J Crit Rev, Vol 2, Issue 3, 1-8 Review Article


ALKALOIDS-IMPORTANT THERAPEUTIC SECONDARY METABOLITES OF PLANT ORIGIN

RAJBIR KAUR1*, SAROJ ARORA2

1Department of Botany, Sri Guru Teg Bahadur Khalsa College, Sri Anandpur Sahib, Ropar 140118, Punjab, India, 2Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar 143005, Punjab, India
Email: rajbir_riar@yahoo.co.in    
 

Received: 11 May 2015 Revised and Accepted: 23 Jun 2015


ABSTRACT

Plants are eminent source of new therapeutic agents that helps to alleviate human ailments and promote health. The noteworthy preventive and protective properties of these substances are related to their strong antioxidative, antimutagenic and anticarcinogenic potential. Among these, alkaloids are important secondary metabolites that are known to possess curative properties and are of prime importance for humankind. On the basis of their biosynthetic precursor and heterocyclic ring system, the compounds have been classified into different categories including indole, tropane, piperidine, purine, imidazole, pyrrolizidine, pyrrolidine, quinolizidine and isoquinoline alkaloids. These are important therapeutic molecules due to their efficacy to prevent the onset of different degenerative diseases by scavenging the free radicals or binding with catalysts of the oxidative reactions, such as some metal ions. These molecules also inhibit the growth and development of microorganisms including bacteria, fungi, protozoans etc. Due to their immense properties, these compounds are in great demand for pharmaceutical formulations and might emerge as valuable metabolite used to cure many lethal diseases like cancer. In this review, we aim to discuss about alkaloids, their biological activities and related mechanism of action for protective behaviour.

Keywords: Alkaloids, Secondary metabolites, Indole alkaloid, Anticancer activities.


INTRODUCTION

Alkaloids constitute an important class of structurally diversified compounds that are having the nitrogen atom in the heterocyclic ring and are derived from the amino acids. The term ‘alkaloids’ was coined by the German chemist Carl F. W. Meissner in 1819 and the word is derived from the Arabic name al-qali that is related to the plant from which soda was first isolated [1]. These compounds are low molecular weight structures and form about 20 % of plant based secondary metabolites. Alkaloids have influenced the human history profoundly due to their wide range of physiological effects on animals and pharmacological properties such as antibiotic, anticancer along with their potential exploitation as narcotics, poisons and stimulants [2]. Till date, about 12,000 alkaloids are isolated from different genera of the plant kingdom.

Different alkaloids and their biological activities

Depending upon their biosynthetic precursor and heterocyclic ring system, alkaloids have been classified into different categories including indole, tropane, piperidine, purine, imidazole, pyrrolizidine, pyrrolidine, quinolizidine and isoquinoline alkaloids. The chemical nature of these alkaloids along with their biosynthetic precursor and distribution are of primary interest. Alkaloids have been widely studied owing to their beneficial biological properties. The different alkaloids have their own specific properties and act useful for the medicinal purposes. The different alkaloids and their structures are given in table 1, and their biological activities have been mentioned in this section.

Indole alkaloids are characterized by the presence of serotonin, chemically known as 5-hydroxytryptamine or 5-HT and others of their kind. About 2,000 compounds are associated to this category of alkaloids with vincamine, vincristine, vinblastine, strychnine, ajmalicine and ajmaline as the most explored members for their biological and pharmacological properties. Vinblastine and vincristine, also known as spindle poison, are often used as anticancer drugs [3].

Tropane alkaloids belong to the families Erythroxylaceae, Convolvulaceae and Solanaceae. They have the 8-azabicyclo [3.2.1] octane nucleus and are derived from the amino acid ornithine. The alkaloids such as scopolamine, hyoscyamine, cocaine and atropine are the important members of this group and have several legitimate medicinal uses. The tropane alkaloids are known to have anticholinergic activities [2].

Table 1: Different alkaloids and their structures

S. No.

Type of Alkaloids

Structures

1.

Indole Alkaloid

2.

Tropane Alkaloid

3.

