Brucea javanica (PROSEA)

Plant Resources of South-East Asia Introduction

List of species

1, twig with flowers and fruits; 2, female flower; 3, male flower; 4, fruit (Iskak Syamsudin)

Brucea javanica (L.) Merr.

Protologue: Journ. Arn. Arb. 9: 3 (1928).

Family: Simaroubaceae

Chromosome number: 2n= unknown

Synonyms

• Brucea sumatrana Roxb. (1814),
• Brucea amarissima (Lour.) Desv. ex Gomes (1872).

Vernacular names

• Indonesia: kuwalot (Sundanese, Javanese), malur (Batak), tambara marica (South Sulawesi)
• Malaysia: embalau padang, kusum, lada pahit (Peninsular)
• Philippines: balaniog (general), magkapayos (Samar-Leyte Bisaya), manongao-bobi (Cebu Bisaya)
• Cambodia: damli thnang, pramat monus
• Laos: ich kone, kom roi, phia²fan
• Thailand: ratchadat (peninsular), ka chaplak (northern), dee khon (central)
• Vietnam: cây suốt, cứt chuột, sầu dâu.

Origin and geographic distribution

B. javanica is widespread and occurs from Sri Lanka and India towards Indo-China, southern China, Taiwan, Thailand, and although rare in the Moluccas and New Guinea throughout the Malesian region to northern Australia. Its patchy distribution in eastern Malesia suggests that it was introduced here by man long ago. It has certainly been introduced in Micronesia (Ponape) and Fiji.

Uses

All parts of B. javanica, but most often the pyrenes and roots, are used medicinally, mainly against amoebic dysentery, diarrhoea, malaria and as a febrifuge. It is known in Chinese traditional medicine, where it is additionally applied for the treatment of haemorrhoids, corns, warts, ulcers and cancer. The pyrenes are well-known under the name "Macassar kernels", and are also applied as an insecticide. The leaves are applied as a poultice against enlarged spleen, scurf, ringworm, boils and centipede bites. A decoction of the roots is also used to treat abdominal pains, coughs and as an important remedy for internal poisoning. In Australia, the bark and roots have been used by Aborigines to treat toothache.

Production and international trade

The pyrenes, roots and occasionally other parts of B. javanica are traded on local markets, but are not of great commercial importance.

Properties

Several quassinoids have been isolated from the fruits of different Brucea species. In general, these compounds have been shown to have strong anti-amoebic, antimalarial and/or cytotoxic (anti-cancer) properties.

One of the major quassinoids found in B. javanica and B. antidysenterica J.F. Miller from Africa is bruceantin. Anti-amoebic, antimalarial and anti-cancer properties of this compound are reported in literature; the antimalarial activity is not simply due to cytotoxic effects. Furthermore, quassinoids (e.g. brusatol) from the fruits, as well as the triterpenoids bruceajavanin A, dihydrobruceajavanin A and bruceajavanin B (from the stems of B. javanica) have been shown to inhibit the growth of the chloroquine-resistant strain Plasmodium falciparum K1 in vitro. Some of the quassinoids (bruceine A, B and D, brusatol) also showed in vivo activity against P. bergei infections in mice after oral dosing. Finally, the quassinoids bruceine A, B and C, present in a chloroform extract of B. javanica fruits, had a very potent activity in vitro against a multi-drug resistant P. falciparum strain with an ID₅₀of 8.66, 8.15 and 1.95 ng/ml, respectively, in comparison with 6.26 ng/ml for the mefloquine reference.

Quassinoids (e.g. bruceolides, bruceantin and bruceantinol) are reported to show inhibitory action against lymphocytic leukaemia and lung carcinoma. Bruceoside A and B (quassinoids) were found to possess lethal toxicity when the methanol extract of B. javanica was administered to mice. Bruceoside C showed potent cytotoxicities against KB, A-549, RPMI and TE-671 tumour cell lines, and bruceosides D, E, and F show selective cytotoxicity in leukaemia and non-small cell lung, colon, central nervous system, melanoma and ovarian cancer cell lines. Other quassinoids found in B. javanica with cytotoxic effects and with potential for cancer therapy include e.g. brusatol and the yadanziosides A-H, O and P.

