The family Rutaceae consists of 150 genera and 1500 species of treelets known to accumulate essential oils (limonene), limonoids, flavonoids (hesperidin), coumarins, and several sorts of alkaloids including, notably, carbazole and acridone alkaloids. The cardinal features to note in field collection are lemon-like aroma of crushed leaves, a blade dotted with several translucent oil glands, white flowers with retrorse petals and conspicuous globose and light green stigma, and green lemon-like fruits. The fruits of several species in this family are edible: lemon (Citrus limon [L.] Burm. f.), sour orange (Citrus aurantium L.), sweet orange (Citrus sinensis [L.] Osbeck), and lime (Citrus aurantifolia [Chaistm.] Swingle).
Western medicine has been using the essential oil of several species of Rutaceae as flavoring ingredient. The essential oil of C. sinensis (orange oil, Oleum aurantii, British Pharmaceutical Codex, 1963) has been used as a flavoring agent and in perfumery. Berg-amot oil (Oleum bergamottae, British Pharmaceutical Codex, 1949) from Citrus bergamia has been used in perfumery in preparations for the hair (cologne spirit or Spiritus coloniensis), lemon oil (Oleum limonis, British Pharmaceutical Codex, 1963) from C. limon, Citrus limonia, and Citrus medica is carminative and used as a flavoring agent, and the dry peel of C. aurantium (Aurantii cortex siccatus, British Pharmacopoeia, 1963) has been used as a flavoring agent and for its bitter and carminative properties. The oil of Ruta graveolens L. (common rue, herb of grace) has been has been used to stop spasms, promote menses, and produce skin irritation (rue, British Pharmaceutical Codex, 1934).
Examples of alkaloid of relative pharmaceutical usefulness so far characterized from Rutaceae are pilocarpine from Pilocarpus jaborandi Holmes. This imidazole alkaloid is occasionally used to treat glaucoma.
In regard to the antineoplastic properties of Rutaceae, this family has attracted a great deal of interest for its ability to elaborate series of cytotoxic benzo[c]phenanthri-dine and acridin alkaloids. Examples of acridin alkaloid are pyrano-acridone and acronycine characterized from Acronychia baueri Scott.
OH OCH Acronycine
Examples of acridin alkaloids used in therapeutics as antineoplastic agents is amsacrine (Amsa P-D®), which is used for the treatment of acute leukemia in adults and malignant lymphomas, refractory to conventional therapy. Amsacrin is an intercalating agent and topoisomerase II inhibitor.
One can reasonably envisage the family Rutaceae as a sockhouse of acridin-like alkaloids that await experimentation as inhibitors of topoisomerase and expect the discovery of antineoplastic agents of clinical value from this family. Looking for such agents, one might look into the medicinal Rutaceae of the Asia-Pacific region, which encompasses about 120 species of plants including Zanthoxylum ailanthoides Sieb. & Zucc, Zanthoxylum bungei Planch, Zanthoxylum piperitum (L.) DC, and Zanthoxylum schinifolium Sieb. & Zucc.
Z. ailanthoides Sieb. & Zucc. (Fagaras [Sieb. & Zucc.] Engl.), or Japanese prickly ash; karasuzanshou (Japanese), shih chu yii, yueh chiao, or la tzu (Chinese), is deciduous small tree that grows to a height of 18 m in Japan, Korea, and China. The bark is grayish-brown
and shows numerous small lenticels and is mottled with dark brown scars of thorns. The leaves are alternate, thick, and odd-pinnate. The folioles are linear-lanceolate, somewhat crenate, and show about 15 pairs of secondary nerves. The fruits are follicles, by three that open to show glossy black seeds of 5-8 mm in diameter (Fig. 89). The follicles are green, pungent, and used as pepper. The fruits are eaten to promote digestion, as tonic, to counteract poisoning, treat sunstroke, diarrhoea, leucorrhea, and dysentry. An infusion of leaves is drunk to treat chills and flux. The pharmacological property of this plant is as-yet unexplored. Note that the Zanthoxylum species are known to elaborate fagaronine and congener.