Quinoline Alkaloid

4.

Isoquinoline Alkaloid

5.

Purine Alkaloid

6.

Piperidine Alkaloid

7.

Pyridine alkaloids

8.

Imidazole Alkaloid

9.

Pyrrolizidine alkaloids

10.

Pyrrolidine alkaloids

x

11.

Quinolizidine alkaloids

Quinoline and isoquinoline are another important heterocyclic aromatic alkaloids formed due to the fusion of the benzene ring to the pyridine ring and are commonly known as benzopyridines. Quinine is an important member of quinoline alkaloids obtained from the bark of Cinchona ledgeriana and C. officinalis. It is found to be poisonous to Plasmodium vivax and three supplementary classes, including the single-celled organisms or protozoans that causes malaria. Other important examples of quinine alkaloids are camptothecin, echinopsine, homocamptothecin, chinidin, cinchonidin, folipdine and dihydroquinine. This class of compounds has been found to possess important biological activities viz. antimalarial, anti-bacterial, antifungal, anthelmintic, cardiotonic, anticonvulsant, anti inflammatory and analgesic activity [4].

Isoquinoline alkaloids, on the other hand, are the structural isomer of quinoline alkaloids. They are divided into many subclasses such as simple isoquinolines, benzylisoquinolines, morphine alkaloids, phthalide isoquinolines, protoberberines and ipecac alkaloids on the basis of an addition of groups. Many important alkaloids like narcotines, protopines, morphine, codeine and thebaine belong to this type of alkaloids. These alkaloids have the tendency to act as analgesic and narcotic drug (morphine), cough suppressant (codeine), muscle relaxant and also exert the antitumor properties associated with papaverine and noscapine respectively and antimicrobial activity linked to sanguinarine [5]. This class of alkaloids are also known to exhibit biological activities like antihyperglycemic, antitumor and antibacterial activity [6].

Purine alkaloids are obtained from purine i.e. adenine and guanine, and are commonly known as xanthenes. Caffeine, theobromine, theophylline and aminophyline are the most important members of this class of alkaloids. They have many beneficial properties such as antioxidant, anti-inflammatory, protects from diabetes, hyperlipidemia and obesity [7, 8].

Piperidine alkaloids occur widely in the plant as well as animal kingdom. It is highly studied and about 700 alkaloids of this structural type are known. The saturated heterocyclic ring, i.e., piperidine nucleus is the characteristic of piperidine alkaloids and these compounds are known for their toxicity. Apart from the toxicity, these compounds possess bactericidal, anti-histaminic, anticancer, central nervous system stimulant and depressant, herbicidal, insecticidal and fungicidal properties [9]. The best known piperidine alkaloid poisons are those of poison hemlock, Conium maculatum. The best known examples of piperidine alkaloids are coniine, lobeline, cynapine. Pyridine alkaloids are similar to piperidine alkaloids except that their heterocyclic nitrogen containing nucleus is unsaturated. The important examples of pyridine alkaloids are anabasin, nicotine, anatabin, anatabine, epibatidine. Pyridine alkaloids have been found to exhibit strong antimicrobial properties and are used for the same purpose [10].

Imidazole alkaloids are derived from amino acid L-histidine containing imidazole ring. Pilocarpine is an important alkaloid of this group and is obtained from Pilocarpus jaborandi. The product is valuable in ophthalmic practices and is used in the treatment of eye-disorders such as glaucoma [11].

The presence of pyrrolizidine alkaloids is restricted to plants belonging to families Boraginaceae, Compositae, Orchidaceae, Leguminosae, Convolvulaceae and Poaceae. Structurally, these alkaloids consist of two five membered rings (necine base) which share a common nitrogen at position 4. Senecionine, heliotrine and clivorine are the common examples of pyrrolizidine alkaloids. Pyrrolizidine alkaloids are produced constitutively in various plants as a defence against herbivores. These are hepatotoxic and may also cause hepatic veno-occlusive disease and liver cancer. Interestingly, their glycosidase inhibitory activity makes them an important compound for the treatment of diseases like cancer and diabetes [12].

