Jedage HD1*, Velhal AB2, Khan ZK3, Lavate GD4, Raskar SM5, Salunke PB6, Patil PS7
1Department of Pharmacognosy, L.N.B. Chhabada Institute of Pharmacy, Raigaon, Satara, 415020, Maharashtra
2,4,7Department of Parmaceutics, L.N.B. Chhabada Institute of Pharmacy, Raigaon, Satara, 415020, Maharashtra
3Department of Pharmaceutical Cemistry, L.N.B. Chhabada Institute of Pharmacy, Raigaon, Satara, 415020, Maharashtra
5Department of Quality Assurance Technique, L.N.B. Chhabada Institute of Pharmacy, Raigaon, Satara, 415020, Maharashtra
6Department of Pharmacology, L.N.B. Chhabada Institute of Pharmacy, Raigaon, Satara, 415020, Maharashtra
The Nothapodytes nimmoniana J. Graham. (Icacinaceae) commonly known as Amruta or narakya and locally as Western Maharashtra (India). It contains presence of major source of alkaloids like Camptothecin and 9- Methoxy camptothecin mainly used for treatment of various types of cancer, for AIDS, in malaria and antibacterial, etc. This article provides an overview of key concepts regarding the Phytochemistry, plant biotechnology and phytopharmacological profile of Nothapodytes nimmoniana J. Graham.
Ayurveda, the science of life, prevention and longevity is believed to be the oldest and most holistic or comprehensive medical system available. Ayurveda is one of the most ancient systems of life, health and cure. Ayurveda is a highly evolved and codifiedsystem of life and health science based on its own unique and original concepts and fundamental principles1.
The traditional medicinal methods, especially the use of medicinal plants, still play a vital role to cover the basic health needs in the developing countries2, About 80% of world population utilizes plant as their primary source of medicinal agents3. India is a home of traditional medicine systems which possess large extent of higher plants approximately 4,00,000 species in the world as compared to animal’s species that are about 5-10 million4.
The medicinal values of these plants are found in some chemical active substances that produce a definite physiological action on the human body5.
One of them Nothapodytes nimmoniana J. Graham contains rich source of potent alkaloids.
The Nothapodytes nimmoniana J. Graham, (Synonyms Nothapodytes foetida Wight, Sleumer. or Mappia foetida Meirs.) belonging to family Icacinaceae. Commonly called as Fetid Tree, tinking Plant in English, Ghenera in Hindi, Narakya, Kalagur, Amruta, in Marathi, Durvasane mara, Kodsa, Hedare in Kannada, Arali, Pillipccu, Choral in Tamil, Ghanera in Konkani, The popular name in the local habitat (Dandeli Wildlife Sanctuary, Karnataka, India) is rbudhavinashini (Sanskrit, literally means destroyer of cancer)6,7.
The plant Nothapodytes nimmoniana J. Graham, is a small tree, 3-8 meter tall, with smooth, grey, wrinkled bark, about 5 millimeter thick. Branchlets are slightly angled, corky, with prominent leaf scars. Alternately arranged leaves are slightly leathery, broadly egg-shaped to elliptic-oblong, 1-25centimeter long and 4-12 centimeter wide. Leaf base is often unequal; tip is pointed to long pointed. Leaves are crowded at the ends of branchlets. Leaf stalks are 3-6 entimeter long. Flowers are bisexual, creamy yellow, foul smelling, about 5 millimeter across, in flat-topped clusters at the end of branches. Petals are hairy inside. Fruits are oblong to ellipsoid, bout 2 x 1 centimeter, smooth, purplish black when ripe, with a single seed8.
Plants of the genus Icacina belongs to the family Icacinaceae (Table 1 and Figure 1). Icacinaceae were first described by Miers in 1851. At that time more than 400 species grouped in about 54 genera were recognized in this predominately pantropical family of tall rain forest, trees, shrubs, and lianas9.
Table 1: Taxonomical classification of Nothapodytes nimmoniana J. Graham.
Figure 1: Aerial parts of Nothapodytes nimmoniana J. Graham.
Habitat and Distribution:
The Nothapodytes nimmoniana J. Graham. Is a small tree distributed in Western Peninsula from Konkan Southward i.e. Nilgiris, Anamalis, Pullneys, North Kanada and Konkan Ghats, broadly the Western Ghats of Maharashtra (Koyananagar, Mahabaleshwara, regions is district of Satara) India, a global biodiversity hot spot, it is also present in some parts of eastern India in Assam, and in the Himalayan foothills in north India, Ceylon. This tree is also distributed in the warmer regions of the Indian subcontinent, Sri Lanka, Myanmar and Thailand, etc.10.
