The family Apocynaceae is probably one of the richest sources of drugs in the plant kingdom. Both alkaloids, e.g. reserpine, vincristine, vinblastine, ajmalicine and serpentine, and steroids, e.g. strophantidine, are found in species of this family. One of the larger indole alkaloid-bearing tribes within this family is Tabernaemontaneae. The tribe Plumerieae comprises well-known genera such as Catharanthus, Vinca, Amsonia, Rhazya and Alstonia.
The Tribe Tabernaemontaneae
For the genera belonging to the tribe Tabernaemontaneae, as presented in Table Genera belonging to the tribe Tabernaemontaneae, we followed the classification of Leeuwenberg. For the most recent classification see Leeuwenberg (1987). In this paper is also reporten, that T. orientalis is a synonym for T. pandacaqui Poir.
Table Genera belonging to the tribe Tabernaemontaneae
|Genus||Tabernaemontana||120 species, tropics|
|Stemmadenia||17 species, America|
|Voacanga||14 species, Africa, Asia|
|Callichilia||7 species, Africa|
|Tabernanthe||1 species, Africa|
|Schizozygia||1 species, Africa|
|Carvalhoa||1 species, Africa|
|Crioceras||1 species, Africa|
|Calocrater||1 species, Africa|
|Daturicarpa||1 species, Africa|
|Pterotaberna||1 species, Africa|
|Woytkowskia||1 species, America|
Tabernaemontaneae are small trees, often shrub-like, bearing fruits with a mostly fleshy, often thick wall. The genus Tabernaemontana, distributed over the (sub-)tropical parts of Asia (about 25 species), Africa (including Madagascar, about 35 species) and America (about 60 species) is described in the literature under various synonyms: Anacampta, Anartia, Bonafousia, Camerunia, Capuronetta, Codonemma, Conopharyngia, Ervatamia, Gabunia, Hazunta, Leptopharyngia, Merizadenia, Muntafara, Ochronerium, Oisthanthera, Pagiantha, Pandaca, Pandacastrum, Peschiera, Phrissocarpus, Protogabunia, Rejoua, Sarcopharyngia, Stenosolen, Taberna and Testupides ().
Many vernacular names are also used, but they might indicate species of different genera, e.g. Mcaucau is used in Africa for both Voacanga africana and Tabernaemontana elegans (). A number of uses have been reported for Tabernaemontana species, and have recently been reviewed. Some examples of applications are: dyes, arrow poison, ornamentals and medicinal. The medicinal uses concern particularly antimicrobial, cytotoxic and analgetic activities. Some species are being cultivated. T. africana (syn. T. longiflora, T. chippii), a small understorey tree growing in light forest or bush, is cultivated in Senegal and Liberia because of its sweet-scented flowers. T. divaricata is cultivated in Pakistan among others as an ornamental plant. This species has also a wide variety of biological activities. Most characteristic secondary metabolites in the genus are the terpenoid indole alkaloids. About 300 different alkaloids have been isolated from Tabernaemontana species. A variety of biological activities have been reported for those alkaloids. So far none of them has been commercialized.
Alkaloids from Tabernaemontaneae
From the genus Tabernaemontana about 300 alkaloids have been isolated. These alkaloids are classified into different types and subtypes (Table Classification of the indole alkaloids occurring in Tabernaemontana species). The ibogan type is isolated from almost every species investigated and is thus characteristic for Tabernaemontana. About 25% of the alkaloids isolated are of the dimeric type. The corynantheanibogan dimeric indole alkaloids, the largest subtype, comprises about 53 alkaloids. Nine dimeric subtypes are isolated. Recently, Baudouin et al. isolated a semidimeric indole alkaloid from T. cerifera, consisting of a corynanthean and a tryptamine moiety.
The genus Voacanga is chemically similar to Tabernaemontana, containing only a few alkaloids which so far have not been isolated from Tabernaemontana (). The genera Tabernanthe and Stemmadenia cannot be distinguished chemically from the genus Tabernaemontana ().
