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Phytochemical and Pharmacological Aspects of Nothapodytes Nimmoniana. an Overview REVIEW ARTICLE

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Phytochemical and Pharmacological Aspects of Nothapodytes Nimmoniana. an Overview REVIEW ARTICLE Vol. 59 No. 1 2013 DOI: 10.2478/hepo-2013-0006 REVIEW Article Phytochemical and pharmacological aspects of Nothapodytes nimmoniana. An overview NAZEERULLAH KHAN*1, ENNUS TAJUDDIN TAMBOLI2, V.K. SHARMA1, SUNIL KUMAR1 1Dr. K. N. Modi Institute of Pharmaceutical Education & Research Modinagar 201204 U.P. India 2Faculty of Pharmacy Jamia Hamdard, Hamdard Nagar New Delhi 110062 India *corresponding author: phone: +9187 91207145, e-mail: [email protected] Summary Nothapodytes nimmoniana (J. Graham) (Icacinaceae), commonly known as Amruta is found in India particularly in Maharashtra, Goa, Kerala, Assam, Jammu and Kashmir as well as Tamilnadu areas. It is an important medicinal plant, the major source of a potent alkaloid, namely camptothecin, of a wide spectrum of pharmacological activities like anti-cancer, anti-HIV, antimalarial, antibacterial, anti-oxidant, anti-inflammatory, anti-fungal and also applied in the treatment of anaemia. Camptothecin is still not synthesized, therefore, its production entirely depends on natural sources. N. nimmoniana is one such plant which yields contain camptothecin in significantly high amount. The plant is gaining interna- tional recognition due to its diversified medicinal uses. It is subjected to excessive har- vest. It has been categorized as a vulnerable and endangered plant. The present review encompasses the phytochemical, analytical, pharmacological, biotechnological, and other specific aspects of N. nimmoniana. Key words: Nothapodytes nimmoniana, camptothecin, pharmacological activities, phytochemistry N. Khan, ET. Tamboli, VK Sharma, S. Kumar 54 INTRODuCTION India’s rich repository of medicinal plant species (1/4 of the world) fulfills health care needs of more than 80% of the population of the country [1]. Out of these plants, 25% are found at Western ghats, a mega biodiversity hot-spot, im- portant site of collection [2]. India ranks second in terms of the volume and value of exported medicinal plants [3]. Several tree species from the western ghats are gaining international recognition due to their newly and recently identified phar- macological and curative properties. This has led to their indiscriminate harvest- ing and hence their very existence is under severe threat. One of them is N. nim- moniana [formerly Mappia foetida Miers], a rich source of the potent alkaloids such as camptothecin (CPT) [(S)-4-ethyl-4-hydroxy-1H-pyrano[3’,4’:6,7]indolizino[1,2-b] quinoline-3,14-(4H,12H)-dione], 9-methoxy camptothecin and mappicine [4, 5]. Leaves, stem wood, stem bark, root bark, root wood and seeds are, in general, used to isolate CPT. For the first time, CPT was isolated from Chinese tree Camp- tothecia acuminata [6], then from a variety of plant species including Merrilioden- dron megacarpum [7, 8], N. nimmoniana [9], Ophiorrhiza mungos [10], O. pumila [11] (Rubiaceae), Eravatamia heyneana (Apocynaceae) and Mostuea brunonis (Loganiaceae) [7]. Among these species, the highest concentration of CPT (0.3% w/w) has been reported in N. nimmoniana [12]. CPT and 9-methoxy-CPT were also isolated as major constituents from Mappia foetida by Professor Govindachari from Mapia foetida leaves and their structures were established from their spectral data as well as by direct comparison with authentic compounds [13]. CPT is an inhibitor of the DNA-replicating enzyme topoisomerase I and is believed to act by stabilizing a strand break in the phos- phodiester backbone of DNA. CPT binds reversibly to a Topo-1-DNA cleavable complex to form a stable ternary complex [14]. Numerous analogs of CPT have been synthesized and proved as potential therapeutic agents [15]. Irinotecan [16] and topotecan [17] are two water-soluble derivatives of CPT, which have been ap- proved by the Food and Drug Administration (FDA) of the United States of Ameri- ca for treating colorectal and ovarian cancer [18]. N. NIMMONIANA: A BRIEF ACCOuNT This plant is known by different names: [2] of N. nimmoniana, durvasanemara, kodsa, hedare (Kannada), ghenera (Hindi), amruta, narkya, kalgur, kalagaura (Ma- rathi), arali, choral, perum pulagi, kal kurinj (Tamil). The plant is native for Indomalaysia and Indochina. Occurs in Western ghats (Shimoga, Sirsi, Ulvi, Hassan, Joida, and B R Hill), South India, Central and South Maharashtra (Pune – Maval taluk, Purandar taluk, Raigad taluk, Sawantwadi taluk 1&2), Sahyadris, Munnar, Goa [19]. Phytochemical and pharmacological aspects of Nothapodytes nimmoniana. An overview 55 It is a small tree, 3-8 m high. Bark smooth, grey, wrinkled, about 5 mm thick. Branchlets slightly angled, corky, with prominent leaf scars. Leaves alternate, slightly leathery, broadly egg-shaped to elliptic-oblong, 1–25 x 