Medicinal Rubiaceae

The family Rubiaceae consists of about 450 genera and 6500 species of tropical and subtropical trees, shrubs, climbers, and herbs that are known to abound with iri-doid glycosides (monoterpenoid alkaloids, tannins, and anthraquinones). When looking for Rubiaceae in field collection, one is advised to look for plants with opposite simple leaves with an interpetiolar stipule, tubular flowers, which are often white, and capsules, berries, or drupes.

The contribution of Rubiaceae to Western pharmaceuticals and medicine is substantial because it is the source for Uncaria gambier (Hunt.) Roxb. (Catechu, British Pharmaceutical Codex, 1963), Cephaelis ipecacuanha (Brot.) A. Rich. (uragoga ipecacuanha, Brazilian ipecacuanha), or Cephaelis acuminata Karsten (Cartagena ipecacuanha) (Ipecacuanha, British Pharmacopeia, 1963), Cinchona calisaya (yellow

cinchona bark), Cinchona ledgeriana (ledger bark), Cinchona officinalis (pale cinchona bark, crown or Loxa bark), and Cinchona succirubra (red cinchona bark) containing quinine. Classical examples of Rubiaceae are Coffea arabica (Arabica coffee), Coffea liberica, and Coffea canephora (Robusta coffee).

In regard to the antineoplastic potentials of Rubiaceae, some evidence has already been presented that clearly demonstrates that anthraquinones inhibit the enzymatic activity of topoisomerase II. An example of antineoplastic anthraquinones that target topoisomerase II is mitoxantrone (Novatrone®), which is currently approved for clinical use in the United States (16). In the Pacific Rim, about 150 species of plants classified within the family Rubiaceae are medicinal, of which Prismatomeris albidiflora, Knoxia valerianoides, Damnacanthus indicus, and Morinda umbellata are known to produce anthraquinones. An interesting development from Rubiaceae would be to investigate its members for anthraquinones and assess them for topoisomerase inhibitors. The discovery of inhibitors of topoisomerase II of clinical antineoplastic value can be reasonably expected.

Prismatomeris albiflora Thaw, non King, (Prismatomeris tetrandra [Roxb.] K. Sch, Prismatomeris malayana Ridl, Coffea tetrandra Roxb.), or son kraal, duck kai dam (Thai), is a treelet that grows to a height of 3 m in the rainforest, on rocky seashores, and in limestone rocks of Vietnam, Burma, Thailand, and Malaysia. The stems show internodes with a median longitudinal ridge ending between each pair of petioles. The leaves are simple,

Fig. 85. Cytotoxic anthraquinones of Prismatomeris fragran.

Rubiadin-1-methyl ether

Fig. 85. Cytotoxic anthraquinones of Prismatomeris fragran.

chartaceous decussate, and stipulate. The stipules are interpetiolar, triangular, and bifid at the apex. The blade is ovate and elliptic and shows 6-10 pairs of secondary and tertiary nerves. The influorescences are terminal and axillary clusters. The flower pedicels are 6 mm-2.1 cm long. The calyx cup is fringed. The corolla is white, tubular, and four- to five-lobed. The fruits are globose and contain one to two grooved seeds.

In Malaysia, a paste of the leaves is used to heal wounds. In Cambodia, Laos, and Vietnam, a decoction of roots is drunk to treat bronchitis, and an infusion of wood is drunk to invigorate and to expel impurities. Malays apply a paste of leaves to wounds to promote healing. The pharmacological potential of P. tetrandra (Roxb.) K. Schk is unexplored. Note that the plant is known to produce anthraquinones such as rubiadin (17). Kanokmedhakul et al. made the interesting observation that the roots and stems of Prismatomeris fragrans contains a series of anthraquinones, of which nordamnacanthal, damnacanthal, rubiadin, and rubiadin-1-methyl ether abrogated the survival of exhibited cytotoxicity to the NCI-H187 cell line cultured in vitro (18). It would be interesting to learn about the topoisomerase activity of these anthraquinones (Fig. 85).

Knoxia valerianoide Thorel, or knoxia root, Peking spurge root, or Hung ya ta chi (Chinese), is an herb that grows to a height of 60 cm in China, Cambodia, Laos, Vietnam, and North India. The roots are tuberous. The leaves are opposite and stipulate, and the blade is lanceolate and shows six to eight pairs of secondary nerves. The flowers are tubular, minute, and four-lobed (Fig. 86). In China, the plant is used to treat ailments related to excretion and to treat dropsy, but is not recommended during pregnancy. In Cambodia, Laos, and Vietnam, it is used to promote the fermentation of alcohol of rice.

Fig. 86. Knoxia valerianoideThorel.