Pyrrolidine alkaloids contain 5-membered, N-containing rings that are derived from amino acids ornithine (or arginine in some cases) and lysine with addition of acetate/malonate units. Putrescine, hygrine and cuscohygrine are some of the important examples of pyrrolidine alkaloids. A lot of research is being carried out on these compounds and they have shown to possess exceptional antibacterial, antifungal and antitubercular properties [13].

Quinolizidine alkaloids consist of two fused 6-membered rings that share nitrogen and show structural variations from simple to complex one. These alkaloids occur primarily in the genus Lupinus and are frequently referred as lupine alkaloids. However, in addition to lupinine and lupanine alkaloids, cytisine and sparteine are the two most widely distributed quinolizidine alkaloids. These alkaloids have been found to exhibit antimicrobial properties against a wide range of microorganisms [14].

Extraction and estimation of alkaloids

Due to the high interest in this valuable compound, researchers from all over the world have tried to find new and better techniques for the extraction and the estimation of alkaloids. Like all the other secondary metabolites, the extraction of alkaloids was also started with the paper chromatography (PC) [15]. It was the most easiest method for extraction, which was rapid and cheap. The whole sample could be analysed in a few minutes with the help of ultraviolet light. Chronologically, it was followed by the similar method of thin layer chromatography (TLC) [16]. This method was also rapid and required the Rf values for the estimation of the alkaloids. It was a reproducible method and had a low detection limit as compared to PC.

High performance liquid chromatography (HPLC) method for the isolation of alkaloids has always been a widely preferred method. One of the earliest known methods for the isolation of alkaloids by HPLC was reported by Wu and Wittick [17]. It is highly accurate and has the ability to detect very small quantities of the compound. Gas chromatography (GC) was another highly appreciated method for the isolation and estimation of alkaloids. Brochmann-Hanssen and Svendsen [18], were the first to report the successful estimation of alkaloids by GC. Although, not as famous as HPLC, this method has been used for both the qualitative as well as quantitative analysis of alkaloids. The wonderful results even at low efficiency and the simple procedure were the main reasons for its acceptance. Other important methods used for the extraction of the alkaloids are microwave assisted method [19], ultrasound assisted method [20], supercritical carbon dioxide extraction method [21] and the combination of ultrasound and surfactants for the extraction of alkaloids [22].

Many methods for the estimation of alkaloids have been formulated. Both the physical and chemical methods are widely used. Among these, chromatographic methods are always of high interest, as these can be employed for both the extraction and estimation processes. The major chromatographic techniques employed for the estimation of alkaloids are PC, TLC, HPLC and GC [23-27]. Along with these methods, some important chemical methods are also used viz. ELISA and radio immuno assay [28]. But the major methods for the characterization of alkaloids are the spectroscopic methods involving mass spectroscopy and NMR [29-32]. These spectroscopic methods can be used either alone or in combination with the chromatographic techniques.

Biological activities of alkaloids

Alkaloids are known for a variety of biological activities and each having its own specific mechanism of action. Most of these mechanisms have been proved, but some have been hypothesised. Here we discuss the important biological activities of alkaloids.

Muscle relaxant

Alkaloids are known to have muscle relaxant property. D-tubocurarine is one such example that possesses the antiparalytic activity due to its ability to obstruct the acetycholine receptor spots which enable the muscles to unwind at neuromuscular intersections [33, 34]. The aporphine alkaloids including corstubenne, magnoflorine, isothebaine and isocorydine, isolated from Mahonia aquifolium were reported to relax the contractions induced by nor-adernaline as compared to those induced by KCl in isolated rat aorta [35].

