Ipecac alkaloids cephaeline

Emetine in A Emetine in B Cephaeline in A Cephaeline in B Psychotrine in A Alkaloids in A Ipecac alkaloids in B Emetine Emetine in A Emetine in B Emetine in C Cephaeline Cephaeline in A Cephaeline in B Emetine Emetine Emetine in B Ipecac alkaloids in B Emetine Emetine in A Emetine in B Cephaeline Emetine Emetine in A Emetine in B Cephaeline in A Emetine Emetine in B Emetine in C Cephaeline... 

The close biogenetic relationship of the ipecac and monoterpenoid indole alkaloids has already been reviewed in several places (3,5,117,287). In the case of the ipecac alkaloids, tracer experiments (288) have shown that labeled geraniol (146) and loganin (148) are incorporated by Cephaelis ipecacuanha into radioactive cephaeline (149) and ipecoside (150). Thus, the C9-C,0 units of the ipecac alkaloid and ipecoside, represented by thickened lines in formulas 149 and 150, are of monoterpenoid origin from geraniol (145), and loganin (147) acts as a precursor for both alkaloids. The incorporation of glycine into the C9 unit of cephaeline (2) in Cephaelis plants has also been reported (289). 

Ipecac alkaloids were extracted and analyzed by HPLC as previously reported [section 1.2]. Two flasks were used for each culture condition. The contents of isoquinoline alkaloids, protoemetine, cephaeline and emetine in the transformed roots, are shown in Fig. (54). 

Ipecac Alkaloids.— The stereochemistry of ipecoside (71) is known by X-ray analysis, and this has been confirmed. Feeding experiments in Cephaelis ipecacuanha have given results which demonstrate that it is not desacetylipecoside (72), as previously supposed cf. ref. 2), but desacetylisoipecoside (73), with the same stereochemistry at C-1 (= C-llb) as cephaeline (76) and emetine (75), which is the true precursor for these alkaloids. Similar results were obtained for cephaeline (76) in Alangium lamarckii On the other hand, desacetylipecoside (72), and not (73), is the precursor for ipecoside (71) (in C. ipecacu-... 

Ipecac alkaloids [178, 195, 196] t Part of the structure of the ipecac alkaloids, e.g. emetine 6.281) and cephaeline 6.280) [heavy bonding in 6.280) is closely similar to the terpenoid fragment of the alkaloids just discussed (Section 6.6.2) the remaining atoms are accounted for by two phenethylamine units. Investigations which have paralleled those of the terpenoid indole alkaloids have established the origins of these alkaloids (see Scheme 6.50). Desacetylisoipecoside 6.277) is the key intermediate for 6.280)... 

Ipecac alkaloids are derived from the amino acid tyrosine and the monoterpene secologanin and are therefore termed terpenoid-isoquinoline alkaloids. They occur in the eudicot families Alangiaceae and Rubiaceae. Two species, Psychotria ipecacuanha (Rubiaceae) and Alangium lamarckii (Alangiaceae), have been investigated in detail with respect to their metabolites and biosynthesis of their alkaloids (Fujii and Ohba, 1998). Roots and rhizomes of P. ipecacuanha are the source of cephaeline and emetine (Fig. 9), two compounds with emetic, expectorant, and amebicidal properties. 

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. 

Ipecac contains 2-2.5% of alkaloids, the principal ones being emetine and cephaeline (Figure 6.67). Typically, in C. ipecacuanha the emetine to cephaeline ratio might be about 2 1, whereas in C. acuminata the ratio ranges from about 1 2 to 1 1. Minor alkaloids characterized include psychotrine and O-methylpsychotrine (Figure 6.68), which are dehydro variants of cephaeline and emetine respectively. 

Ipecac, the root of a Brazilian plant, contains several alkaloids of which two, emetine and cephaeline, produce local irritation and nausea and emesis, by central and local action, without danger of side effects. 

Ipecac is the root of Cephaetis ipecacuanha, or of C. acuminata, a perennial shrub growing in Brazil and other South American states (Figure 44.1). It contains three alkaloids — emetin, cephaelin, and psychotrin. The dose of the powdered drug as an expectorant is from 1/2 to 2 grain (0.03 to 0.13 g) as an emetic, 15 to 30 grain (1.0 to 2.0 g) (Table 44.1). 

Emetine was first described in 1817 by Pelletier, the discoverer of quinine. However, Pelletier was actually dealing with a mixture of the alkaloids of ipecac, that is, emetine, cephaeline, and psychotrine (see Grollman, 1962). 

The efficacy of ipecac in amebic infections depends upon its content of alkaloids, the principal ones being emetine and cephaeline. Both are amebicidal, but emetine is much more active. Cephaeline is more toxic than emetine, except for the heart, and causes more nausea and vomiting. Emetine constitutes more than one half of the total alkaloidal content of ipecac. 

