Emetine and Related Alkaloids

Ankorine, cephaleine, and psychotrine have been isolated from 

Alangium salviifolium and ankorine from A. kurzii. Full 

Michael addition of 6,7-dimethoxy-l-methyl-3,4-dihydroisoquinoline to the unsaturated ester (76) and the product converted into 

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Emetine and Related Alkaloids.—A review on the ipecac alkaloids has ap-peared. (— )-Alangiside (208) is a terpenoidal lactam recently isolated from Alangium lamarckii Thw. (Alangiaceae). The structure was proven by chemical correlation with desacetylipecoside (209) (Scheme 13). ... 

The translation step where proteins are assembled following the code of messenger RNA has a few instances of inhibition by alkaloids [361]. Emetine and tubulosine block peptide bond formation, acting similarly to the antibiotic cycloheximide by blocking translocation of the growing peptide chain from the A site to the P site of the ribosome. They evidently bind to a specific ribosomal site [362]. Homoharringtonine may act similarly [363]. Lycorine may act at the level of termination [364]. Narciclasine and related alkaloids of the Amaryllidaceae prevent binding of the 3 end of aminoacyl-tRNA to the peptidyl transferase site of the ribosome [365, 366]. Mescaline may act similarly [367]. 

The policy adopted in this ninth volume of The Alkaloids is once again to furnish a comprehensive annual survey of the alkaloid literature. As a result of unavoidable omissions in the eighth volume, a two-year coverage is provided of tropane alkaloids and, within the isoquinoline group (Chapter 8), of the chemistry of emetine and related bases, dibenzopyrrocolines, benzophenanthridines, and colchicine. The chapter on Miscellaneous Alkaloids also surveys the literature of the period July 1976— June 1978 purines are no longer included. 

As in the period 1967-1982 covered by the previous review (7), the longstanding clinical usefulness of emetine (1) and its various biological activities 1,12) (Section VII) are responsible for the development of many methods suitable for both rapid and accurate analysis of this alkaloid and related bases. Table I lists these methods and the literature contained in Chemical Abstracts, Volumes 97 (1982)-125 (1996), with the exception of a few references. 

A third major group, including emetine and a series of structurally related alkaloids, involves condensation of the same amine precursor (3,4-dihydroxyphenylethylamine or dopamine) with a carbonyl group from secologanin—an iri-doid monoterpene precursor. Most of these compounds have been isolated from two families, the Rubiaceae and the Alan-giaceae. 

The scope of this technique is given by the reactivity of the hydroxy group in phenols, and the amino-group in anilines and related compounds. The method was originally devised for the determination of naphthols and pyrazolons, but was later used for the determination of several alkaloids (morphine, cephaeline, emetine), phenolic compounds (phenol, catechol, orcinol, guaiacol etc.), sulpha drugs,< < and capsai-... 

Total stereoselective syntheses of emetine and ( )-dihydroprotoemetine and stereoconservative syntheses of deoxytubulosine, cephaeline, and emetine from secologanin have been reported, as has the synthesis of the related alkaloid, desmethylpsychotrine. ... 

Emetine and other related alkaloids are biosynthesized from dopamine and secologanin of mevalonate origin through a glycosidic intermediate, desacetylipe-coside (Fig. 5.2.14) (6). Alkaloids having biogenetic importance, such as protoemetine, have also been found in the same plant (7). 

Nicotine boldine and other aporphine alkaloids C-toxiferine coniine and other piperidine alkaloids cytisine and other quinohzidine alkaloids epibatidine tubocurarine Berbamine, berberine, and other isoquinoline alkaloids cinchonidine and other quinoline alkaloids corynanthine, yohimbine, and other indole alkaloids emetine ephedrine ergometiine and related ergot alkaloids Ergocornine and related ergot alkaloids bulbocapnine and related aporphine alkaloids anisocycline, stylopine, and related protoberberine alkaloids salsolinol and related isoquinohnes BicuculUne, cryptopine, hydrastine, and related isoquinoline alkaloids securinine harmaline and related beta-carboline alkaloids Corymine, strychnine, and related indole alkaloids Histrionicotoxin and related piperidines ibogaine and related indole alkaloids nuciferine and related aporphine alkaloids... 

When the heart can no longer pump an adequate supply of blood to meet the metabolic needs of the tissues or in relation to venous return, cardiac failure may ensue. The causes of cardiac failure are complex, but stem from mechanical abnormalities (e.g., pericardial tamponade), myocardial failure (e.g., cardiomyopathy and inflammation), and arrhythmias. In high-output failure, the cardiac output, which may be normal or even higher than normal, is not sufficient to meet the metabolic requirement of the body. Cardiac failure may predispose a patient to congestive heart failure, which is a state of circulatory congestion. Toxic injury, caused by agents such as doxorubicin, the alkaloid emetine in ipecac syrup, cocaine, or ethyl alcohol, is another way by which the functional integrity of the heart may also be compromised. 

Gupta et al. [72] performed an extensive structure-activity comparison regarding cross-resistance in two emetine-resistant CHO cell variants. This study showed that phenanthroindolizidine alkaloids, phenanthroquinolizidine alkaloids, and emetine-related benzoquinolizidines may have the same site of action. The conformation of emetine was suggested to have a close spatial relationship to the other three compound classes, and thus, they could bind to the same hypothetical binding site, Fig. (7). 

Most of the activity in the field of Ipecacuanha alkaloids has been of the synthetic nature. One new alkaloid, alangamide (7), from Alangium lamarckii Thw., has been identified and several analytical methods for separation and quantitative determination have been reported. Unexceptional routes to tubulosine and its relatives have been developed. Details and extensions of synthetic work related to emetine have been reported and should be of general interest (these investigations are discussed in greater detail in the following chapter). N-Chain extension of emetine with amino-acid residues has been reported. ... 

Inspection of the empirical formulas indicates a close relation between the Ipecac alkaloids which chemical study was soon to verify. Much of the early work on emetine was subsequently shown to be erroneous because the starting material was impure. The free alkaloid is amorphous but well characterized salts, especially the hydrobromide and the hydriodide, are obtainable. 

From a South African plant Cassinopsis ilicifolia (Icacinaceae), deoxytubulosine has been obtained (112). It is interesting to note that the closely related emetine-tubulosine alkaloids occur in three completely distinct families namely the Rubiaceae, Alangiaceae, and Icacinaceae. 

The therapeutic value of cularine alkaloids is virtually unknown due chiefly to the small number of cularine alkaloids that were known until quite recently. A few pharmacological properties of cularine were reported in 1940 when it was compared with hydrastine and papaverine (Reynolds 1940). Recently, in a study to establish the structural features responsible for the important biological activities of the alkaloids (—)-emetine, (—)-cryptopleurine and (—)-tylocrebrine, which belong to different families, a large number of related compounds have been examined. Cularine was found to exhibit no cross-resistance to emetine-resistant mutants of Chinese hamster ovary cells (Gupta et al. 1980). 

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