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Amino acids play an important role in cellular processes and are building blocks for peptides and proteins, which take part in regulatory processes within each organism. Hence a large variety of biotechnologically or synthetically produced therapeutic drugs are peptides and proteins. Due to the chiral nature of amino acids and the large variety of common, uncommon and newly synthesized amino acid type compounds, stereoselective separation tools combined with mass spectrometric detection are important in research as well as purity control of therapeutics in industry. Since structural isomers and epimers of common amino acids are isobaric to each other, stereoselective separation is key to their identification. For this purpose zwitterionic quinine and quinidine type chiral stationary phases Chiralpak ZWIX(+) and Chiralpak ZWIX(-) were investigated for their separation performance for underivatized and 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC; AccQ) derivatized proteinogenic amino acids, uncommon amino acids and their isobaric analogs such as allo-threonine, homoserine, allo-isoleucine and homocysteine by HPLC-ESI-QTOF-MS. Cystine and homocystine were reduced with dithiothreitol and S-alkylated with iodoacetic acid and iodoacetamide. In general, derivatization with AQC and thiol alkylation increased the detection sensitivity and resolution of acidic, basic and polar amino acids significantly (e.g. separation factor of Asp increased from 1.00 to 2.29 for Asp-AQC). In addition, throughout this study a u- 13 C 15 N-L-amino acid metabolomics mixture was added to the DL-amino acid test solution and used as a co-eluting peak assignment standard to identify the corresponding u- 12 C 14 N-L-amino acid peak and hence determine the elution order of the enantiomer pairs for complex mixtures within a single run, employing the same separation conditions for underivatized and AQC-derivatized amino acids and their isobaric analogs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The bifunctional nature of the cinchonidine squaramides has been successfully employed to catalyze the enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones with 2-enoylpyridines under mild reaction conditions. Through this methodology, a broad range of optically active heterocyclic derivatives bearing both pyrazole and pyridine motifs have been synthesized in yields up to 88% and enantiomeric excess up to 96%.

Background Quinine (QT) is an important anti-malarial drug; however, there is little information about its effects on the gut. Therefore, this study aimed to investigate the effects of a therapeutic dose of QT on the healing of gastric ulcer in rats. Methods Male Wistar rats weighing 150-200 g were divided into three groups: control rats without ulcer (group 1), ulcerated rats treated with 1 mL/kg (p.o.) normal saline (NS) (group 2), and ulcerated rats treated with 10 mg/kg (p.o.) QT (group 3). Ulcers were induced by serosal application of 80 % acetic acid to the stomach of rats anaesthetized with 50 mg/kg thiopentone sodium and treatment was given three times daily. Healing was assessed on days 3, 7 and 10 after ulcer induction by macroscopic measurement of: ulcer area, histology, lipid peroxidation, superoxide dismutase activity and gastric mucus secretion. Results At day 3, there was no significant difference (p>0.05) in ulcer areas between NS- and QT-treated rats. By day 10, however, the percentage area healed in NS treated (59.6±2.35 %) was significantly higher (p<0.05) than in QT rats (49.0±2.20 %) and clearing of inflammatory cells and re-epithelization was greater in NS-treated group. By days 7 and 10, lipid peroxidation was significantly higher in QT animals, when compared with NS-treated rats and controls (p<0.05). Superoxide dismutase activity and mucus secretion were significantly (p<0.05) higher in NS-treated than QT-treated rats. Conclusions QT delayed ulcer healing by prolonging the inflammatory phase of healing, increasing oxidative stress, reducing antioxidant activity and gastric mucus secretion.