Antioxidant property

The alkaloids are known to possess antioxidant activities due to their ability to act as scavenger of free radicals, metal chelating activity or electron or hydrogen donation ability. A quinoline alkaloid, obtained from the aleurone layer of Oryza sativa cv. Heugjinmi, was reported to exhibit moderate antioxidative characteristics using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals as substrate [36]. In 2004, Herraiz and Galisteo [37] examined the radical scavenging ability of twenty-nine indoles and their analogs against 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical cations and found the higher radical scavenging ability at physiological pH. The norditerpene alkaloids including linearilobin, linearilin, lycotonine browniine, isolated from the roots of Delphinium linearilobum (Trautv.), were reported to exhibit antioxidant activity using DPPH and metal chelating assays [38]. Moura et al. [39] reported the ROS scavenging ability, antimutagenic and antigenotoxic activities of beta-carboline alkaloids, found in medicinal plant and variety of foods, using Saccharomyces cerevisiae strains and comet assay in V79 cell line [39]. In another study, El-Desouky et al. [40] reported the strong DPPH radical scavenging ability of pyrrole alkaloid isolated from Arum palaestinum Boiss whereas Correche et al. [41] reported the antioxidant and cytotoxic effect of alkaloids such as berberine, canadine, anonaine and antioquine in a similar manner as were found for alpha-tocopherol and trolox.

Anticancer activity

The vinblastine and vincristine alkaloids obtained from Catharanthus roseus (Apocynaceae) are popularly used for the treatment of patients suffering from leukemia and hodgkin’s disease. These alkaloids exert chemopreventive effect by terminating or causing depolymerisation of protein microtubules that forms the mitotic spindle in cell division. This results in hindrance in division and separation of tumour cells and reduces the incidences of cancer. Divalent calcium cation (Ca2+) is known to regulate energy output and cellular metabolism by acting as a major signalling molecule during cell signal transduction. Vinca alkaloids are found to decrease calcium uptake rate and its amount into mitochondria and thus might lead to a change in cytoplasmic Ca2+concentration that appears to enhance the cytotoxicity by selective release of cytochrome c or increasing the production of ROS [42]. Wani et al. [43] and Goto et al. [44] reported the cytotoxic effect of camptothecin alkaloids in B-388 leukemia system and human peripheral blood mononuclear cells due to the induction of tumour necrosis factor (TNF) and inhibitory activity on type I DNA topoisomerase. Likhitwitayawuid et al. [45] reported the cytotoxic and antimalarial activity of extracts prepared from tubers of Stephania pierrei due to the presence of isoquinoline and aporphine alkaloids. Similar activities, related to benzylisoquinoline alkaloids, obtained from Stephania spp., Cyclea spp. and Berberis curare were reported by Angerhofer et al. [46].Gul and Hamann [47], in a review, concluded that marine sources including sponges, tunicates, red algae, acorn worms are rich in indole alkaloids and are known to show cytotoxic effects in a number of cancer cell lines including P-388, HCT-8 (human colon cancer cell lines), A-549 (human lung cancer cell lines), MDAMB (human mammary cancer cell lines), MCF7 (breast cancer cell lines), mouse neuroblastoma N-18 cells, human hepatoma Hep-G2 cells and murine lymphoma L-1210 cells. These alkaloids include dragmacidin, staurosporine, grossularine, halocyamine, hyrtiosins, gelliusines and kapakahines. The roots of Aconitum yesoense var macroyesoense and of Aconitum japonicum and Delphinium elatum are known to possess diterpenoid alkaloids like kobusine. Wada et al. [48] reported the cytotoxic effect of these alkaloids against A172 human malignant glioma cells. Sorbicillactone A was a novel type alkaloid isolated by Bringmann et al. [49] from the sponge derived fungus Penicillium chrysogenum and was also reported to exhibit cytostatic activity against murine leukemic lymphoblasts (L5178y). In addition, it also exhibit cytopathic effects against HIV-1 [49]. It was reported that the alkaloids isolated from the methanolic extract of the fresh ripe fruits of Emblica officinalis exhibited strong cytotoxic activity as well as inhibitory activity against gram positive and gram negative pathogenic bacteria [50]. The aporphine alkaloids of Magnolia grandiflora L. were reported to have cytotoxic activities against tumour cell lines including Hela (cervix tumour cancer cell lines), HEPG2 (hepato cellular carcinoma cell lines), U251 (brain tumour cell lines). These alkaloids have high to moderate antiviral activity against Herpes simplex and Poliovirustype-1 respectively [51]./fig. 1 depicts the mechanism of action of alkaloids at cellular level and their interaction with different transcription factors related to apoptosis, cell cycle arrest, DNA repair processes and ceramide accumulation. The effect of alkaloids on oxidative stress inducing agents could also be well understood from fig. 1. Umezawa et al. (1996) reported that conophylline, a vinca alkaloid isolated from the plant Ervatamia microphylla, exhibited tumor suppressing effect by effecting the Ras expressing genes [52]. It has been reported by Frederich et al. (2003) that Iso strychnopentamine-an indol monoterpenic alkaloid, isolated from Strychnos usamberensis exerted chemopreventive effect as a result of induction of apoptosis and cell cycle arrest. Induction in apoptosis is related by the translocation of phosphatidylserine from inner layer to an outer layer of plasma membrane, chromatin condensation, DNA fragmentation, activation of caspases 3 and 9 cascades and inhibition of RNA synthesis. These cytological modifications resulted in the arrest of cell cycle in G2-M phase [53]. Scutellaria barbata has been widely used as an antitumor agent in traditional Chinese medicine. Wang and co-workers (2011) reported that antiproliferative effects of alkaloids extract of Scutellaria barbata is due to the induction of apoptosis and cell cycle arrest in G2/M phase [54]. DNA damaging effect of deoxyamphimedine–a pyridoacridine alkaloid, isolated from Xestospongia sponges found in Philipines, is related to reactive oxygen species related phenomenon. Neoamphimedine–another member of this class, is reported to effect cytotoxicity via topoisomerase-2-dependent DNA aggregation/catenation. Deoxiamphimedine resulted in the production of ROS that attack DNA as a result of single strand breaks (SSB) and double strand breaks (DSB) [55].