Table Classification of the indole alkaloids occurring in Tabernaemontana species
|Alkaloid type||Approx. number Examples of members of this type of alkaloids|
|Ibogan||103||Coronaridine, voacangine, ibogamine, pandoline, dichomine, ibophyllidine|
|Corynanthean||68||Serpentine, yohimbine, vobasine, akuammiline, ervatamine|
|Plumeran||30||Voaphylline, tabersonine, minovincine, vincadifformine|
|Aspidospermatan||11||Stemmadenine, apparicine, vallesamine, condylocarpine, tubotaiwine, olivacine|
|Vallesiachotaman||5||Vallesiachotamine, camptothecine, angustine|
|Bis-indole||78||Conodurine, voacamine, vobparicine, ervafoline, bonafousine, tetrastachyne|
Tabernaemontana spp: Pharmacology
The pharmacology of the individual alkaloids has been excellently reviewed by Van Beek and van Gessel. In Table Pharmacological activities of some Tabernaemontana alkaloids some alkaloids with interesting pharmacological effects are mentioned. The most often encountered activities are antimicrobial and cytotoxical, which is in agreement with the use of Tabernaemontana plant extracts in traditional medicine. However, several other interesting biological activities have also been reported. The Tabernaemontana alkaloids thus seem to be of great interest for further pharmacological research, as so far only a few alkaloids have been studied for biological activity.
Table Pharmacological activities of some Tabernaemontana alkaloids
|Antimicrobial||Strong activity for many dimeric indole alkaloids: conodurine, conoduramine, voacamine, vobparicine|
|Cytotoxic||Camptothecine, 9-methoxy-camptothecine, olivacine, serpentine, coronaridine|
|Cardiovascular||Voacamine, voacorine, vincamine|
Tabernaemontana spp: Conclusions and Prospects
Cell and tissue cultures of species belonging to the Tabernaemontaneae are capable of producing a wide variety of indole alkaloids in relatively large amounts. Main alkaloids are of the aspidospermatan or plumeran type. Selected cell lines can be useful in the study of the biosynthesis of these alkaloids. A prerequisite for such study is a cell line whose biosynthetical pathway contains less branches, with only a few products being formed, preferentially belonging to the same alkaloid type.
Screening of cell lines must not be restricted to selection on species level, but also within one species or even from one plant much variability can be obtained. We screened nine cell lines of al divaricata suspension culture, which were initiated from leaves of the same plant. One cell line produced only aspidosper-matan-type alkaloids such as vallesamine, apparicine and tubotaiwine. This cell line can be used for biosynthetical studies. Alkaloid production of these cell lines varied from 0 to 12 mg/1, with apparicine and voaphylline as main alkaloids.
The production of dimeric indole alkaloids is an important property of cultures of this tribe. Further studies on the dimerization process may throw some light on the inability of cell suspension cultures, e.g. Catharanthus roseus, to produce dimeric indole alkaloids. Production by and recovery of dimeric indole alkaloids from cultures can be dependent on simple chemical factors such as extraction method and pH. The availability of the dimer moieties in respect to compartimentation, cell differentiation and chemical environment can be another obstacle in the dimerization process. From vobasinol and apparicine some dimers can be produced even without the use of enzymes. Both moieties are present in relatively large amounts, but no dimeric indole alkaloids could be isolated from the suspension culture of T. elegans. It still remains unsolved why no dimeric indole alkaloids are formed. Other secondary metabolites, such as triterpenes, simple tryptophan alkaloids and phenolics can be used in the study of the regulation of the secondary metabolism. The triterpenes and phenolics can be regarded as stress metabolites (or even as phytoalexins). Their production, which will use precursors also from the alkaloid biosynthetical pathway, can be provoked by treating the cultures with an elicitor preparation. “Optimization” of culture conditions can result in a suppression of this stress metabolism, which can be recognized by the fact that these cultures are only slightly coloured (almost white), whereas cultures with high levels of stress metabolites are coloured yellow to brown. Further studies on the value of these stress indicators and their relation to alkaloid production capacity of the suspension cultures can be of use for screening programmes of alkaloid-producing cultures.
The production of tryptamine and simple tryptophan alkaloids indicates an imbalance in availability of the precursors tryptamine and secologanin or an inadequate functioning of the enzyme strictosidine synthase. It should be emphasized that still little fundamental knowledge of the pathway leading to secologanin exists. Further research in this field should be of interest.
The influence of light and the nutrient uptake from the medium resembles the results obtained with Catharanthus roseus cell suspension cultures. Differences at this level between cultures belonging to the same subfamily but to different tribes are apparently small. For large-scale alkaloid production in bioreactors the stimulation of alkaloid production by light might be a technical and economical disadvantage, but also screening and optimization procedures can raise product yields to (commercially) interesting levels.
It might be concluded that although only a few species have been investigated and most of them only superficially, the results so far invite more research in detail on cell and tissue cultures of Tabernaemontaneae species, especially if also the (new) alkaloids and stress metabolites are found to be of pharmacological interest.
Selections from the book: “Medicinal and Aromatic Plants II”, 1989.