B. antidysenterica also contains quassinoids with similar cytotoxic effects (e.g. bruceanols A, B, D, E, F, G, H, bruceantinosides A-C, yadanziosides G, N, M, P) as well as bruceanic acids (A, the methyl ester of A, B-D). Cytotoxic canthin-6-one alkaloids, biosynthetically derived from tryptophan, are also reported in the literature.

Clinical observations of improvement in clinical manifestations after administering B. javanica oil emulsion intravenously to patients with brain metastasis from lung cancer have been experimentally confirmed in rabbits by positive effects on intracranial hypertension.

The crude extract of B. javanica has been found to be very effective against the internal parasite Blastocystis hominis at an active concentration of 500 μg/ml as compared with 10 μg/ml for metronidazole, the active standard drug for B. hominis. Bruceoside D showed in vitro anti-tuberculosis activity. However, the activity on the test organism, Mycobacterium tuberculosis, was low, with 7% inhibition at 12.5 μg/ml.

Adulterations and substitutes

The Cinchona alkaloid quinine, and the synthetic antimalarials derived from it (e.g. chloroquine) are widely in use for the classical treatment of malaria. Artemisinin (a sesquiterpene lactone from Artemisia annua L.) and its synthetic analogues (e.g. β-artemeter and sodium artesunate) comprise a class of new antimalarials, which are of interest, since resistance to the malaria-causing parasites is developing fast. Other Simaroubaceae that might be of interest in this respect include Eurycoma, Picrasma and Quassia, whereas Dichroa species (Saxifragaceae) warrant some atttention as well.

Description

• A monoecious or dioecious shrub or small tree up to 10 m tall with soft-haired twigs and leaves.
• Leaves arranged spirally, imparipinnate, 20-50 cm long, exstipulate; leaflets 3-15, opposite, short petiolulate, ovate-oblong to ovate-lanceolate, margin bluntly serrate or crenate, secondary veins unbranched and terminating in a marginal gland.
• Inflorescence axillary, pubescent, composed of small cymes united into bracteate, raceme-like thyrses.
• Flowers unisexual, 4-merous, small, greenish-white to greenish-red or purple; sepals connate at base; petals free; disk intrastaminal, thick, 4-lobed; stamens short, vestigial or absent in female flowers; ovaries superior, free, each with a single, pendent ovule, styles free or coherent at base, subulate, bent outwards over the top of the ovary.
• Fruit consisting of 1-4 hardly fleshy drupelets; drupelet 2-ribbed, dry, purplish-black and 4-5(-7) mm long when mature, pyrene with wrinkled endocarp.
• Seed ovoid, with thin testa and very thin endosperm.
• Seedling with epigeal germination; cotyledons emergent, leafy; hypocotyl elongated; first two leaves opposite, subsequent ones arranged spirally; first few leaves 3-foliolate, later ones with increasing number of leaflets.

Growth and development

In a germination test in Peninsular Malaysia fruits of B. javanica had a germination rate of about 35% within 11-273 days.

All shoots are orthotropic. Growth is rapid and flowering starts early. Flowering and fruiting can be throughout the year. Pollination is probably by insects. Small fruit bats eat the fruits and thus disperse the seed. However, the life span is only a few years and plants have to be regenerated from seed.

Other botanical information

A second Malesian species, B. mollis Wallich ex Kurz (synonyms: B. luzoniensis S.Vidal, B. macrobotrys Merr., B. acuminata Li), is found in Indo-China, Thailand and the Philippines and may contain similar medicinally active compounds. The African B. antidysenterica is a well-known medicinal plant with similar applications.

Ecology

B. javanica is very common preferring open localities such as light secondary forest and thickets, forest edges, ridges, and even occurring in sunny places on sandy dunes and on limestone. It grows under both per-humid and seasonal conditions, from sea-level up to 900 m altitude.

