Quaternary alkaloids

Gourd or Calabash Curare. This type, exported in small gourds, is said to be made from Strychnos toxifera Schomb., and this was confirmed by King, who isolated from botanically authenticated material collected in British Guiana, an amorphous, quaternary alkaloid indistinguishable from curarine prepared from gourd curare, and Wieland et al. have isolated from this species alkaloids which they have also found in this type of curare. Other Strychnos spp. from the same territory examined by King contained alkaloids, but not of the curarine type. 

These results seemed to establish with certainty that the active component of tube curare is derived from Chondrodendron tomentosum, but the matter again became doubtful when King reported that in the stems of a carefully authenticated specimen of the plant, collected at Tarapoto in Peru, he had found 1-curine and Z-tubocurarine chloride. This is the first recorded natural occurrence of the latter and seems to indicate either that the alkaloidal components of the plant are not constant in character, or that the botanical description of Chondrodendron tomentosum covers two species containing the dextro- and Icevo- quaternary alkaloids respectively. 

The process of isolation finally adopted by the former authors consists in precipitating as reineckates the water-soluble bases contained in a methyl alcoholic extract of the curare. The mixed reineckates are further purified, by solution in acetone and precipitation with water as often as may be necessary. The product so cleaned represents the bulk of the biological activity of the crude drug the mother liquors may contain curine (p. 374), which indicates a menisperm as one of the components of such curares. The mixed reineckates are then fractionated chromato-graphically over alumina and the components isolated as chlorides by the use of silver sulphate and barium chloride in succession. This process has been modified in detail by Schmid and Karrer, who have also found that with their curare, the more soluble reineckate fraction includes less potent quaternary alkaloids. 

The total crude alkaloid from tlie soluble reineckate fraction had the low curarising potency 25 mgm./kilo frog. It consisted mainly of quaternary alkaloids and nothing crystalline lias so far been obtained from the non-quaternary portion. 

Quaternary alkaloids Chelidonium maius SiOj Aqueous buffered MeOH UV 355 nm — 7... 

Figure 11.17a to Figure 11.17d show densitograms from the separation of Che-lidonium majus quaternary alkaloids. Various volumes of the extract solution of the same concentration, from 0.2 to 1.6 ml, were introduced to the adsorbent layer. Thus, the following portions of extract of 0.25, 0.5, 1, and 2 mg were chromatographed by the use of threefold development with the multicomponent eluent. The densitograms depict fast loss of resolution with the increase of the introduced sample [114]. 

Figure 11.28 shows densitograms from the separation of Chelidonium majus quaternary alkaloids [114]. It is clearly apparent that multiple development results in better separation of the component bands. Threefold development results in separation or partial separation of eight alkaloid bands (Figure 11.28b), whereas after one run, only four zones — chelirubine, sanguinarine, chelilutine, and chelerithrine... 

Since the configuration at C-16 is undetermined, both quaternary alkaloids diploceline and 16-epidiploceline, isolated from the root bark of Strychnos goss-weileri Exell (54), could be represented by formula 50. The absolute configurations of the C-3 and C-15 have been determined by CD measurements, and the cis junction of C/D rings is supported by H-NMR data [8 4.58 (C3—H), 8 3.58 (N—CH3) for diploceline]. 

The quaternary alkaloid anhydroalstonatine (70), which has a completely aromatic yohimbane ring system, has been isolated from Alstonia venenata R.Br. (64). 

It is a general feature of alkaloid chemistry that less is known about the quaternary alkaloidal components than the tertiary bases due to the difficulties encountered in handling the isolation and analyses of these highly polar compounds. It is interesting to note, however, that in the pavine series, 5 naturally occurring A -metho salts as against a total of 15 tertiary pavine alkaloids have been recognized. 

The principal type of ether cleavage classically employed in bisbenzyliso-quinoline alkaloid research is reductive reaction with Na/NH3, which cleaves diphenyl ether linkages, providing characterizable fragments. Numerous examples are to be found in Section II,C. A drawback is that methylenedioxy (e.g., see Section II,C, 131) and certain alkoxy (e.g., see Section II,C, 130) functions are also attacked, leading occasionally to ambiguous results quaternary alkaloids also suffer Hofmanmelimination (e.g., see Section II,C,131). 

Chemical ionization (CI)-MS can be used to study alkaloids that are not amenable to examination by electron impact (EI)-MS. For example, the quaternary alkaloid thalirabine (Section II,C, 123), undergoes fragmentation under the conditions of EI-MS and does not show a parent ion however, the CI-MS shows a double Hofmann elimination product which retains the skeletal atoms (32). Field desorption (FD)-MS has similar utility, as in the case of cycleanine IV-oxide (Section II,C,17) for which FD-MS shows the parent ion not detectable by EI-MS (65). Desorption/CIMS (D/CIMS) was used on dihydrosecocephar-anthine (Sec. H,C,30) and related bases (80,292a). 

The bisbenzylisoquinolines have been the subject of many pharmacological studies, motivated originally by the knowledge that quaternary alkaloids of this type are the active constituents of tube curare. Certain nonquaternary bisbenzylisoquinolines, notably belonging to the curine group, are also smooth muscle re-laxants many bisbenzylisoquinolines are hypotensive, and a few possess anti-... 

Platydesmine (5 R = H), the biosynthetic precursor of dictamnine and other furoquinoline alkaloids, has been detected for the first time in a Haplophyllum species H. perforatum).5 Choisya ternata is known to contain O-methyl-balfourodinium salt (4 R = OMe), but now AT-methylplatydesminium salt (4 R = H) has been isolated in equal amount to (4 R = OMe) from the stalks and roots (4 R = OMe) is the predominant quaternary alkaloid of the leaves.3... 