The root of the ipecac is commonly used as an expectorant in the treatment of bronchitis, croup, asthma amoebacide and whooping cough, as an emetic in cases of poisoning, and an amoebacide in amoebic dysentery. It has appeared in the Japanese Pharmacopoeia (2001) as ipecac, powdered ipecac and ipecac S)nxip [6]. The ipecac is rich in isoquinoline alkaloids such as emetine, cephaeline, psychotrine. 

The supply of ipecac has fluctuated for many years because it is collected mainly from wild habitat. The Rio variant is now becoming difficult to obtain commercially, and the high price favors cultivation, but only modest success has been achieved from the efforts made to grow the plant in Malaya and India. The ipecac used in Japan is imported from abroad at a rate of 100%, consequently giving variation of alkaloid value and ratio of emetine and cephaeline [10]. 

Ipecac contains many isoquinoline alkaloids as mentioned above and the value of the regenerated plants through tissue culture greatly depends on their phytochemical similarities to the crude drug. Therefore, improved HPLC system for the analysis of the isoquinoline alkaloids, not only emetine and cephaeline but also minor constituents, was investigated [19]. 

Although the ion pair HPLC for emetine and cephaeline using sodium 1 -heptanesulfonate as a counter ion and methanol for a mobile phase was previously reported [20], compounds other than emetine and cephaeline in the leaf extract of ipecac were not well-separated. Therefore, a different type of ODS column, TSK gel ODS-120A column (4.6 mm i.d. x 250 mm, TOSOH Co., Japan) was selected because it previously provided a good separation of the tropane alkaloids [21-23] and the Papaver alkaloids [24]. 

The alkaloid contents of adventitious shoots in liquid medium were quantified by HPLC, Fig. (20). They produced alkaloids, especially cephaeline (0.4 - 0.6% dry weight), and there was no obvious difference in alkaloid contents among different concentrations of BA. This result indicates that ipecac shoots, formed on intemodal segments, have the capabilities of alkaloid biosynthesis. 

A one-year-old Cephaelis ipecacuanha plant propagated through shoot-tip culture (section 1.1) in a greenhouse accumulated ca. 2 mg emetine and ca. 2 mg cephaeline, respectively, in its roots ca. 0.2 g total dry weight). On the other hand, the root culture of ipecac cultured for 7 weeks in 50 ml MS medium containing 0.01 mg/1 5,6-Cl2-IAA yielded almost the same amounts of alkaloids, 0.6 mg emetine and 2.4 mg cephaeline. Thus the root culture of ipecac is a realistic economic source of the isoquinoline alkaloids. 

The isoquinoline alkaloid contents in the transformed and non-transformed plants are indicated in Table 16. Alkaloid contents in the leaves were higher than those in the roots despite transformation. Cephaeline was the major alkaloid in all parts of in vitro plants as well as the root cultures. Alkaloid contents in the transformed plants, both in the leaves and roots, were lower than those of non-transformed plants except emetine in the roots. Any advantageous effects of T-DNA integration into ipecac on the alkaloid accumulation in the regenerated plants were not observed as previously reported for Duboisia hybrid [79] and Hyoscyamus muticus [103]. 

Syrup of ipecac is available as a nonprescription product in many countries. It is derived from the dried rhizome and roots of the Cephaelis ipecacuanha or Cephaelis acuminata plant. These plants contain the potent emetic alkaloids emetine and cephaeline, which induce vomiting by both direct local gastrointestinal effects and central nervous system actions. Emesis following syrup of ipecac ingestion typically occurs within 20 min of ingestion and persists for 30-120 min. 

In the meantime, the formation of the main alkaloids in C. ipecacuanha under a variety of conditions has been extensively investigated emetine (1) in callus cultures (49) and under the effects of L-tyrosine supplementation (5t)) emetine (1) and cephaeline (2) in Panamanian ipecac (57), in Nicaraguan ipecac (52), in regenerates obtained by clonal propagation (53,54), in tissue cultures (55) and under the effects of exogenous feeding of shikimic acid and L-phenylalanine (55), in cell suspension and excised root cultures (57), in adventitious root cultures (58), and in callus cultures (56,59) and the effects of age and electrokinetic potential (60) ipecoside (7) in the roots (61) and the effect oi Azotobacter, leaf mold, and farmyard manure on alkaloid content (62). In addition, micropropagation systems for C. ipecacuanha have been developed (63-65). 

O-methylpsychotrine, and emetamine [7], Fig. (2), emetine and cephaeline being the principal active ingredients. Emetine having a more expectorant and less emetic action than cephaeline is the most commonly used alkaloid in medicine [8], Emetine hydrochloride is used in the treatment of amoebic dysentery by injection. Strong emetic action of the alkaloids characterizes an ipecac syrup that is the first choice of drug in the case of infant intoxication [9]. 

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