Curare, alkaloids types

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. 

Streptomyces distallicus the structure elucidation and synthesis have also been made by them.165 A wide variety of porphyrins which are derivatives of porphin (125 R = H) occur in nature and exert three biological functions (a) oxygen storage and transport, as in hemoglobin, (b) cellular respiration as in the cytochromes, and (c) photosynthesis, as in the chlorophylls for detailed discussion of structures and synthesis of naturally occurring porphyrins, see references.166 Recent developments in the chemistry of polypyrrolic compounds have been reviewed.167 Several naturally occurring indole alkaloids have dimeric structures of type B,168 an example of which is c-toxiferine-I, a calabash curare alkaloid found in South American species of Strychnos.169... 

The ability of plants to utilize both the major biogenetic routes (to CCLXIX and CCLXX) is amply demonstrated by the various Stryehnos species, some of which elaborate the strychnine family of alkaloids, some of which (the South American Stryehnos) elaborate yohimbine types (curare alkaloids). Even more striking is the biosynthesis in the one plant Gdsemium sempervirens (not a Stryehnos) of both gelsemine... 

An important factor in stimulating the early structural studies of Erythrina alkaloids during the 1940 s was the discovery of their curariform activity (cf. Craig 1955) this appears to be associated with the spiroamine moiety, and in contrast with the curare alkaloids, which are quaternary salts, the Erythrina alkaloids are all tertiary amines. Many other types of pharmacological activity have also been discovered with Erythrina alkaloids, e.g. sedative, hypotensive, CNS depressing, laxative and diuretic properties. 

Alkaloids of Pot Curare. This variety of curare is a dark brown, comparatively dry extract. According to Boehm, it contains protocurine, colourless hair-like needles, m.p. 306° (dec.), a base of low toxicity and yielding crystalline salts. A second alkaloid of similar type is protocuridine prisms, m.p. 274-6°, sparingly soluble in all ordinary solvents. The poisonous constituent is protocurarine, a red powder, easily soluble in water, and giving characteristic colour reactions with nitric acid and with oxidising agents in sulphuric acid, this latter reaction indicating a Strychnos spp. as a possible botanical source. 

The material first used by Wieland et al. was gourd curare from the middle Orinoco district, near Urbana, in Bolivar State, Venezuela, but in the fomth paper (1941) results are recorded for curares from Colombia and Venezuela, for which more precise details of origin are not available and there is considerable difference in the nature and quantity of the alkaloids in the various samples used. An examination has also been made of the bark of Strychnos toxifera, and one of the alkaloids (toxiferine II) it contains has been found in some of the curares examined. In all, ten alkaloids have been obtained and characterised and, with the exception of curine, they are all of quaternary type. They are named toxiferine, dihydrotoxiferine, or calabash-curarine (shortened to C-curarine in practice) according to type, and the variants within the type are distinguished by numbers, or numbers and letters, e.g., toxiferine I, toxiferine Ilb. 

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-... 

The development and use of muscle relaxants, to allow a reduction in the level of anesthesia during surgery, follows entirely from studies of South American arrow poisons (44)and particularly from the isolation by King (45) of pure D-tubocurarine (29) in the 1930s, from tube curare. Another of the South American blowpipe poisons, calabash curare, was used for similar purposes and developed (46,47), to give alcuronium (30) from the alkaloid C-toxiferine 1 (31). Both types of curare paralyze skeletal muscle by a similar mechanism, antagonizing the effect of acetylcholine at the neuromuscular junction (48). 

The genus Malouetia occurs in both Africa and South America. It is distinguished by the same types of alkaloids as Funtumia and Holarrhena. Of particular interest is the isolation of the quaternary alkaloid malouet-ine with curarizing effect in the African Malouetia, bequaertiana Woods. It is probable that the same effect produced by the Venezuelan drug guachamacd can be attributed to some alkaloids of the South American Malouetia (3). 

Chapter 3 by Mary D. Menachery surveys the alkaloids of South American Menispermaceae (moonseed family). Many different structural types are included in this family. The alkaloidbearing plants are woody-vines, shrubs, or small trees. Several of these species possess potent curare activity. The chemistry as well as pharmacology of these alkaloids is summarized. 

There have already appeared many chapters on Strychnos alkaloids, including those of calabash curare, in previous volumes (7-6) of this treatise. Although extensive studies on Strychnos alkaloids were carried out and many of the main structural classes of alkaloids were determined by the mid-1960s, various types of new alkaloids have since been found and efficiently characterized, sometimes even from small pieces, of herbarium specimens of Strychnos plants. 

On the basis of structure the dimers can be clearly divided into two groups. The first is comprised of alkaloids with identical or very closely related components in which the same centres act as linkage positions. The Calycanthaceous and Calabash-curare-South American Strychnos alkaloids make up this group. The second group consists of dimeric bases in which the alkaloid components are of a different structural type (e.g. geissospermine, vinblastine, and tubulosine) or in which two similar halves are linked unsymmetrically through two different centres e.g. macralstonine). The bisindole alkaloids will be discussed in this order. ... 

Some of the most difficult structural problems in the indole alkaloid field are associated with the bisindole alkaloids of the vobtusine type. Since 1955, vobtusine has been isolated on numerous occasions, often in large quantities, from the Apocynaceae species Callichilia, Conopharyngia, Rejoua, and Voacanga A correct molecular formula could only be determined by high-resolution mass spectrometry. In 1966 a partial structure was proposed for the alkaloid and later in the same year a complete structure was put forward. An unambiguous structural proof is, however, still lacking. The difficulty arises from the complete resistance of the alkaloid and its derivatives to cleavage, in contrast, for example, to the dimers of the voacamine and vinblastine types. Non-cleavable dimers occur also in calabash-curare but in these cases chemical correlation with cleavable alkaloids has been possible (see Section 2, p. 209). To date no bisindole alkaloid related to vobtusine has been found which can be split into monomeric units. 