Fagaronine and nitidine from Zanthoxylum species represent two of the more potent antitumor benzo[c]phenanthridines of Rutaceae. Both of these alkaloids have been shown to inhibit the enzymatic activity of topoisomerase in a way similar to camptothecin (28,29). It would be interesting to learn whether further study on Z. ailanthoides Sieb. & Zucc. discloses any benzo[c]phenanthridine alkaloid of anti-neoplastic value.
Zanthoxylum bungei Planch. (Zanthoxylum simulans Hance.), or Szechuan pepper, Chinese pepper, Szechuan peppercorn, Sichuan pepper, Chinese prickly ash, jiao mu ch'in chiao, ta chiao, hua chiao, chuan jiao (Chinese), sokusho (japanese), or ch'onch'o (Korean), is a deciduous shrub growing to 6 m tall. The plant is native to China and Taiwan. The bark shows stout, woody, horizontal thorns. The leaves are compound-spiral and exstipulate. The blade comprises three pairs of folioles plus a terminal one. The lateral folioles are broadly elliptic, crenate, punctured with numerous oil translucent oil cells, and show four to five pairs of secondary nerves. The rachis is minutely winged. The fruits consist of 3-4-mm reddish-brown tuberculate follicles that are split open to show a black seed (Fig. 90).
The drug consists of the small, red tuberculate follicles enclosing black, round glossy seeds, which are aromatic, pungent, with a somewhat acrid aftertaste. It is a carminative and a stimulant, it promotes sweating, is an emmenagogue, astringent, and an
Fig. 90. Zanthoxylum bungei Planch.
anthelmintic, and is used as a condiment of high value for vital process. An infusion of carpels in vinegar is instilled in ears to remove insects or worms. The plant is known to contain chelerythrine chloride, which inhibits the aggregation of rabbit platelet in vitro via inhibition on thromboxane formation and phosphoinosi-tides breakdown (30). Chelerythrine, which occurs in members of the family Papaver-aceae, has been reported to inhibit the enzymatic activity of protein kinase C and to exert cell-growth inhibitory effect via the induction of apoptosis in numerous cancer cell lines (31,32). What is the topoisomerase activity of chelerythrine?
Zanthoxylum piperitum (L.) DC., or Japanese peppercorn, Japanese pepper tree, Sichuan pepper, hajikami, sanshou (Japanese), shu chiao, ch'uan chiao, or nan chiao
(Chinese), is a spiny, deciduous, thorny shrub that grows to 3-4 m in height in China, Japan, and Korea. The leaves are compound, spiral, and exstipulate. The blade consists of six to seven pairs of folioles, which are thick and glossy, about 3-6 cm long, elliptic-ovate, resinous, fragrant, and crenate. The rachis is thorny. The fruits are 4 mm in diameter, on terminal panicles, bright red becoming purple when ripe, and split in two to free a single, black, glossy, seed that is pungent and tastes like lemon or ginger (Fig. 91). The drug consists of the dried follicles, which are used to stimulate digestion, malaria, dysentry, spermatorrhea, galactorrhea, excessive urination, and as a tonic. The carpels are used eternally to expel parasites. The seeds are eaten to promote urination, treat dropsy, invigorate kidneys and bladder, and treat asthma. The seeds are used in China and Japan as a substitute for pepper. The pharmacological potential of this plant is unexplored. Zanthoxylum schinifolium Zieb. & Zucc. (Zanthoxylum schinnifolium), or Korean pepper, yai chiao or yeh chiah (Chinese), is a tree that grows in China, Japan, and Korea. The trunk is armed with broad, fattened, woody, horizontally arranged thorns. The leaves are compound, spiral, and exstipulate. The blade shows three to five pairs of folioles. The folioles are lanceolate, asymmetrical, minutely serrate, and bright green. The flowers are minute and greenish-white in panicles. The fruits are pink and split to reveal a very aromatic gray and dull seed.
The follicles are used to treat asthma and cough and to mitigate painful swollen breasts. A paste of the leave is applied to contusion. Essential oil distilled from the follicles induced apoptotic death in HepG2 human hepatoma cells in a concentration- and time-related manner, and inhibited tumor development of mice inoculated with Huh-7 human hepatoma cells (33).
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