d- and l-2-Hydroxyglutaric acid (d- and l-2-HG, respectively) are metabolites related to some diseases (2-hydroxyglutaric aciduria, cancer), which make their identification and analysis crucially important for diagnostic purposes. Chiral stationary phases (CSP) based on tert-butylcarbamoyl-quinine and -quinidine (Chiralpak QN-AX and QD-AX), and the corresponding zwitterionic derivatives (Chiralpak ZWIX(+) and Chiralpak ZWIX(-)) were employed in a weak anion-exchange mechanism to perform the enantiomer separation of d- and l-2-HG without derivatization. QD-AX CSP showed the most promising separation and therefore optimization of eluent, additives, and temperature, required for the baseline separation of solutes was carried out. Depending on experimental conditions resolution values ranged up to 2.0 with run times <20min and MS-compatible conditions. Inversion on the elution order of d- and l-2-HG was possible by using the pseudo-enantiomeric QN-AX CSP., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Quinine, a bitter-tasting, short-acting alkaloid drug extracted from cinchona bark, was the first drug used widely for malaria chemoprophylaxis from the 19th century. Compliance was difficult to enforce even in organized groups such as the military, and its prophylaxis potential was often questioned. Severe adverse events such as blackwater fever occurred rarely, but its relationship to quinine remains uncertain. Quinine prophylaxis was often counterproductive from a public health viewpoint as it left large numbers of persons with suppressed infections producing gametocytes infective for mosquitoes. Quinine was supplied by the first global pharmaceutical cartel which discouraged competition resulting in a near monopoly of cinchona plantations on the island of Java which were closed to Allied use when the Japanese Imperial Army captured Indonesia in 1942. The problems with quinine as a chemoprophylactic drug illustrate the difficulties with medications used for prevention and the acute need for improved compounds., (© The American Society of Tropical Medicine and Hygiene.)

In this study, we will show how a Dutch pharmaceutical consortium of cinchona producers and quinine manufacturers was able to capitalize on one of the first international public health campaigns to fight malaria, thereby promoting the sale of quinine, an antimalarial medicine. During the 1920s and 1930s, the international markets for quinine were controlled by this Dutch consortium, which was a transoceanic cinchona-quinine enterprise centered in the Cinchona Bureau in the Netherlands. We will argue that during the interwar period, the Cinchona Bureau became the decision-making center of this Dutch cinchona-quinine pharmaceutical enterprise and monopolized the production and trade of an essential medicine. In addition, we will argue that capitalizing on the international public health campaign in the fight against malaria by the Dutch cinchona-quinine enterprise via the Cinchona Bureau can be regarded as an early example of corporate colonization of public health by a private pharmaceutical consortium. Furthermore, we will show how commercial interests prevailed over scientific interests within the Dutch cinchona-quinine consortium, thus interfering with and ultimately curtailing the transoceanic circulation of knowledge in the Dutch empire., (© The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

10,11-Didehydroquinine is a simple, low molecular weight supergelator which forms, in nonpolar media, stable chiral organogels composed of unique double-helix nano-sized fibers. A novel gelation mechanism involves a hydrogen bonding network formed by an acidic alkyne proton of the Cinchona gelator and the carbonyl group of ethyl acetate used as a solvent.

How and when the medical value of Cinchona bark was discovered is obscure, but it is said that the powder was given to a European for malaria for the first time in the 1630s. The bark was brought to Europe by Spanish missionaries and it was recommended by the cardinal Juan de Lugo. In the 1660s, the use of Cinchona bark became known in England - and in Denmark by Thomas Bartholin. It was used for the treatment of malaria, but several debates on its value continued up to the 1730s. However, successful treatment of malaria was obtained by Thomas Sydenham, Robert Tabor and Francesco Torti. Sydenham emphasized a modern view that Cinchona bark was a unique specific drug for the treatment of malaria, and the treatment was fully accepted when Torti's Therapeutice specialis appeared. In the early 18th century, botanical expeditions were arranged in search of the most valuable Cinchona species for cultivation. The content of quinine was impor- tant, and determination of quinine was realized when Pierre Pelletier and Joseph Caventou isolated the alkaloid from the bark in 1820. Dutch plantations and quinine industry dominated the market, but the supply of quinine came to an end when the Japanese occupied Indonesia in 1942, cutting off the rest of the world from the main supplies of Cinchona. Synthetic antimalarials were developed and chloroquine became the drug of choice, but the intensive use of these drugs caused drug resistance. Chloroquine-resistant strains of P. falciparum are now treated with other drugs as artemisinin and artemether.