The active principles of curare were early recognized to be water-soluble quaternary alkaloids. Tube-curare was studied by King, who isolated (3) the crystalline quaternary bisbenzylisoquinoline alkaloid, d-tubocurarine (I), in 1935. The main plant constituent of tube-curare is the bark of menispermaceous plants, particularly of the genus Chondro-dendron, and d-tubocurarine was later isolated (4) from C. tomentosum. Further work led to the isolation and structural elucidation of many more bisbenzylisoquinoline alkaloids from these sources (5). 

Only a few of the quaternary alkaloids so far isolated have high curare-activity, and these are responsible for the toxicity of the curares and bark extracts the majority of the pure alkaloids are inactive or only weakly active. At present there is no evidence against the view that all the toxic alkaloids of calabash curare are derived from Strychnos species it is probable that the same also holds true for most of the nontoxic curare alkaloids. 

The first chemical work on calabash curare was carried out in 1897 by Boehm (8), who isolated a highly active amorphous material which was named curarine. This was soluble in water and insoluble in ether, so it is probable that Boehm was handling a mixture of crude quaternary alkaloids. Much later (1935), King described (9) the preparation of an equally active amorphous quaternary iodide from the bark of S. toxifera. However, the first isolation of well-characterized crystalline alkaloids was achieved by H. Wieland and his school (10-13). Calabash curares were extracted with methanol, and the water-soluble quaternary alkaloids in the extract were precipitated as the reineckate salts this mixture was then fractionated by adsorption chromatography on alumina. The various reineckate fractions so obtained were converted into the corresponding chlorides by successive treatment with equivalent quantities of silver sulfate and barium chloride some of the quaternary alkaloids then crystallized as the chlorides or as the picrates. C-Curarine1... 

The quaternary alkaloids are commonly isolated and handled as the chlorides, and it is therefore convenient to use the name of the alkaloid to mean alkaloid chloride. Thus throughout this chapter, C-calebassine means C-calebassine chloride, and other alkaloids will be treated in the same way. Anions other than chloride will be named, e.g., toxiferine I picrate. The letter C- is used to indicate that the alkaloid is derived from a calabash. 

This same Brazilian calabash curare also yielded (28) a quaternary alkaloid, C2iH27N20 , mp of iodide 235°-238°, [a]D +41° (96% ethanol). This was named lochneram, since it was proved (28) to be identical with A lj-metho lochnerine (XLIX). Moreover, lochneram gave only acetaldehyde when subjected to ozonolysis and is therefore regarded as the pure ethylidene isomer (XLIX). 

The similar dilute acid-catalyzed transformation of toxiferine I dichloride was investigated by Battersby and Hodson (84, 31), who isolated two crystalline quaternary products from the reaction mixture. One was shown to be identical with a quaternary alkaloid, provisionally called A8, which they had previously isolated (15) from S. toxifera bark... 

This pale-yellow quaternary alkaloid, picrate mp 189°, [a]D of chloride — 930° (in water), was first isolated from a calabash curare (12) it was subsequently isolated from other calabash curare preparations (34, 35) and has been identified chromatographically in extracts from the bark of S. mitscherlichii (33) and other Strychnos species (7). The identification of C-fluorocurarine is greatly helped by its deep-blue fluorescence in UV-light. Analyses of the crystalline iodide and anthraquinone sulfonate showed its molecular formula to be C2oH23N20+ (12), which is in agreement with all subsequent work. The properties of C-fluorocurarine, particularly its low toxicity and high Rc values, suggest that it is a C20 alkaloid rather than a double molecule. This was confirmed (102) by application of the partial quaternization method to one of its derivatives (see subsequent discussion) the method cannot be applied to C-fluorocurarine itself, since on pyrolysis it is not smoothly demethylated to the... 

Blomqvist L, Brandange S, Gawell L, Leander K, Liining B (1973) Studies on Orchidaceae Alkaloids XXXVII. Dendrowardine, a Quaternary Alkaloid from Dendrobium wardianum. Acta Chem Scand 27 1439... 

A quaternary alkaloid present in hydrastis, in various species of Berberis, and in many other plants. 

The formation of the methylenedioxy bridge in Berberis has been found to be caused by the demethylating activity of a peroxidase (POD) found within the vesicle. It was also found that the cytochrome P450-requiring enzyme (canadine synthase) from microsomes of Berberis, Thalictrum and Coptis species formed the methylene bridge in (S)-tetrahydrocolumbamine (Ikezawa et al, 2003), but not in the quaternary alkaloid columbamine (Galneder et al, 1988 Zenk, 1995). Because of the substrate specificity of canadine s)mthase, the berberine pathway is considered to be that presented in Fig. 2.5 (Rueffer and Zenk, 1994). Columbamine, once proposed as an alternative route to berberine, is however converted to palmatine by a specific methyltransferase first isolated from Berberis wilsoniae cell cultures (Rueffer and Zenk, 1985 Ikezawa et al, 2003). 

Barberry (pipperidge bush) is a vernacular name for Berberis vulgaris (the European barberry), but it can also refer to Mahonia aquifolium and Mahonia nervosa. In the USA only the Mahonia species have had official status as a source of barberry, but Berberis vulgaris is said to serve similar medicinal purposes and to contain similar principles. Its root bark yields the quaternary isoquinoline alkaloid berberine and several other tertiary and quaternary alkaloids. Berberine is also found... 

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