Artabotrys (PROSEA)

Plant Resources of South-East Asia Introduction

List of species

Artabotrys R.Br. ex Ker Gawl.

Protologue: Bot. Reg.: t. 423 (1820).

Family: Annonaceae

Chromosome number: x= unknown; Artabotrys hexapetalus: 2n= 16, 18

Major species

• Artabotrys hexapetalus (L.f.) Bhandari,
• A. suaveolens Blume.

Vernacular names

• Indonesia: pisang-pisang (used for most Annonaceae)
• Malaysia: mempisang (used for most Annonaceae)
• Vietnam: móng rồng.

Origin and geographic distribution

Artabotrys comprises about 100 species and has a widespread distribution in the Old World tropics.

Uses

In India, A. hexapetalus is used in traditional medicine for treatment of vomiting, biliousness, anti-fertility and diseases of blood and heart. As a Chinese folk medicine, the root and fruits of A. hexapetalus are applied to treat malaria and scrofula, respectively. In Indonesia and India a decoction or infusion of the leaves of A. suaveolens is used against cholera. In the Philippines, a decoction of the bark and roots of A. suaveolens is prescribed as an emmenagogue and for women after parturition.

Production and international trade

Although medicine derived from A. hexapetalus originating from China is on the world market, no data are available on production and trade.

Properties

From A. suaveolens , several aporphin type alkaloids have been isolated, e.g. the non-phenolic artabotrine (synonyms: isocorydine, luteanine), artabotrinine and the phenolic suaveoline. Purified artabotrine acts on the muscular system and stopped respiration in guinea-pigs. Furthermore, the methylderivative of artabotrine, i.e. methyl-isocorydine is reported to be a long lasting ganglion blocker with a sympathic / parasympathic activity ratio of 6/1.

Nine isoquinoline alkaloids have been isolated from the bark of A. maingayi Hook.f. & Thomson, from Peninsular Malaysia: four noraporphines (norstephalagine, 3-hydroxynornuciferine, anonaine and nornuciferine), one 7-hydroxyaporphine (ushinsunine), three oxoaporphines (atherospermidine, liriodenine and lysicamine), and one protoberberine. The effects of the main aporphine alkaloids, norstephalagine and atherospermidine, have been studied on the Ca-dependent contractile activity of smooth muscle preparation (uterus). Both norstephalagine and atherospermidine show relaxant activity on rat uterine contractions induced by KCl or rhythmic contractions induced by oxytocin in the presence of Ca²⁺, but only atherospermidine can relax oxytocin- or vanadate-induced contractions in a Ca-free medium.

Furthermore, a wide range of isoquinoline alkaloids have also been isolated from the bark of A. venustus King, from Peninsular Malaysia: five noraporphines (nornuciferine, asimilobine, anonaine, norstephalagine, norushinsunine), two aporphines (nuciferine, lirinidine), (S)-reticuline, norcorydine, two berberines (discretamine, 10-O-demethyldiscretine) and the catecholic artavenustine.

In addition, besides some common flavonoids / organic acids (e.g. taxifolin, fumaric acid), 2 flavonol glycosides artabotryside A (synonym arapetaloside A; quercetin-3-O-α-L-rhamnopyranosyl(1->2)-α-arabinofuranoside) and artabotryside B (synonym arapetaloside B; kaempferol-3-O-α-L-rhamnopyranosyl(1->2)-α-L-arabinofuranoside are reported for the leaves of A. hexapetalus.

Methanolic extracts of stem parts of A. hexapetalus showed significant in vitro activity against tissue culture cells of human KB, A-549 lung carcinoma and HCT-8 colon tumour, as well as murine P-388 and L-1210 lymphocytic leukaemia. The active fraction consists of alkaloids. The principal active components are 2 aporphine alkaloids: liriodenine and atherospermidine. Liriodenine demonstrated potent cytotoxicity against KB, A-549, HCT-8, P-388 and L-1210 cells with ED₅₀values of 1.00, 0.72, 0.70, 0.57 and 2.33μg/ml, respectively. Atherospermidine posseses cytotoxic activity against KB cells at an ED₅₀ value of 2.5μg/ml.

