25,37 synthesis Emetine

This success was now further extended to the indole derivatives by replacing a dimethoxybenzene ring to an indole ring. Thus it was suggested that photocyclization of enamides prepared from harma-lane by acylation with 2- or 3-furoyl chloride would provide a novel synthesis of the biologically useful alkaloid ajmalicine and the hitherto untouched alkaloid hirsuteine. This synthetic strategy was just an another extension of the above emetine synthesis as shown in the scheme. 

The correctness of the revised structure and relative stereochemistry of ankorine was confirmed by a total synthesis closely paralleling the emetine synthesis by PreobrazhenskiiJ... 

Scheme 10.34. Catalyst controlled synthesis of 12 stereoisomers of emetine.

This drug has a direct amebicidal effect against trophozoites E. histolytica in tissues, and it is not active against cysts in either the lumen or intestinal walls, or in other organs. The mechanism of action of emetine consists of the blockage of protein synthesis in eukaryotic (but not in prokaryotic) cells. It inhibits the process of polypeptide chain formation. Protein synthesis is inhibited in parasite and mammalian cells, but not in bacteria. 

G. Synthesis of Emetine Analogs Synthesis of Indole Alkaloid Analogs... 

The emetines include emetine and dehydroemetine. These drugs act only against trophozoites. Their mechanism of action is based on eukaryote protein synthesis. They are parenterally administered because oral preparations are absorbed erratically and may induce severe vomiting. They are widely distributed and accumulate in liver, lungs and other tissues. The emetines are slowly elimination via the kidneys. Local side-effects in the area of the intramuscular injection are pain, tenderness and muscle weakness. Serious toxicity is common if the drugs are given for more than 10 days. Side effects include nausea, vomiting, diarrhoea but also cardiotoxicity. 

Emetine and dehydroemetine are natural alkaloid obtained from Cephaelis ipecacuanha and synthetic analog respectively. They are effective against tissue trophozoites of . histolytica. It has no effect on cysts but effective in amoebic liver abscess also. It acts by inhibiting protein synthesis by arresting intraribosome translocation of tRNA-amino acid complex. Dehydroemetine is less toxic than emetine and very effective drug for tissue amoebiasis. It is more rapidly eliminated from the body than emetine. 

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. 

Emetine and cephaeline are both potent inhibitors of protein synthesis, inhibiting at the translocation stage. They display antitumour and antiviral as well as antiamoebic activity, but are too toxic for therapeutic use. In recent studies, O-methylpsychotrine has displayed fairly low effects on protein synthesis, but a quite potent ability to curb viral replication through inhibition of HIV-reverse transcriptase. This may give it potential in the treatment of AIDS. 

The diastereomers were separated by column chromatography and pure 134 was used for the synthesis of emetine 111 and tubulosine 112. As intermediates in the... 

For the synthesis of emetine 111, benzoquinolizidine 134 was treated with phe-nylethylamine 133 and trimethyl aluminum to give amide 146 which could then directly be transformed into the desired imine 147 using POCI3. The final step towards emetine 111 was transfer hydrogenation using (S,S)-122, which allowed the introduction of the fourth stereogenic centre with a d.s. > 98 1 (Scheme 5.29). 

Emetine is the main alkaloid found in the root of Cephadis ipecacuanha [102], which has been used for centuries as an emetic and was subsequently shown to be a potent antiamebic [103], A concise synthesis of this compound as well as a small library of analogues was recently reported by Tietze and co-workers [104], who made use of their powerful three-component domino-Knoevenagel-condensation/ hetero-[4+2] reaction sequence previously described in Section 8.1. 

An alternative stereospecific synthesis of emetine has been accomplished from ethyl trans-5-ethyl-2-oxopiperidine-4-acetate by conversion into the lactim ether (107), which was allowed to react with 3,4-dimethoxyphenacyl bromide to give the ketone (108 R R2 = O). Reduction of this with sodium borohydride, followed by hydrogenolysis of the resulting alcohol, gave (108 R1 = R2 = H), which has previously been converted into emetine.135 The reaction of (107) with 3-benzyloxy-4-methoxyphenacyl bromide and with 4-benzyloxy-3-methoxyphenacyl bromide afforded analogues of (108 RJR2 = O), which were converted into 9-O-desmethylpsychotrine (109 R1 = H, R2 = Me) and 10-0-desmethylpsychotrine (109 R1=Me, R2 = H) respectively.136,137... 

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. 

Tetrabenazine or 2-oxo-3-isobutyl-9,10-dimethoxyhexahydrobenzo-[a]quinolizine (LVI) (229), which has apparently emanated from work related to the synthesis of emetine, has obtained much attention recently. In spite of the absence of an indole ring system, it seems to possess sedative reserpine-like activity. Tetrabenazine has been pharmacologically studied in great detail (230). 

Kametani el al. (29,30) have reported another stereoselective synthesis of ( )-emetine (1). Condensation of the dihydroisoquinoline 83 with the unsaturated malonate 84 gave the tricyclic lactam 85 which furnished... 

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. 

Emetine and dehydroemetine exert a direct aniebicidal action on various forms nf E. Iihwlyiica. They arc protoplasmic poisons that inhibit protein synthesis in pnilo/iKil and mammalian cells by preventing protein elongation. Because their effect in intestinal amebiasis is solely. symptom-... 

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