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The microbial transformation of four Cinchona alkaloids (quinine, quinidine, cinchonidine, and cinchonine) by endophytic fungi isolated from Cinchona pubescens was investigated. The endophytic filamentous fungus Xylaria sp. was found to transform the Cinchona alkaloids into their 1-N-oxide derivatives.
The synthesis and conformational analyses of several 9-N-acylamino(9-deoxy)cinchona alkaloids is presented. Peptides were connected to cinchona alkaloids via a 9-amino group. The synthesis of the new cinchona alkaloid derivatives was performed straightforwardly from 9-amino(9-deoxy)dihydroquinidine via coupling with carboxylic acid chlorides and several dipeptides. Both alkaloid derivatives with the configuration of the corresponding natural product as well as its unnatural epimer were studied. The conformations of the prepared derivatives in solution were determined by NMR spectroscopy. It is shown that the conformation is strongly influenced by the configuration at the 9-position.
[reaction: see text] Intramolecular 1,3-dipolar cycloadditions of cinchona azides to the C10-C11 alkyne and C10-C11 olefin unit of the alkaloid have been designed via tandem strategy. A variety of fused triazoles and triazolines with a bis-azahomotwistane skeleton have been prepared. In trifluoroethanol, O-mesylcinchonidine 7-OMs and NaN(3) furnish triazole 8 as well as cage-expanded 1,5-diazatricyclo[4.4.1.0(3,8)]undecane derivative 10. Both fused triazoles 8 and 10 are formed with retention of configuration at C9 and C3, respectively. 1-Azabicyclo[3.2.2]cage expansion is shown to be reversible.
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For most potent antimalarial activity, the cinchona alkaloids appear to require certain electronic features, particularly a sufficiently acidic hydroxyl proton and an electric field direction pointing from the aliphatic nitrogen atom towards the quinoline ring. These observations are the result of an analysis of molecular electronic properties of eight cinchona alkaloids and an in vivo metabolite calculated using ab initio 3-21G quantum chemical methods in relation to their in vitro IC50 values against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum parasites. The purpose is to provide a profile of the electronic characteristics necessary for potent antimalarial activity for use in the design of new antimalarial agents and to gain insight into the mechanistic path for antimalarial activity. Distinguishing features of the weakly active epiquinine and epiquinidine include a higher dipole moment, a different direction of the electric field, a greater intrinsic nucleophilicity, lower acidity of the hydroxyl proton, a lesser electron affinity of the lowest unoccupied molecular orbitals, and a higher proton affinity than the active cinchona alkaloids. A moderately potent quinine metabolite possesses some, but not all, of the same electronic features as the most potent cinchona alkaloids. Both the positioning of the hydroxyl and aliphatic amine groups and their electronic features appear to play a crucial role for antimalarial potency of the cinchona alkaloids, most likely by controlling the ability of these groups to form effective intermolecular hydrogen bonds.
The electrospray ionization (ESI) mass spectra of 16 cinchona alkaloid compounds were studied for the first time. The electron ionization (EI) spectra of 22 cinchona alkaloids were also recorded, 14 of which had not been examined previously. In the case of EI the characteristic direction of the fragmentation is the scission of the C8-C9 bond. Under EI the cleavage of the C4'-C9 bond occurs only in the case of hydrogenated cinchona alkaloids, whereas the C9-O bond cleavage can be observed in the case of ester and ether derivatives. At a low capillary exit voltage (CapEx) in the ESI measurements there is no fragmentation, and only the [M + H](+) and in some cases the double protonated [M + 2H](2+) ions can be detected. On increasing the CapEx the characteristic primary direction is the cleavage of the C9-O bond, which was observed in the case of epialkaloids and esterified or etherified cinchona derivatives, respectively. Copyright 2000 John Wiley & Sons, Ltd.
Following a short historical review of the facts which lead to the discovery of the specific action of the cinchona bark, an analysis is made of the obstacles encountered for more than two centuries by scientific expeditions to the identification, among the maze of natural hybrids, of the varieties of cinchona producing large amounts of quinine, and to obtain the best seed to establish plantations in other continents. Charles Ledger, a British general tradesman, was able to achieve that thanks to his alert spirit of observation, his (and that of his Bolivian servant Manuel) long experience of the Andes, and the chance that brought them to fall upon a group of exceptional cinchonas which had grown on an impervious slope of the Andes. Eventually the seeds were collected and Ledger offered them to the British and Dutch governments. Whereas the British failed to recognise their importance, the Dutch did not. They created extensive plantations in Java from which the world's demand for quinine was met, and the Dutch detained the practical monopoly of its production.
Cinchona-alkaloid/Selectfluor combinations efficiently fluorinate a variety of carbonyl compounds in a highly enantioselective manner to furnish chiral alpha-fluorocarbonyl compounds. The DHQB/Selectfluor combination is effective for the enantioselective fluorination of indanones and tetralones 1 in up to 91% ee. The first enantioselective syntheses of chiral derivatizing reagents 3 was accomplished with high ee and in high chemical yields by the DHQDA/Selectfluor combination. 3-Fluorooxindoles 7 were prepared with ee up to 83% using the (DHQ)2AQN/Selectfluor or the (DHQD)2PYR/Selectfluor combination. Since the combinations are conveniently prepared in situ from readily available reagents, the present system represents a practical method for enantioselective fluorination. X-ray crystallography and 1H NMR analyses of the cinchona alkaloids/Selectfluor combination have established that the species that mediate this novel reaction are N-fluoroammonium cinchona alkaloid tetrafluoroborates, which adopt open conformations.
