Cinchona

The medicinal use of quinine, an antimalarial agent, dates back over 350 years. Quinine is the chief alkaloid of cinchona, the bark of the South American cinchona tree, otherwise known as Peruvian bark, Jesuit s bark, or Cardinal s bark. In 1633, an Augustinian monk named Calan-cha of Lima, Peru, first wrote that a powder of cinchona given as a beverage, cures the fevers and tertians. By 1640, cinchona was used to treat fevers in Europe, a fact first mentioned in the European medical literature in 1643. The Jesuit fathers were the main importers and distributors of cinchona in Europe, hence the name Jesuit s bark. Cinchona also was called Cardinal s bark because it was sponsored in Rome by the eminent philosopher, Cardinal de Lugo. 

The cinchona tree belongs to the Rubiaceae family and is a native of the eastern slope of the Andes but has been largely planted in India, Sri Lanka, Indonesia, and Myanmar, with the result of improving the quinine-yielding value of many species by cultivation. There are two official species  

Cinchona, the dried bark of Cinchona ledgeriana, C. calisaya, C. officinalis, and of hybrids of these and of other species of Cinchona, yielding, when assayed by a prescribed process, not less than 5% of total alkaloids. 

Cinchona rubra, red cinchona, is the bark of C. Succirubra or of its hybrids, containing not less than 5% of cinchona alkaloids. From it is prepared the compound tincture of cinchona. 

Cinchona bark contains 21 natural alkaloids (3 of which are official), 8 artificial alkaloids, 2 simple acids, 2 tannic acids, a resinoid, and a coloring matter, with characteristics as follows  

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A catalytic enantio- and diastereoselective dihydroxylation procedure without the assistance of a directing functional group (like the allylic alcohol group in the Sharpless epox-idation) has also been developed by K.B. Sharpless (E.N. Jacobsen, 1988 H.-L. Kwong, 1990 B.M. Kim, 1990 H. Waldmann, 1992). It uses osmium tetroxide as a catalytic oxidant (as little as 20 ppm to date) and two readily available cinchona alkaloid diastereomeis, namely the 4-chlorobenzoate esters or bulky aryl ethers of dihydroquinine and dihydroquinidine (cf. p. 290% as stereosteering reagents (structures of the Os complexes see R.M. Pearlstein, 1990). The transformation lacks the high asymmetric inductions of the Sharpless epoxidation, but it is broadly applicable and insensitive to air and water. Further improvements are to be expected. 

Alkaloid of cinchona bark used to treat malaria)... 

Alkylation of protected glycine derivatives is one method of a-amino acid synthesis (75). Asymmetric synthesis of a D-cx-amino acid from a protected glycine derivative by using a phase-transfer catalyst derived from the cinchona alkaloids (8) has been reported (76). 

Mixtures of cinchona alkaloids, known as totaquine, are easier to produce and have been employed in treatment. Totaquine has been standardized to contain a minimum of 15% quinine. 

The success of quinine inspired the search for other antimalarials. The greatest impetus for the development of synthetic dmgs came this century when the two World Wars intermpted the supply of cinchona bark to the combatants. A stmcturally related 4-quinolinemethanol is mefloquine (65, Lariam [51773-92-3]) which now serves as an effective alternative agent for chloroquine-resistant P. falciparum. This is a potent substance that requires less than one-tenth the dose of quinine to effect cures. There are some untoward side effects associated with this dmg such as gastrointestinal upset and dizziness, but they tend to be transient. Mefloquine is not recommended for use by those using beta-blockers, those whose job requires fine coordination and spatial discrimination, or those with a history of epilepsy or psychiatric disorders. A combination of mefloquine with Fansidar (a mixture of pyrimethamine and sulfadoxine) is known as Fansimef but its use is not recommended. Resistance to mefloquine has been reported even though the compound has not been in wide use. 

QuinidJne. Quinidine, an alkaloid obtained from cinchona bark (Sinchona sp.), is the dextrorotatory stereoisomer of quinine [130-95-0] (see Alkaloids). The first use of quinidine for the treatment of atrial fibrillation was reported in 1918 (12). The sulfate, gluconate, and polygalacturonate salts are used in clinical practice. The dmg is given mainly by the oral (po) route, rarely by the intravenous (iv) route of adniinistration. It is the most frequentiy prescribed po antiarrhythmic agent in the United States. The clinical uses of quinidine include suppression of atrial and ventricular extrasystoles and serious ventricular arrhythmias (1 3). 