A chiral chromatography method enabling the simultaneous diastereo- and enantioseparation of N(α)-Boc-N(4)-(hydroorotyl)-4-aminophenylalanine [Boc-Aph(Hor)-OH, 1] was optimized with a quinine-based zwitterionic stationary phase. The polar-ionic eluent system consisting of ACN:MeOH:water-49.7:49.7:0.6 (v/v/v) with formic acid (4.0mM) and diethylamine (2.5mM), allowed the successful separation of the four acid stereoisomers: αd,d-/d,l-1=1.08; αd,l-/l,d-1=1.08; αl,d-/l,l-1=1.40. According to the in-house developed synthetic procedure and the recorded electronic circular dichroism spectra, the following stereoisomeric elution order was readily established in the optimal chromatographic conditions: d,d-1

The isolation of quinine from cinchona bark in 1820 opened new possibilities for the mass-production and consumption of a popular medicine that was suitable for the treatment of intermittent (malarial) fevers and other diseases. As the 19th century European empires expanded in Africa and Asia, control of tropical diseases such as malaria was seen as crucial. Consequently, quinine and cinchona became a pivotal tool of British, French, German and Dutch empire-builders. This comparative study shows how the interplay between science, industry and government resulted in different historical trajectories for cinchona and quinine in the Dutch and British Empires during the second half of the 19th century. We argue that in the Dutch case the vectors of assemblage that provided the institutional and physical framework for communication, exchange and control represent an early example of commodification of colonial science. Furthermore, both historical trajectories show how the employment of the laboratory as a new device materialised within the colonial context of agricultural and industrial production of raw materials (cinchona bark), semi-finished product (quinine sulphate) and plant-based medicines like quinine. Hence, illustrating the 19th century transition from 'colonial botany' and 'green imperialism' to what we conceptualise as 'colonial agro-industrialism'., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

We report a chiral high-performance liquid chromatographic enantioseparation method for free α-aminophosphonic, β-aminophosphonic, and γ-aminophosphonic acids, aminohydroxyphosphonic acids, and aromatic aminophosphinic acids with different substitution patterns. Enantioseparation of these synthons was achieved by means of high-performance liquid chromatography on CHIRALPAK ZWIX(+) and ZWIX(-) (cinchona-based chiral zwitterionic ion exchangers) under polar organic chromatographic elution conditions. Mobile phase characteristics such as acid-to-base ratio, type of counterion, and solvent composition were systematically varied in order to investigate their effect on the separation performance and to achieve optimal separation conditions for the set of analytes. Under the optimized conditions, 32 of 37 racemic aminophosphonic acids studied reached baseline separation when we employed a single generic mass-spectrometry-compatible mobile phase, with reversal of the elution order when we used (+) and (-) versions of the chiral stationary phase.

The fluorescent tag 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC; AccQ Fluor reagent kit from Waters) is a commercial N-terminal label for proteinogenic amino acids (AAs), designed for reversed-phase separation and quantification of the AA racemates. The applicability of AQC-tagged AAs and AA-type zwitterionic compounds was tested for enantiomer separation on the tert-butyl carbamate modified quinine and quinidine based chiral stationary phases, QN-AX and QD-AX employing polar-organic elution conditions. The investigated test analytes included the enantiomers of the positional isomers of isoleucine (Ile), threonine, homoserine, and 4-hydroxyproline. Furthermore, β-AAs, cyclic, and heterocyclic AAs including trans-2-amino-cyclohexane carboxylic acid and trans-2-aminocyclohexyl sulfonic acid, phenylalanine derivatives substituted with halides with increasing electronegativity and 3,4-dihydroxyphenylalanine, cysteine-related derivatives including homocysteic acid, methionine sulfone, cysteine-S-acetic acid, and cysteine-S-acetamide as well as a small range of aminophosphonic acids were enantioseparated. A mechanistic interaction study of AQC-AAs in comparison with fluoresceine isothiocyanate-labeled AAs was performed. The chiral and chemoselective recognition processes involved in enantiomer separation and retention was systematically discussed. Special emphasis was set on the influential factors exhibited by the chemistry, branching position, and spatial properties of the investigated zwitterionic analytes. The general interest to separate and distinguish between different types of branched-chained AAs and metabolic side products thereof lies in the toxicity of some of these compounds, which makes for instance allo-Ile an attractive candidate in disease-related biomarker research.