The bark and roots of A. hexapetalus furthermore contain sesquiterpenes and alkaloids that possess antimalarial and antitumour activity respectively. The leaves contain cardiovascular principles. Also an alcoholic extract of the pericarp showed a positive inotropic and chronotropic effect on all types of experimental animals. The cardiac stimulant and uterine stimulant activity is attributed to the glycosides, whereas the relaxant action on the plain muscles and hypotensive effect, which could be partly cholinergic and partly resulting from vasodilatory activity, are probably due to the presence of the essential oil.

Ethanolic (90%) extracts of A. hexapetalus leaves, when administered orally at 250 mg/kg during early pregnancy, result in a 66% anti-implantation activity in albino rats. In addition, ethanolic (50%) and benzene (50%)leaf extracts of A. hexapetalus markedly increased ovarian weight and corpora lutea parameters of adult guinea-pigs. Antifertility activity of A. hexapetalus has been corroborated in rats. Ethanolic (50%) and benzene (50%) leaf extracts of A. hexapetalus have been shown to disrupt the normal oestrous cycle in rats and have also prolonged the duration of leucocytic stage of vaginal smear in the same species. Furthermore, both these extracts have been reported to possess significant anti-oestrogenic activity when tested in immature female bilaterally ovariectomized rats. In view of its antifertility and its anti-oestrogenic activity, oestrogen-dependent biochemical parameters in the uterine tissue of rats were assessed. Uterine glycogen levels were significantly reduced, perhaps due to the anti-oestrogenic effect. Total protein contents, non-protein nitrogen level and total solid matter were elevated, perhaps due to the anti-oestrogenic effect.

Arteflene (Ro 42-1611), which is a semi-synthetic derivative resembling Qinghaosu (artemisinin) was recently developed from biosynthetic intermediates isolated on guidance of activity from A. hexapetalus. The compound was evaluated extensively against various drug-sensitive and drug-resistant Plasmodium falciparum in vitro and P. berghei in mice. The potential therapeutic and prophylactic activities were compared with chloroquine, mefloquine, quinine as well as artemisinin and its derivatives artemether and artesunic acid. Experimentally arteflene proved to be a highly effective antimalarial drug. The suppressive and prophylactic properties were comparable to chloroquine and superior to artemisinin, artemether and artesunic acid. It was consistently rather more active against drug-resistant than against drug-sensitive strains of P. falciparum. Drug interactions in vitro and in vivo with chloroquine, mefloquine and quinine revealed an additive to synergistic effect with arteflene. Three different dose schedules (1500 mg twice a day for 24, 48 or 72 h, respectively) of arteflene were furthermore tested on patients in Brazil with confirmed P. falciparum malaria. All the doses were effective but only 2 of 16 patients (both on the highest dose regimen) achieved a radical cure.

In an open-labelled, randomized trial in children with uncomplicated P. falciparum malaria in Gabon, patients received single oral doses of either 25 mg/kg of arteflene suspension or 15 mg/kg of mefloquine tablets. High-grade (RII and RIII) resistance was observed in 8 of the 20 patients receiving the single dose of arteflene, but in none of the 21 mefloquine-treated patients. At day 28, only one patient in the arteflene group, compared with all 21 patients in the mefloquine group, was cured. Arteflene cleared fever slightly but not significantly faster than mefloquine and the 50% and 90% parasite clearance times were comparable in both treatment groups. In vitro results in the arteflene group suggest an increase in arteflene resistance when comparing sensitivity of paired parasite isolates before treatment and at recrudescence. Both treatment regimens were well tolerated. It is concluded that single dose mono-therapy with arteflene was not effective in curing children suffering from uncomplicated P. falciparum malaria in Gabon, whereas mefloquine proved to be highly effective for this purpose.

Leaf extracts of A. hexapetalus show strong inhibitory activity against the fungal plant pathogens Xanthomonas campestris pv. campestris and Drechslera oryzae (Cochliobolus miyabeanus) and several phytopathogenic bacteria. Leaf extracts of A. hexapetalus show a 100% inhibition of Fusarium oxysporum f. sp. lentis, which causes wilt disease in lentil, and Ustilago maydis and U. nuda, diseases of maize and barley. Leaf extracts strongly inhibit hatching of eggs of Meloidogyne nematodes.

Adulterations and substitutes

Some of the compounds isolated from Artabotrys are also recorded for other plants, e.g. isocorydin (artabotrine) from Corydalis, or atherospermidine which is the main cytotoxic compound found in Thalictrum sessile Hayata.