4–12 cm, base often unequal, apex acute to acuminate, margin entire, hairless above, thinly hairy beneath, crowded at the ends of branchlets, lateral nerves 8-10 pairs, leaf stalks 3–6 cm long. Flower in cymes, creamy yellowish, foul smelling (strongly foetid), about 5 mm across, in terminal corymbose cymes, petals hairy inside. Drupes ovoid, 1.25–1.9 cm long smooth, purplish black when ripe. Seed 1 or 2, albuminous. The fruit resembles jamun or jambul fruit in taste and appear- ance [20]. Since there is no convenient synthetic source for CPT, we depend on raw ma- terial from natural populations. Camptotheca acuminata (tree of Chinese origin) and N. nimmoniana are the only convenient sources for large scale extraction and purification of CPT [21]. As CPT accumulates in stem and root of N. nimmoniana, whole tree is cut to generate biomass for extraction. In Indian market, the current demand for its biomass is 500–700 metric tons a year. In Maharashtra, overexploi- tation and habitat destruction for raw material has led to population decline by 50–80% in last decade. Total loss has been recorded from certain areas. Currently, the species population density is as low as 1-2 individuals/hectare in some areas. However, it extends up to 30–40 individuals/hectare at some localities such as for- est of Mahabaleshwar, Satara where populations of N. nimmoniana survive against the severe threat of destruction [22]. Figure 1 Different parts of N. nimmoniana tree A) mature leaves with fruits, B) stems, C) immature leaves, D) mature stem Vol. 59 No. 1 2013 N. Khan, ET. Tamboli, VK Sharma, S. Kumar 56 R R 2 3 R 1 O N N O OH O R R R 1 2 3 Camptothecin H H H 9-Aminocamptothecin H NH H 2 Topotecan OH CH N(CH ) H 2 3 2 O Irinotecin N N H CH CH 2 3 O SN38 OH H CH CH 2 3 Figure 2. Major chemical constituents reported from N. nimmoniana N. nimmoniana trade and importance in traditional medicine In India, research on clinical trials of CPT is conducted only at laboratory scale. Countries like Japan, USA and Spain are into the commercialization of CPT as a drug. These countries import dried raw material from India which is now one of the lead- ing exporters worldwide. According to State Forest Department records, the annual demand from Japan for dried stem of N. nimmoniana was 200–300 tons in 1994 [22]. Since then, there has been an increasing trend. The trade volume increased to 1600 tons in 2002. In 2006–2008, the reported trade in the volumes has exceeded 1000 tons, whereas unreported trade is thought to be at least twice the reported one. The ever-increasing worldwide market of Irinotecan and Topotecan (semi synthetic CPT analogues) has currently reached 1000 million US dollars, which represents approximately 1 ton of CPT raw material [23]. To meet this ever increasing demand for CPT related drugs from all over the world, more and more plants are being cut, dried and exported. This export business is completely managed by private sec- tor. The collectors have trained local tribal and rural laborers in cutting and drying processes. They are paid Rs. 10-15/ kg of dried stems and exported at the price of 1500 US dollars per kg (meaning Rs. 60,000 i.e. 1000 times higher price) [24]. Phytochemical and pharmacological aspects of Nothapodytes nimmoniana. An overview 57 Traditionally, the aqueous extract of N. nimmoniana has been used as anti can- cer [25]. It’s medicinal use has not been reported in any codified systems of Indian medicine. In fact, CPT is regarded as one of the most promising anticancer drug. In recent years, CPT has also emerged as a promising drug to be used in AIDS che- motherapy. The anti HIV activity of CPT is due to the inhibition of Tat-mediated transcription from the viral promoter. It is also active against parasitic trypano- somes and leishmania. CPT is also active against the malaria, antibacterial activity and anti-inflammatory activity from the leaves of N. nimmoniana Miers. N. nimmoniana: cultivation and collection N. nimmoniana is cultivated in moist, deciduous place. It requires average an- nual rainfall of approximately 4000-7000 mm with 8–9 months of dry period. In India, it is grown under a wide range of conditions from the coastal areas up to altitude of 2300 m. In general, the crop is raised in south India’s warm climate. Well drained, aerated fertile soils with a pH value ranging from 5.0 to 6.0 are the most favorable conditions for its cultivation. Seeds are used for cultivation. The seeds are shown on the seed beds in winter and early spring, the optimum temperature for germination is 12–35°C. Percentage seed germination depends on seed weight. If seed weight is high, per cent germination will be higher. N. nim- moniana, a tree crop, has got a 7–8-year-long gestation period. CPT yield depends on the age of plant. If the plant age is high, then per cent yield will also be higher. Highest percentage of CPT is produced by root wood, and minimum by the leaves.
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