The pharmacological property of K. valerianoides Thorel. is unexplored, but the plant is known to produce anthraquinones including 2-ethoxymethylknoxiavaledin, 2-formyl-knoxiavaledin, 2-hydroxymethylknoxiavaledin, knoxiadin, damnacanthal, nordamna-canthal;, ibericin, 3-methylalizarin, and damnacanthol (19).

D. indicus Gaertn. is a little shrub that grows in a geographical zone spanning from the Himalayas, North India, China, Japan, and the Philippines. The stems are terete, minutely hairy, and develop slender, interpetiolar, stipular woody thorns. The leaves are opposite and simple. The blades are broadly lanceolate, thick, dark green and glossy above, and light green below. The base of the blade is cordate and the apex is apiculate.

Fig. 87. Damnacanthus indicus Gaertn.

The flowers are white and in pairs. The fruits are red berries at axil of leaves (Fig. 87). In China, it is used to treat rheumatism, mitigate headache, and heal piles. D. indicus Gaertn. is known to abound with anthraquinones, but its pharmacological potential remains unexplored to date (20,21). Note that damnacanthal is a common component of the Damnacanthus species. Faltynek et al. made the interesting observation that damnacanthal inhibits the enzymatic activity of tyrosine kinase, which is involved in the propagation of metastases (22). An interesting development from this observation would be to assess the topoisomerase inhibitory activity of the Damnacan-thus species, an activity that could be associated with tyrosine kinase inhibition, hence enormous chemotherapeutic potentials.

Neonauclea pallida (Reinw. ex Havil.) Bakh f. (Nauclea pallida Reinw. ex Havil, Nau-cleapurpurascens sensu K. & G., Neonauclea calycina sensu Corner.), or hooded bur-flower tree, bengkal batu (Malay, Indonesian), or krathum khao (Thai), is a bush that grows to 2 m tall in Burma, Thailand, the Andamans, Sumatra, Java, and Borneo. In Indonesia, the leaves are used externally to promote urination. The stem is glabrous. The leaves are simple, opposite, and stipulate. The blade is glabrous, chartaceous, 16 X 8 cm, with 8-12

Fig. 88. Botanical hallmark of Morinda species: syncarps.

pairs of secondary nerves. Fruiting peduncle is axillary and terminal; the young flowering heads are enclosed in a pair of bracts. A wood extract of this plant afforded a series of anthraquinones including damnacanthal and morindone, which inhibited the enzymatic activity of topoisomerase II with IC50 values of 20 and 21 (ig/mL, respectively (21). Morinda officinalis How, or pa chi t'ien, ba ji tian, pa kit tian (Chinese), hagekiten (Japanese), or p'agukch'on (Korean), is a shrub native to China, mainly the Guangdong, Guangsi, and southern Fujian provinces. Note that Morinda fruits are easily recognized syncarps (Fig. 88). The drug consists of the roots and is sweet and acrid in taste, fawn outside and moniliform, and purplish yellow-white inside. In China, the roots are used to treat beriberi, quiet the visceral organs, regulate urination, treat rheumatic conditions, fight sterility, and increase mental power. The roots should not be taken by pregnant or lactating women. The root of M. officinalis How. abounds with series of anthraquinones including rubiadin, rubiadin-1-methyl ether, 1-hydroxy- anthraquinone, 1-hydroxy-2-methylanthraquinone, 1,6-dihy-droxy-2,4-dimethoxyanthraquinone, 1,6-dihydroxy-2-methoxyanthraquinone, 1-hydroxy-2- methoxyanthraquinone physcion, 2-methyl-anthraquinone, and damna-canthal (21). Damnacanthal is widespread in Morinda species and known to inhibit the enzymatic activity of tyrosine kinase and topoisomerase (22,23). Hiwasa et al. noted that human fibroblast UVr-1 cells treated with damnacanthal prior to ultraviolet irradiation presented more DNA fragmentation (24). Using immunoblot analysis, they showed that pretreatment with damnacanthal followed by ultraviolet irradiation increased the levels of phosphorylated extracellular signal-regulated kinases and stress-activated protein kinases, suggesting a stimulation effect of damnacanthal on ultraviolet-induced apoptosis. In regard to the stimulant property mentioned above, it is interesting to mention that the plant extract (25-50 mg/kg) showed antidepressant properties in rats similar to clinically antidepressant drug desipramine (5-10 mg/kg [25]). This activity is, to date, believed to be mediated by oligosaccharides. Li et al. (26,27) showed that oligosaccharides (P6) protected PC12 cells from corticosterone-induced apoptosis in a concentration- and time-dependent manner. Can we reasonably expect oligosaccharides to cross the hemato-encephalic barrier and act in the brain? Probably not.

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