Yin et al. (2005) reported the induction of apoptosis by the modulation of ROS synthesis by another alkaloid 6-methoxydihydrosanguinarine [56]. Similar type of mechanism of action was reported for quaternary benzo[c] phenanthridine alkaloids including sanguilutine and chelilutine [57]. TNF-α–a cytokine, is known to play a pivotal role in the regulation of inflammation. Conophylline was reported to down regulate the expression of the TNF-α receptors on the cell surface and in this way inhibit the TNF-α induced NF-κB activation [58]. Yui et al. (2001) reported that Amaryllidaceae alkaloids, lycorine and lycoricidinol inhibited the TNF-α production either by inhibiting the protein synthesis or by altering the cysteine/methionine incorporation into the macrophages [59]. Lycorine and its synthetic derivative are known to induce cell cycle arrest, up regulate the expression of pro-apoptotic proteins (caspase 3, 7 and 9) and down regulate the antiapoptotic proteins (Mcl-1, Bcl-2) [60].

Ceramide accumulation is another remarkable process associated with cancer chemoprevention. The increased availability of ceramide within the cell either by activating sphingomylinase or by blocking degradation of ceramide under the cytotoxic effect of chemotherapeutic agent resulted in modulation of associated cell signalling pathways. The resultant effect of this alteration is cell cycle arrest, terminal cell differentiation and apotosis [61]. Ceramide induced cell death is reported to be of two types depending on the dependency of transcription factors. The component alters the activity of apoptosis related proteins of BCl-2 family and its relation with preapoptotic proteins (Bax and Bad). The over expression of antiapoptotic proteins might block the ceramide mediated cell death without having an effect on its generation [62]. The much exploited role of Vinca alkaloids including vincristine and vinblastine in treatment of leukemia might be due to increased accumulation of ceramide in cells. Vinblastine has been reported to elevate the levels of cellular ceramide even at 1.5nM concentration that furthermore induced cell death in KB-3-1 human epidermoid carcinoma cells [62].