In vitro production of active compounds

Canthin-6-one alkaloids can be produced by cell suspension cultures of B. javanica. The total yield of alkaloids produced in cells and medium is in excess of 2.0 mg/g on a dry weight basis. The major alkaloids produced are canthin-6-one, 11-hydroxycanthin-6-one, 5-methoxycanthin-6-one and 11-methoxycanthin-6-one.

Handling after harvest

After the mature fruits have been collected, the fruit pulp is removed. The pyrenes that remain are washed and dried in the sun.

Genetic resources and breeding

Since B. javanica is common in anthropogenic habitats and has a large area of distribution, the risk of genetic erosion seems limited.

Prospects

The various quassinoids found in the seed of B. javanica that possess both antimalarial and anti-cancer activity merit further research. Because of the growing resistance of malaria parasites to the well-known, and even newer, antimalarials currently in use, there is a continuous need to develop new compounds to control this almost global infectious disease. The quassinoids and the canthin-6-one alkaloids might also have good potential for the development of a cytostatic drug to treat various cancers.

Literature

• Anderson, M.M., O'Neill, M.J., Phillipson, J.D. & Warhurst, D.C., 1991. In vitro cytotoxicity of a series of quassinoids from Brucea javanica fruits against KB cells. Planta Medica 57(1): 62-64.
• Fukamiya, N., Okano, M., Miyamoto, M., Tagahara, K. & Lee, K.H., 1992. Antitumor agents, 127. Bruceoside C, a new cytotoxic quassinoid glucoside, and related compounds from Brucea javanica. Journal of Natural Products 55(4): 468-475.
• Kitagawa, I., Mahmud, T., Simanjuntak, P., Hori, K., Uji, T. & Shibuya, H., 1994. Indonesian medicinal plants. VIII. Chemical structures of three new triterpenoids, bruceajavanin A, dihydrobruceajavanin A, and bruceajavanin B, and a new alkaloidal glycoside, bruceacanthinoside, from the stems of Brucea javanica (Simaroubaceae). Chemical and Pharmaceutical Bulletin 42(7): 1416-1421.
• Kupchan, S.M., Britton, R.W., Lacadie, J.A., Ziegler, M.F. & Sigel, C.W., 1975. The isolation and structural elucidation of bruceantin and bruceantinol, new potent antileukemic quassinoids from Brucea antidysenterica. Journal of Organic Chemistry 40(5): 648-654.
• Lee, K.H., Tani, S. & Imakura, Y., 1987. Antimalarial agents, 4. Synthesis of a brusatol analog and biological activity of brusatol-related compounds. Journal of Natural Products 50(5): 847-851.
• Lu, J.B., Shu, S.Y. & Cai, J.Q., 1994. Experimental study on the effect of Brucea javanica oil emulsion on rabbit intracranial pressure. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih 14(10): 610-611 (in Chinese).
• Nooteboom, H.P., 1962. Simaroubaceae. In: van Steenis, C.G.G.J. (Editor): Flora Malesiana. Series I, Vol. 6. Wolters-Noordhoff Publishing, Groningen, the Netherlands. pp. 209-212.
• Ohnishi, S., Fukamiya, N., Okano, M., Tagahara, K. & Lee, K.H., 1995. Bruceosides D, E, and F, three new cytotoxic quassinoid glucosides from Brucea javanica. Journal of Natural Products 58(7): 1032-1038.
• O'Neill, M.J., Bray, D.H., Boardman, P., Chan, K.L., Phillipson, J.D., Warhurst, D.C. & Peters, W., 1987. Plants as sources of antimalarial drugs, Part 4: Activity of Brucea javanica fruits against chloroquine-resistant Plasmodium falciparum in vitro and against Plasmodium berghei in vivo. Journal of Natural Products 50(1): 41-48.
• Pavanand, K., Nutakul, W., Dechatiwongse, T., Yoshihira, K., Yongvanitchit, K., Scovill, J.P., Flippen-Anderson, J.L., Gilardi, R., George, C., Kanchanapee, P. & Webster, H.K., 1986. In vitro antimalarial activity of Brucea javanica against multi-drug resistant Plasmodium falciparum. Planta Medica 52(2): 108-111.

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Authors

• Arbayah H. Siregar