This group of natural alkaloids occurs in the various species of the two Rubiaceous genera. Cinchona and Bemijia, indigenous to the eastern slopes of the Andes between latitudes 10° N. and 20° S. 

It is over three centuries since cinchona bark came into use in European medicine, and no other natural drug has had so much written about it. There are the stories, sometimes legendary, of its discovery by Europeans, vigorous early discussions of its therapeutic value, the destruction of the S. American cinchona trees to meet the demand for bark, the labours of botanical explorers in collecting seed for the formation of plantations, the establishment and development of these plantations in Ceylon, India and Java, the competition between them, the gradual emergence of Java as the world s most important source of supply of cinchona bark, and the development of the manufacture of quinine sulphate in Europe, the United States and the Tropics. ... 

The disadvantage in war periods of relying on a single source of supply for an essential commodity became evident when Java was invaded by the Japanese in March 1942, the world being thereby deprived of about 90 per cent, of its customary supply of cinchona bark. Quinine was ther still considered an indispensable drug for the treatment of malaria an<3 its use had to be restricted to that purpose stocks of quinidine wew similarly reserved for use in cardiac disease, In efforts to deal with th<... 

It will be interesting to see how much of this activity will survive in post-war conditions, especially in competition with new, synthetic, anti-malarial drugs developed during the war and revival of the Java cinchona industry, which is apparently making progress. 

The cinchona alkaloids of practical importance are quinine, quinidine, cinchonine and cinchonidine, but, in addition, over twenty others have been isolated from cinchona and cuprea species. Their names and formulae are as follows ... 

As the re-introduction of mixtures of cinchona alkaloids for use in medicine has given rise to some discussion, a list of the principal papers on this subject is given. Several of these provide analyses of locally produced totaquina. Applezweig and Ronzone have described an ion exchange process for the preparation of totaquina. 

Analyses of Cinchona Barks. For galenical preparations, pharmacopoeia recognition is usually restricted to barks of cultivated cinchona species known to yield total alkaloids satisfactory in composition thus, the British Pharmacopoeia 1932 prescribes the varieties to be used, and specifies not less than 6 per cent, of total alkaloids, of which at least half must be quinine and cinchonidine, determined by the process prescribed. Numerous other processes have been published and references to the more important of these are given under the following headings —identifica-... 

Numerous new salts and additive compounds of cinchona alkaloids, and especially of quinine, have been described, of which only a few can be mentioned as examples quinine additive compounds with sulph-anilamide, t quinine salts of (+) and (—)-pantothenic acid, °( > quinine sulphamate and disulphamate, °( organo-mercury compounds of quinine and cinchonine such as quinine-monomercuric chloride. Various salts and combinations of quinine have also been protected by patent, e.g., ascorbates and nicotinates. 

Cmchonine, C19H22ON2. This alkaloid is usually present in cinchona and cuprea barks. One of the best sources is Cinchona micrantha bark. It occurs in the crude quinine sulphate mother liquors. The mixed alkaloids recovered from these may be extracted with ether to remove quinidine and cinchonidine and the insoluble residue boiled with successive small quantities of alcohol, from which cinchonine crystallises on cooling. The crude alkaloid is neutralised with dilute sulphuric acid and the sulphate recrystallised from boiling water. Cinchonine so prepared contains quinidine, from which it may be freed by crystallisation from boiling alcohol until it ceases to exhibit fluorescence in dilute sulphuric acid. It will then still contain 10 to 15 per cent, of dihydrocinchonine, which may be removed by reprecipitation as the cuprichloride, B. 2HC1. CuClj, or by the simpler mercuric acetate process of Thron and Dirscherl. ... 

Detection. Cinchonine is sparingly soluble in all ordinary solvents, is not fluorescent in dilute sulphuric acid, is dextrorotatory, forms a soluble tartrate and hydriodide and does not give the thalleioquin reaction. Hesse s homocinchonine has been shown to be impure cinchonine. Cinchonidine, C49H22ON2. This alkaloid occurs in most varieties of cinchona bark, but especially in C. succiruhra. 

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