Ethno – medical properties and uses:
Nothapodytes nimmoniana J. Graham. Contain camptothecin, are mostly used for the treatment of lung uterine breast cervical cancer and AIDS11,12,13. It is also used in colorectal and ovarian cancer14,15,16. Plant derived drugs are used to cure mental illness, skin diseases, tuberculosis, diabetes, jaundice, hypertension, anti-oxidant, anti-inflammatory, anti-fungal and also applied in the treatment of anaemias, etc. It is also active against parasitic trypanosomes and leishmania. Medicinal plants play an important role in the development of potent therapeutic agents. Plant derived drugs came into use in the modern medicine through the uses of plant material as indigenous cure in folklore or traditional systems of medicine.
Traditionally, the aqueous extract of Nothapodytes nimmoniana J. Graham. has been used as anti cancer17.
Phytoconstituents from Nothapodytes nimmoniana J. Graham.
Preliminary qualitative chemical tests show the presence of alkaloids, carbohydrates, saponins, steroids, terpenoids, phenolics, coumarins and fixed oil, etc.18
Desorption electrospray ionization was employed for fast and direct ambient detection of the anti-tumor drug, camptothecin, and its derivative, 9-methoxycamptothecin in Nothapodytes nimmoniana J. Graham. Different parts of the plant such as leaves, stems and bark were examined. The ion intensities suggest that the concentration in bark is higher than that in the leaves and stems7.
Nothapodyte nimmoniana J. Graham. (Figure 2) CPT (Molecular Formula C20H16N2O4 and Molecular weight 348.4) Is a rich source of the potent alkaloid Camptothecin (CPT), 9-methoxy camptothecin and minor alkaloids mappicine19,20,21,22. It alsocontains 3-etooctadec-cis-15-enoic acid (16.0%), palmitic acid (12.3%), stearic acid (4.2%), oleic acid (16.2%), linoleic acid (11.6%) and linolenic acid (39.7%). Other chemical constituents isolated from this plant are acetylcamptothecin, (+)-1-hydroxypinoresinol, Ω-hydroxypropioguaiacone, p-hydroxybenzaldehyde, scopoletin, uracil, thymine, sitosterol, sitosteryl-β-D-glucoside, 3-β-hydroxystigmast- 5-en-7-one, stigmast-5-en-3-β, 7-α-diol, 6-β-hydroxystigmast-4-en-3-one, sitost-4-en-3-one, linoleic acid, trigonelline, and pumiloside isolated from the stem of N. nimmoniana and characterized23.
Figure 2: Structure of Camptothecin (CPT)
Topotecan is 4-ethyl-4,9-dihydroxy-10-[(dimethylamino)methyl]-1H-pyrano[3’,4’: 6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione; irinotecan is S)-4,11-diethyl- 3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo1H-pyrano[3’,4’:6,7]-indolizino[1,2-b] quinolin-9-yl-[1,4’bipiperidine]-1’-carboxylate, SN-38 is 7-ethyl-10-hydroxycamptothecin.
In the present study, the seven phenotypic variants of Nothapodytes nimmoniana J. Graham. such as dry leaf, fresh barks of plant, induced callus, somatic embryo and suspension culture (In exogenous medium and in pallet) in 100 mg/ml were analyzed for CPT content by TLC (Thin Layer Chromatography) and HPLC (High Performance Liquid Chromatography). TLC and HPLC analysis confirm the presence of CPT in dry leaf, fresh barks of the plant, induced callus and somatic embryo. Out of which bark extracts possessed a maximum amount of CPT, i.e. 377.77 μg/g, which supposed to be the first choice of CPT source. Results conclude that the CPT is present in all samples used except exogenous suspension culture, out of which soxhlet bark extract possesses the maximum amount of CPT24.
The variation in content of camptothecin from the bark of Nothapodytes nimmoniana J. Graham., using HPLC analysis. The bark drug receives three seasons viz. monsoon, winter and summer in months of August, December and May. This serves a rationale to our study, where we find monsoon (August) to accumulate higher levels of CPT (1.337 gram/100 gram dry bark powder) in barks of Nothapodytes nimmoniana J. Graham. As compared to summer (May)25.