With the isolated rectus abdominis preparation of frogs the mode of action is found to be of the curare type. Like i/-tubocurarine, all the alkaloids investigated antagonise acetylcholine contractions. C-Alkaloid E (51) and C-toxiferine (38) are the most active. 

The seeds of Erythrina species are known to contain toxic alkaloids, as well as blood clotting substances, which may be of value in the treatment of thrombosis. The seeds, stem and root bark of some Erythrina species have been used also to stupefy fish, as narcotic, purgative, and diuretic [1,4], while crushed seeds of some have been used as rat poison. All the Erythrina species examined have yielded alkaloids, mostly of the erythrinaline type, having the curare like poisoning action [1,4]. Several of the more common species are used for decorative purposes in gardens and city streets. 

A considerable amount of information had been accumulated on curare, the South American arrow poisons, before 1900. The results of the early work were very inaccurate because of the complexity and variation of the composition of the mixtures of alkaloids involved. Boehm (7, 8) distinguished the types of curare preparations by the type of container in which they were packed. They were (a) para, tube, or bamboo curare, packed in bamboo tubes (b) pot curare, exported in small earthenware pots and (c) gourd or calabash curare, packed in small gourds. Boehm prepared active curarizing samples from these materials, tubocurarine from tube curare, protocurarine from pot curare, and curarine from gourd curare. These were impure, non-crystalline alkaloids which, for the most part, were quaternary ammonium compounds. The curarine of Boehm is the material used in much of the early experimental work.. ... 

In searching for possible useful curarizing agents as well as for clues to the structures of the calabash and toxiferine alkaloids, a number of quaternary salts of open and closed carboline-type compounds have been examined. Some of these compounds which are possible open-chain fragments of the toxiferines, are indicated by formulas IX-XVIII. 

Lycopodine. Formula see Lycopodium alkaloids. CifiHjjNO, Mr 247.38, mp. 116°C, [d -24.5° (C2H5OH). A Lycopodium alkaloid of the C. N type from many club moss species (Lycopodiaceae). It is the most widely distributed Lycopodium alkaloid and usually occurs as the major alkaloid. It was first isolated over 100 years ago from a clubmoss species. L. is toxic and exerts a curare-like paralysing activity. Several syntheses have been reported. ... 

Strychnos alkaloids. A group of monoterpenoid indole alkaloids that are not exclusively isolated from Strychnos plants and do not exclusively belong to the strychnidine type. The most well-known members of this group of alkaloids are strychnine, its methoxy-lated derivative brucine, the toxiferines, and curare, as well as vomicine which all have structures derived from the strychnidine skeleton. 

As described previously, the origins of the three types of curare are the extracts of Chondodendron (Menispermaceae) and/or Strychnos (Loganiaceae) plants. Among them, the toxic components of Strychnos plants are C-curarine and C-toxiferine I, etc.These constituents are alkaloids derived from tryptophan and are described in the next (Section 2.15).The C- is the initial of calabash. On the other hand, the toxic principle of tubocu-rare is d-tubocurarine, an alkaloid derived from phenylalanine. The alkaloid was first isolated as a hydrochloride from tubocurare and is preserved in the Museum of the British Society of Pharmacy [1]. The chemical structure of d-tubocurarine was first proposed as a bisbenzylisoquinoline with two quaternary ammonium moieties. This was revised in 1970 to be the structure with one tertiary and one quaternary amine after X-ray crystallographic analysis [2]. 

Curare is a mixture of plant products that is used to poison the tips of arrows for hunting and sometimes for warfare. The peoples that made these combinations of ingredients used many types of plants, but several of these plants contain BIQ and bisbenzylisoquinoline alkaloids (Bisset, 1985 Cordell, 1981). 

Most curares derived from Strychnos species in South America are known as calabash curares because they are stored in a calabash or small gourd. Curares of this type are regarded as the most paralytic natural or synthetic neuromuscular blocking agents. At least seven alkaloids have been isolated that are more active than fi -tubocurarine (see Chapter 32). For example, C-toxiferine (48) is about 10 times as active, and C-alkaloid G (49) and E (50) are 100 times more active, being active at 1 fxg per kg (Cordell, 1981). 

Calabash curare, prepared from plants of the genus Strychnos, is packed in hollow gourds. It contains a large number of alkaloids and is extremely poisonous. The alkaloids contain an indole ring system and can be divided into 3 types the yohimbine type (e.g. mavacur-ine), the strychnine type (e.g. Wieland-Gumlich aldehyde) andthehfrindole type (e. g. calabash toxiferin-I). 

The terpenoid alkaloids are considered to be derived from prenyl units that undergo enzymatic cycUzatiOTi, while the nitrogen atom is inserted in the skeleton on a late stage in the biosynthesis. Some of the terpenoid alkaloids exhibit potent cardiovascular, cytotoxic, and antinociceptive activity, while others show extreme toxicity. The mode of action of some diterpenoid alkaloids including curare-like activity has also been studied. More investigations are needed on this type of alkaloids to provide a detailed understanding of the interdependence between stmcture, activity, and mode of action in order to develop future dmg candidates. 

Similar types of alkaloids have been isolated from the plants of the closely related species such as Funtumia and Malouetia. It is interesting to note that an alkaloid isolated from the wood of an African Malouetia was reported to possess a curarizing effect (87). 

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