Ipecac alkaloids synthesis

Emetine [EM e teen] and dehydroemetine [de hye dro EM e teen] are alternate agents for the treatment of amebiasis. They inhibit protein synthesis by blocking chain elongation1. Intramuscular injection is the preferred route. Emetine is concentrated in the liver where it persists for a month after a single dose. It is slowly metabolized and excreted and can accumulate. Its ty2 is 5 days. The use of these ipecac alkaloids is limited by their toxicities. Dehydroemetine is probably less toxic than emetine. Close clinical observation is necessary when these drugs are used. Among the untoward effects are pain at the site of injection, transient nausea, cardiotoxicity (e.g., arrhythmias, congestive heart failure), neuromuscular weakness, dizziness, and rashes. 

One of the highlights covered in the last review on the ipecac alkaloids (3) was the discovery of the active amebicide ( )-2,3-dehydroemetine (136) by Brossi and co-workers (63), and its synthesis (63,130-132) and amebicidal... 

Sophisticated physical techniques have had a major impact on alkaloid research, particularly on the determination of novel structures. Progress in this area will be reviewed periodically, and the chapter on Elucidation of Structural Formula, Configuration, and Conformation of Alkaloids by X-Ray Diffraction is the first of a series of such reviews. Attention is given to chemical methodology, found to be most valuable in alkaloid synthesis, presented here in the chapter on Application of Enamide Photocyclization in Alkaloid Synthesis. Of a more traditional nature is the presentation of alkaloid classes, which have not been reviewed for many years and where considerable new material has accumulated. Hence, two chapters, namely, The Imidazole Alkaloids, last reviewed in Vol. Ill (1953) and Ipecac Alkaloids and (3-Carboline Congeners, reviewed in Vol. XIII (1971), are included. 

Brown RT, Lashford AG, Pratt SB (1979) Stereoconservative synthesis of ipecac alkaloids from secologanin. J Chem Soc Chem Commun 367-369... 

The antidiarrhoeal drug ipecac, which was introduced into Europe from Brazil in 1658, contains the amoebicidal alkaloids emetine (12) and cephaeline. Emetine remained the major remedy for amoebic dysentery and amoebic hepatitis for many years. Cephaeline is less active and more toxic. ( j-2-Dehydroemetine, which is made by synthesis, is equiactive with (—)-emetine and less toxic, but other chemical modification has not yielded better amoebicides. From investigations of synthetic routes to the benzoquinolizine moiety the tranquilizer tetrabenazine (13a) was discovered. The very similar compound benzquinamide (13b) is also a tranquilizer and antiemetic. 

The monoterpene isoquinoline alkaloids are constituents of the genus Cephaelis and selected other Rubiaceae species. C. ipecacuanha (ipecac) is a powerful emetic whose active principle is emetine, derived through the condensation of dopamine and secologa-nin (Fig. 33). Emetine is also a powerful amebicide, antiviral, and inhibitor of protein synthesis. It is now largely replaced by synthetic dehydroemetine. 

The extracts of ipecac, P. ipecacuanha, yield several alkaloids of which (-)-emet-ine (6) is the major one. The isolation, structure elucidation, resolution [16-18] and synthesis [19-26] of emetine has been fully worked out. 

Emetine (Fig. 7-9) in the form of the crude drug obtained from the roots and rhizomes of Ipecac (Cephaelis ipecacuanha) has been in use since the seventeenth century. The alkaloid, as the hydrochloride, has been used parenterally to treat amebic dysentery. It is also effective in hepatic infestation, but not against amebic cysts. Because of its cardiac toxicity and emetogenic properties, it has been superseded by metronidazole and chloroquine, but it is still used as an alternative. The amebicidal mechanism of emetine is protein synthesis inhibition by interference of peptidyl-RNA translocation. Since this action is general to eukaryotic cells, its relative selectivity in the presence of mammalian cells is not well understood. Unrelated uses of Ipecac (presumably due to its alkaloid content) are as an expectorant in cough preparations and an emergency emetic (Syrup of Ipecac). 

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