Nuclear factors such as NF-κB have an important role in the process of inflammation. Its presence is reported in cells that expresses cytokines, chemokines, growth factors, cells adhesion molecules and some acute phase proteins. The activation of NF-κB involves the phosphorylation of IκBs by serine residues (Ser32, Ser36) via the IκB kinase (IKK) signal-o-some complex. The phosphorylated IκB are ubiquitous and their degradation by 26s proteosome liberated free NF-κB that is translocated to the nucleus where it binds to κB binding sites in the promoter regions of target genes and induces the transcription of pro-inflammatory mediators e. g. iNOS, COX-2, TNF-α and IL-1B,-6 and-8 [63]. Another important factor iNOS (inducible Nitric Oxide Synthase) is expressed in response to interferon-γ, lipopolysaccharide (LPS) and various pro-inflammatory cytokines. NO modulates acute and chronic inflammatory response by acting as potent vasodilator and thus maintain vascular homeostasis. The expression of COX-2 is induced in immune cells such as macrophages in various stress conditions that led to increase in prostaglandins (PGs) level. The elevated PGs level resulted in tumor growth due to angiogenesis and inhibition of apoptosis [63]. Poncirin isolated from the fruits of Poncirus trifoliata is a potent inhibitor of LPS-induced NO, PGE2, TNF-α and IL-6 production in macrophages cells and it acts at transcription level. Inhibitory effect of Poncirin was found to be associated with NF-κB inactivation via the blockage of IκB-α phosphorylation. In addition to this, poncirin significantly declined the TNF-α and IL-6 release and their mRNA expression alongwith reduction of COX-2 and iNOS expression in macrophages cells in dose dependent manner [63]. Quinoline alkaloids isolated from Evodia rutaecarpa showed inhibitory effects against NF-κB activity [64].

In addition to this, Benzyisoquinoline alkaloids due to the presence of phenolic hydroxyls or similar reactive groups are reported to act as inhibitors of lipid peroxidation stimulated by Fe2+/cysteine in rat liver microsomal fractions [65]. Martefragin A-an indole alkaloid, isolated from red alga Martensia fragilis has been reported to show inhibitory activity on NADPH-dependent lipid peroxidation in rat liver microsomes [66].

Antimicrobial and amoebicidal activity

The alkaloids of phenanthridine nature, isolated from Chelidonium majus Linn. were reported to exhibit antifungal activity against the clinical drug-resistant yeast isolates [68]. De Luca (2006) found the imidazole derivatives having an immense therapeutic potential and also reported their antibacterial activity. It was also found that the compounds with imidazole moiety act as p38 MAP Kinase and 5-Lipoxygenase inhibitors [69]. Lohombo-Ekomba and co-workers demonstrated that the bisbenzylisoquinoline alkaloids such as cycleanine and cocsoline isolated from Albertisia villosa have antibacterial, antifungal, antiplasmodial activities in addition to cytotoxic potential related to these alkaloids [70]. Diterpenoid alkaloids isolated from Delphinium spp. were known to possess moderate antifungal activity, along with antifeedent activity against the insect species Spodoptera littoralis and Leptinotarsa decemlineata [71]. Gul and Hamann, in their review on indole alkaloids, have mentioned the antiviral activities of Eudistomin, a novel oxathiazepine ring containing alkaloids isolated from Eudistoma olivaceum against RNA viruses such as Coxsachie A-21 and equine rhinovirus and against DNA viruses such as HSV-1, HSV-2, Vaccinia virus [47]. Wright et al. (1992) demonstrated that Dragmacidin alkaloids isolated from Spongosorites sp. were reported to inhibit in vitro replication of feline leukemia virus (FeLV) whereas Bokesch et al. (2000) showed the anti-HIV effect of Coscinamide alkaloids isolated from Coscinoderma sp [72, 73]. In 2000, Wright et al. assessed the antiplasmodial property against Plasmodium falciparum, antiamoebic against Entamoeba histolytica and cytotoxic activities against KB cells (human carcinoma of the nasopharynx) of twenty-one alkaloids including allocrytopine, columbamine, dehydroocoteine, jatrorrhizine, norcorydine, thalifendine, and ushinsunine [74]. Hymete and co-workers reported that the presence of alkaloids saponins and phenols in Echinops ellebeckii and E. lingisetus, and found them being the main factors contributing to their inhibitory activity against Candida albicans, earthworms, Staphylococcus aureus [75].