Description

• Climbers or scandent shrubs.
• Leaves alternate, simple; petiolate.
• Flowers bisexual, solitary or in fascicles, leaf-opposed, borne on thickened, hooked peduncles; sepals 3, valvate, free or variably united at the base; petals 6, valvate in 2 whorls, the inner petals somewhat smaller, spoon-shaped, connivent about the reproductive organs; stamens numerous, closely arranged, connective with a truncate, dilated apex; carpels numerous, containing 2 basal ovules.
• Fruit a monocarp, cylindrical to ellipsoid, sessile, clustered on a toughened receptacle, indehiscent, 1-2-seeded.
• Seed oblong, aril absent.

Growth and development

Artabotrys has cleistogamous flowers and seems to be completely autogamous; to date no pollinators have been observed. A. hexapetalus and A. suaveolens can be found flowering and fruiting throughout the year.

Other botanical information

Artabotrys is badly in need of revision. According to a classification based on both flower and fruit characters of Annonaceae from all over the world, Artabotrys is placed in an informal group which also includes the Asian genera Anaxagorea, Cyathocalyx, Drepananthus, Marsypopetalum, Meiogyne and Xylopia.

Ecology

Artabotrys can be found in dry thickets and secondary forest as well as moist primary forest in gaps.

Propagation and planting

A. hexapetalus is propagated by seeds, cuttings or layering.

Husbandry

A. hexapetalus thrives on all soil types, and preferably grows in damp, semi-shaded locations. As the plant is climbing with hooks, it may well be grown against walls, trellises and through thickets as a hedge plant.

Harvesting

Leaves of Artabotrys are plucked whenever the need arises. Stems are cut and further divided into small pieces, with or without further removal of the bark. Roots are simply dug up.

Genetic resources and breeding

The Artabotrys species treated here are either widely distributed or commonly cultivated. They may even occur in disturbed forest. All this indicates that they are not very liable to genetic erosion. A. hexapetalus although commonly cultivated, it appears to be becoming rare in natural habitats in its native area.

Prospects

With the still growing, widespread resistance to the antimalarials commonly used in medicine, the search for new effective compounds is of the greatest interest. It is therefore only logical to attempt to exploit the massive potential found in nature. Since arteflene has shown biological activity in humans, there might be future potential for Artabotrys to serve as a biological source for medicine. The effects of the alkaloids, e.g. anti-tumour and anti-fertility, merit further research in order to fully evaluate their possibilities.

Literature

• Cavé, A., Cassels, B.K., Hocquemiller, R., Leboeuf, M., Davoust, D., Deverre, J.R., Khan, K.C. & Hadi, A.H.A., 1986. Artavenustine, a catecholic berberine from Artabotrys venustus King. Journal of Natural Products 49(4): 602-607.
• Cortes, D., Torrero, M.Y., D’Ocon, M.P., Candenas, M.L., Cavé, A. & Hadi, A.H.A., 1990. Norstephalagine et atherospermidine, deux aporphines d’Artabotrys maingayi relaxantes du muscle lisse [Norstephalagine and atherospermidine: two smooth muscle relaxant aporphines from Artabotrys maingayi]. Journal of Natural Products 53(2): 503-508.
• Hofheinz, W., Burgin, H., Gocke, E., Jaquet, C., Masciadri, R., Schmid, G., Stohler, H. & Urwyler, H., 1994. Ro 42-1611(arteflene), a new effective antimalarial: chemical structure and biological activity. Tropical Medicine and Parasitology 45(3): 261-265.
• Prakash, A.O., 1980. Effect of Artabotrys odoratissimus extracts on rat uterine glycogen, protein and nonprotein nitrogen. Planta Medica 38: 54-61.
• Radloff, P.D., Philipps, J., Nkeyi, M., Sturchler, D., Mittelholzer, M.L. & Kremsner, P.G., 1996. Arteflene compared with mefloquine for treating Plasmodium falciparum malaria in children. American Journal of Tropical Medicine and Hygiene 55(3): 259-262.
• Wu, Y.C., Chen, C.H., Yang, T.H., Lu, S.T., McPhail, D.R., McPhail, A.T. & Lee, K.H., 1989. Cytotoxic aporphines from Artabotrys uncinatus and the structure and stereochemistry of artacinatine. Phytochemistry 28(8): 2191-2195.

Selection of species

• Artabotrys hexapetalus
• Artabotrys suaveolens

Authors

• N.O. Aguilar