HPLC analysis of camptothecin content in various parts of Nothapodytes foetida (Wight) Sleumer collected on different periods from the month of October to February, Plant materials (Roots, Stems, Leaves and Fruits) of Nothapodytes foetida (Wight) Sleumer were collected and Dried materials were extracted with Methanol. In our investigation, the CPT content was highest in roots followed by fruits then in stems and leaves of Nothapodytes foetida (Wight) Sleumer. The similar pattern variation in accumulation of CPT is observed. The results of the present study also showed that concentration of CPT accumulated in the root of Nothapodytes foetida (Wight) Sleumer collected in the month of February was about 13 fold higher in comparison with the roots when collected in October26.
Leaf and stem materials from ten individuals of Nothapodytes nimmoniana J. Graham. From each locality were collected. Then simple micro extraction method done with methanol. The Stem were found to be better options over leaf materials for CPT accumulation of Nothapodytes nimmoniana J. Graham. along the Western Ghats, India27.
A comparative study of camptothecin from the indigenous plants namely Nothapodytes foetida, Ophiorrhiza mungos and Ophiorrhiza rugosa indicated highest yields of camptothecin and 9-methoxy camptothecin in Nothapodytes foetida. The other two plants Ophiorrhiza mungos and Ophiorrhiza rugosa contained low levels of alkaloids28.
A rapid capillary electrophoresis procedure was developed for determining the anti-cancer components, camptothecins, in Nothapodytes foetida (Wight) Sleumer. The hydrophobic compound was extracted from plant tissue (ca. 1 mL of DMSO for 100 mg of dried plant tissue) with a water-miscible organic solvent, DMSO, at elevated temperature (60 °C). The extract was directly injected into the separation capillary (untreated fused silica, 34 centimeter in length, 75 micrmeter (µm) i.d.) and analysed in MEKC mode (369 nm). Within 5 minute of migration, camptothecins were successfully separated and quantified by adding organic modifiers to the running buffer (20% DMSO, 90 mm SDS in 10 mm borate buffer, pH 8.60). The linear dynamic range for camptothecin was from 5 to 400 µg/mL. This method was proven to be very suitable for monitoring the amount of camptothecins during the cultivation of the medicinal plant29.
Biotechnology of Nothapodytes nimmoniana J. Graham:
The production of camptothecines from callus cultures of Nothapodytes foetida (Wight) leumer, the callus culture developed from leaf explants of Nothapodytes foetida (Wight) Sleumer, were found to have biosynthetic potential to produce camptothecine and 9-methoxy camptothecine. The amount of camptothecine and 9-methoxy camptothecine produced in callus was low, than the intact plant. However, the yield improvement strategies have to be developed before commercialization of this technique for the production of camptothecine from tissue cultures30.
Organogenesis from the cultures of Nothapodytes foetida (Wight) Sleumer raised on TDZ supplemented media regeneration from the callus cultures was reported first time. The dual role of Thidiazuron (TDZ) promoting proliferation of shoots and shoot differentiation from the callus31.
Entophyte was isolated from the seed of Nothapodytes nimmoniana J. Graham. and was examined and confirmed as a anticancer drug i.e. camptothecin, when grown in Sabouraud liquid culture media under shake flask conditions. The presence of anticancer compound Camptothecin in this fungus was confirmed by chromatographic and spectroscopic analysis in comparison with authentic or marketed camptothecin32.
The endophytic fungus Entrophospora infrequens for the production of Camptothecin. Twigs (Younger and Older) from Nothapodytes nimmoniana J. Graham. growing in the Jammu and Mahabaleshwar regions in India were used for the isolation of 52 strains of endophytic fungi and were tested and confirmed for their ability to produce the Camptothecin33.
Camptothecin was reported to be produced from the endophytic fungus isolated from the inner bark of Nothapodytes nimmoniana J. Graham. These reports suggested the possibility to develop arge–scale production of anticancer compound i.e. Camptothecin34.
The assessment of callus in different genotypes of Nothapodytes nimmoniana J. Graham. The Camptothecin content was analyzed and confirmed35.
Reported rapid clonal propagation of Nothapodytes nimmoniana J. Graham.36
Reported here the in vitro multiplication of Nothapodytes nimmoniana J. Graham. (through seedling explant cultures.37
Reported here the growth and production of camptothecin by cell suspension cultures of Nothapodytes nimmoniana J. Graham.38
Large scale isolation of Camptothecin from Nothapodytes foetida: An improved process, through hot extraction process and precipitation process with some organic solvents.39
Pharmacology of Nothapodytes nimmoniana J. Graham.