Quinine, one of Cinchona alkaloids, has been of great interest from medical, synthetic, and supramolecular viewpoints. However, unaccountably, the guest-free (GF) crystal of quinine containing no solvent or other molecules has not been reported for nearly three decades, although GF crystals of other Cinchona alkaloids, such as quinidine, cinchonidine, and cinchonine, are already known. In this study, we successfully revealed the crystal structure of quinine, which belongs to the P2(1) space group with the cell parameters of a=6.0587(1), b=19.2492(5), c=22.2824(7) Å, β=92.1646(11)°, and V=2596.83(12) Å(3). Interestingly, the crystal has three crystallographically independent molecules in the cell (Z'=3) that are connected through a N(quinoline)⋅⋅⋅H-O hydrogen bond to form a pseudo three-two-fold (3(2)) double-helical motif. The helical motif is completely different from those observed in GF crystals of other Cinchona alkaloids. Hierarchical comparison on the crystal structures of a series of Cinchona alkaloids including quinine clearly demonstrated that only small structural differences of a molecule, particularly the position of the vinyl group, cause a significant variety of assembly manner in the crystalline state. There have been no reports systematically demonstrating such steric effect in crystals of Cinchona alkaloids, and, therefore, the present system contributes to the design of desired functional crystal structures., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The electrochemical behavior of quinine was investigated by cyclic voltammetry (CV) and square wave voltammetry (SWV) using surfactant. The reduction peak current of quinine increases remarkably in presence of 1% CTAB. Its electrochemical behavior is quasi-reversible in the Britton-Robinson buffers of pH 10.38 by exhibiting the well-defined single cathodic and anodic waves and the ratio of I(p)(a)/I(p)(c) approaching one at the scan rate of 500 mVs(-1). On the basis of CV, SWV and Coulometry, electrochemical reduction mechanism of quinine has been proposed which has shown that protonation occurs on the nitrogen of the quinoline moiety. Linearity was obtained when the peak currents (I(p)) were plotted against concentrations of quinine in the range of 30.0-230.0 ng mL(-1) with a detection limit of 0.132 ng mL(-1) in SWV and 90.0-630.0 ng mL(-1) with a detection limit of 0.238 ng mL(-1) in DPV. Fast and sensitive SWV has been applied for the quantitative analysis of quinine in bark of Cinchona sp. and in soft drinks and a good recovery was obtained. The accuracy and precision of the method are determined and validated statistically. No interferences from other food additives were observed. The relative standard deviation for intraday and interday assay was 0.89 and 0.73% (n=3) respectively., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Laser-desorbed quinine and quinidine have been studied in the gas phase by combining supersonic expansion with laser spectroscopy, namely, laser-induced fluorescence (LIF), resonance-enhanced multiphoton ionization (REMPI), and IR-UV double resonance experiments. Density funtional theory (DFT) calculations have been done in conjunction with the experimental work. The first electronic transition of quinine and quinidine is of π-π* nature, and the studied molecules weakly fluoresce in the gas phase, in contrast to what was observed in solution (Qin, W. W.; et al. J. Phys. Chem. C2009, 113, 11790). The two pseudo enantiomers quinine and quinidine show limited differences in the gas phase; their main conformation is of open type as it is in solution. However, vibrational circular dichroism (VCD) experiments in solution show that additional conformers exist in condensed phase for quinidine, which are not observed for quinine. This difference in behavior between the two pseudo enantiomers is discussed.

Photophysical properties of the organocatalyst cupreidine (CPD) and its chromophoric building block 6-hydroxyquinoline (6HQ) in protic and nonprotic polar solvents (methanol and acetonitrile) were investigated by means of UV-vis absorption, and steady state and time resolved fluorescence spectroscopy. The effects of the catalytically relevant interactions with electrophilic and hydrogen bonding agents (p-toluene sulfonic acid and water) on their spectral characteristics were studied. In neutral CPD in acetonitrile, quenching of fluorescence occurs due to electron transfer from the quinuclidine nitrogen to the excited quinoline chromophore. Protonation suppresses this process, while complexation with water leads to enhanced excited state proton transfer from the 6'-OH group to the quinuclidine nitrogen, and emission occurs from the anionic form of the chromophore. The weakly emitting zwitterionic form of the hydroxyquinoline chromophore is readily formed in methanol, but not in acetonitrile.

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.