) were obtained. Recoveries were concentration-independent (97.2% and 89.8% for 4000 and 10 000 microg/L, respectively). This sensitive, simple assay for quinine in various matrices meets the current requirements for bioanalytical assays and may be used to monitor quinine levels in patients developing severe malaria with acute renal failure during hemofiltration. The optimal quinine dose in this situation is not really established and to improve clinical care, quinine concentrations might be explored to improve efficacy and minimise potential toxicity.