Elevated serum enzymes were observed due to all four cinchona alkaloids in male Sprague-Dawley rats after four day treatment. Only a slight effect on bile flow and excretion of phenolphthalein glucuronide in bile was noted. Animals treated with cinchona alkaloid for four days and then receiving CCl4 showed a partial protection against CCl4 induced hepatotoxicity. The levels of serum enzymes were lowered as compared to animals treated with CCl4 alone. Bile flow and excretion of phenolphthalein glucuronide in bile showed a trend of restoration towards control levels. All four cinchona alkaloids probably inhibit microsomal enzymes, thereby, inhibiting the bioactivation of CCl4 and hence reducing the toxicity.
We report a sensitive method for the estimation of quinine (Qn), cinchonine (Cn), and cinchonidine (Cnd) and a new method based on fluorescence enhancement and detection and quantification of quinidine (Qnd) from Cinchona stem bark and its formulations, using HPTLC. Standard solutions of Qn, Qnd, Cn, and Cnd were applied on precoated HPTLC plates and developed with chloroform/diethylamine (9.6:1.4 v/v). The plates were scanned and quantified at 226 nm for Qn, Cn, Cnd and for Qnd at 366 nm in fluorescence and reflectance mode ([symbol: see text] K400 filter). The method was validated for precision, accuracy and repeatability. Further, the stem bark of Cinchona officinalis and some herbal and homeopathic formulations were evaluated for their individual alkaloid content applying the developed method.
Enantioselective Michael additions of cyclic beta-ketoesters to methyl vinyl ketone catalyzed by cinchona alkaloids were studied. The results revealed that the induced enantioselectivity was significantly influenced by both the structure of the catalyst and that of the substrate. Interesting differences in the effect of the structure of the alkaloid on the enantioselectivity of this reaction in the case of three beta-ketoesters were discovered. High enantioselectivities were obtained in the reaction of ethyl 2-oxocyclopentanecarboxylate and ethyl 2-oxocyclohexanecarboxylate (up to 83 and 80%, respectively) at a low cinchona:reactant ratio of 1:500. As the specific rotations of the product enantiomers were unknown, they were determined by optical rotation and chiral GC measurements and verified by NMR experiments.
The synthesis and chromatographic evaluation of the enantiomer separation capabilities of covalently immobilized calix[4]arene-cinchona carbamate hybrid type receptors derived from quinine (QN) and its corresponding C9-epimer (eQN) in different solvents are reported. The receptors display complementary enantiomer separation profiles in terms of elution order, chiral substrate specificity, and mobile phase characteristics, indicating the existence of two distinct chiral recognition mechanisms. The QN-derived receptor binds the (S)-enantiomers of N-acylated amino acids more strongly, shows preferential recognition of open-chained amino acids, and superior enantioselectivity in polar media such as methanol/acetic acid. In contrast, the eQN congener preferentially recognizes the corresponding (R)-enantiomers, displays good enantioselectivity (alpha up to 1.74) for cyclic amino acids, and enhanced stereodiscriminating properties in apolar mobile phases, e.g., chloroform/acetic acid. A comparison of the enantiomer separation profiles with those of the corresponding QN and eQN tert-butyl carbamate congeners indicates no significant level of cooperativity between the calix[4]arene module and the cinchona units in terms of overall chiral recognition, most probably as a consequence of residual conformational flexibility of the calixarene module and the carbamate linkage.
A systematic and comprehensive study of the conformational spaces of the Cinchona alkaloids quinine, quinidine, cinchonine, cinchonidine, epiquinine, epiquinidine, epicinchonine, and epicinchonidine using the semiempirical PM3 method is described. The results were analyzed in terms of syn/anti and open/closed/hindered and alpha/beta/gamma conformations. Special emphasis was given to the torsion angles T(1) (C(4a')-C(4')-C(9)-C(8)), T(2) (C(4')-C(9)-C(8)-N(1)) and T(3) (H-O(9)-C(9)-C(8)) that define the backbone and the hydroxy conformation, respectively. The results reveal the quasi-enantiomeric relationships between quinine and quinidine and between epiquinine and epiquinidine, and the main structural differences that exist between the therapeutically active Cinchona alkaloids, quinine and quinidine, and their inactive epimers, epiquinine and epiquinidine. The lowest energy conformation of quinine and quinidine is anti-closed-alpha. The lowest energy conformations of epiquinine and epiquinidine are anti-open-beta and anti-open-alpha, respectively. Low energy conformations with an intramolecular hydrogen bond (N(1.)H(.)O(9)) were found in epiquinine (the global minimum) and epiquinidine, but not in quinine and quinidine.
NMR analyses of quinidine and other cinchona alkaloids and their monoprotonated salts in deuterium oxide and in deuterochloroform revealed that the molecules assume new conformations in polar and nonpolar media, affecting the protonation site and hydrophilic-lipophilic characteristics. The ion-pair feature of the salts is lost and the molecules assume a neutral feature when they are transferred from an aqueous to a lipoid phase. Hydrophobic bonds between the molecules and their environment and within the molecule itself may affect the binding of cinchona alkaloids to membranes in biological fluids.