The methanol extracts of leaf and stem of Nothapodytes nimmoniana (Grab.) Mabb. Antioxidant activity of methanol extracts were determined using various in vitro models like DPPH (1,1-diphenyl-2-picryl hydrazine) ABTS•+ (2,2’-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) Ferrous iron chelating ability, Reducing power. In the above four assays, methanol extracts showed antioxidant potential to varying degrees. Stem showed maximum antioxidant activity of 84.35 % to 250 μg/ml by DPPH method as compared to the standard. It was concluded that the methanol extracts of different parts of Nothapodytes nimmoniana J. Graham. showed significant antioxidant activity40.
The Petroleum ether, chloroform and methanol, leaves and stems extracts of Mappia foetida. Were tested for their antibacterial activity. The methanol fractions were found to be most ffective against the entire tested organism41.
Here determined the effects of Camptothecin, a potent and specific topoisomerase - I inhibitor, on erythrocytic malaria parasites in vitro. In Plasmodium falciparum species, camptothecin trapped protein-DNAcomplexes, inhibited nucleic acid biosynthesis and was cytotoxic. These results provided the proof for the concept that topoisomerase-I was a vulnerable target for new antimalarial drug development42.
The anti-inflammatory activity of the Nothapodytes nimmoniana J. Graham. By carrageenan - induced hind paw edema method in rats. The activities of the extracts were compared with control and standard ibuprofen induced group. All the drugs were administered oral rout. When compared with petroleum ether extract, the anti – inflammatory activity of ethanolic extract was found to be more effective and 200 mg/kg dose of ethanolic extract significantly (p Value less than 0.01) reduced the inflammation, which was comparable with that of the standard, ibuprofen43.
The immunomodulatory activity of an extract of the novel fungal endophyte Entrophospora infrequens isolated from Nothapodytes nimmoniana J. Graham. The study evaluated the bioactivities of chloroform and methanol extracts of Entrophospora infrequens with respect to their immunomodulatory potential in vitro and in vivo (in Balb/c mice). The endophyte Entrophospora infrequens was found to synthesize Camptothecin, which was positively tested in chloroform. This showed for the first time the immunomodulatory potential of this neoteric Camptothecin – producing endophyte from Nothapodytes nimmoniana J. Graham.44.
Here was reported potent antitumor activity of 10-methoxy-9-nitrocamptothecin. The high cytotoxic potency of 10-methoxy-9-nitrocamptothecin was paralleled with its ability to increase the cellular accumulation of DNA damage. These results suggested that cell cycle regulation might contribute to the anticancer properties of 10-methoxy-9-nitrocamptothecin and strongly supported further anticancer development of 10-methoxy-9-nitro-camptothecin45.
The Camptothecin activated S or G2-M arrest and the homologous recombination repair pathway in tumor cells46.
The plant alkaloid Camptothecin caused DNA damage by specifically targeting DNA opoisomerase, effectively devastating a broad spectrum of tumors47.
Reported a new naturally occurring alkaloid, acetylcamptothecin, along with 17 known compounds from Nothapodytes foetida (Wight) Sleumer, Among these, scopoletin, camptothecin, 9-Omethoxy camptothecin and O-acetylcamptothecin showed significant cytotoxic activity48.
The in vitro cytotoxicity of an endophytic fungus isolated from Nothapodytes nimmoniana J. Graham. The in vitro cytotoxicity of fractions / extracts from endophyte was carried out while ethyl acetate fraction and it showed sufficient growth inhibition against all cell lines49,50.
The leaf, bark and root of methanol extract of Nothapodytes foetida (Wight) Sleumer, was done study on breast cancer cell line (ER negative) and cervical cancer cell line (SiHa).
In the present study, focused on the anti tumor potential of leaf, bark and root extracts of Nothapodytes foetida (Wight) Sleumer. Camptothecin, an anti-cancer agent is present in Nothapodytes foetida (Wight) Sleumer. This study indicates that the extracts kill the cancer cells, in dose and duration dependent manner. The results revealed that the leaf extract was more efficient in killing the cell at low concentration than the other two extracts.
Camptothecin is an anticancer quinoline alkaloid effective against colon cancer. It acts by inhibition of the enzyme DNA topoisomerase - I.
The present review study is helpful for identification, genuity, detection and prevention of adulteration. It is also beneficial for research scholars, scientists and industries.
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Received on 11.02.2018 Modified on 23.02.2018
Accepted on 18.04.2018 ©A&V Publications All right reserved