The quinoline alkaloids including skimmianine, kokisaginine and masculine isolated from Raulinoa echinata were reported to exhibit antifungal activity against Leucoagaricus gongylophorus, the symbiotic fungus of leaf cuttings ants (Atta sexdens) and in vitro against trypomastigote forms of Trypanosoma cruzi [76]. Wirasathien et al. demonstrated that aporphine alkaloids isolated from the aerial part of Pseuduvaria setosa were known to display antituberculosis activity against Mycobacterium tuberculosis, antimalarial activity against Plasmodium falciparum and cytotoxic activity against epidermoid carcinoma (KB), breast cancer (BC) and small cell lung cancer (NCI-H187) cell line [77].Nibret et al. reported the in vitro inhibitory effect of four pyrrolizidine alkaloids including senecionine on bloodstream forms of Trypanosoma brucei and human leukaemia HL-60 cells. It was found that among the four alkaloids, senecionine showed moderate antitrypanosomal activity with an IC50 value of 41.78µg/ml [78].

Fig. 1

Other activities

Berberine, an alkaloid isolated from Berberis vulgaris L., has been found to ameliorate type 1 diabetes due to the reduction in Th17 and Th1 cytokine secretion. The decreased secretion is achieved with the suppression of Th17 and Th1 differentiation by activating ERK1/2, and by inhibiting p38 MAPK and JNK activation (it down-regulated the activity of STAT1 and STAT4) respectively [79]. Cottam et al. demonstrated that compounds with purine, pteridine, quinazoline ring system were reported to inhibit the production of tumour necrosis factor–alpha (TNFα) in human peripheral blood monocytes and thus acts as an anti-inflammatory agents [80]. The powdered leaves and roots of Mallotus oppositifolium were reported to be rich in alkaloids and have been demonstrated to exhibit antioxidant and anti-inflammatory activities in beta-carotene linoleate model system and carrageenin induced rat paw oedema animal model [81]. In a review, Barbosa-Filho and co-workers evaluated the anti-inflammatory activity of 171 alkaloids of different structural groups in different models. It was concluded that Carrageenin-induced paw oedema was the most widely used model determining anti-inflammatory activity and about 137 alkaloids were effective against inflammation, with isoquinoline alkaloids being the most effective one [82]. The phenoxazone alkaloids isolated from red-orange bracket fungus Pycnoporus cinnabarinus was also reported to exhibit anti-inflammatory activity as well as antiviral and antimicrobial activities [83]. Hansch and Verma reported that camptothecin derivatives were found to act as DNA topoisomerase I (topo I) inhibitors whereas Motiur Rahman et al. related the cytotoxic activities of 2,2-dimethy-2H-pyran derived alkaloids with their potential to inhibit the topoisomerase I and II activities [84, 85].

CONCLUSION

These important class of secondary metabolites have been found to exhibit many important biological properties such as muscle relaxant, analgesic and antioxidant properties. These are used for the curative purposes and are helpful for the mankind. Interestingly, it has been found that alkaloids are not only beneficial to humans, but in certain cases may even be life threatening. Certain alkaloids have shown to cause paralysis, asphyxia or in some extreme conditions death of the patient. A large number of extraction and estimation methods of alkaloids have been formulated. These are developed to ease the researchers in the study of this metabolite and these methods are improvements to the previous methods.

With the advancements in the field of science and technology, alkaloids are being exploited for various purposes. Scientists have been able to synthesize halogenated alkaloids, which have made it easier to study the various gene clusters. Alkaloids have also been utilized for the pharmaceutical and curative purposes. It is hoped that this valuable metabolite may be used to cure many lethal diseases like cancer. We would like to conclude that alkaloids are useful for plants, animals, as well as humans. They can be employed for pharmaceutical purposes, due to its presence in almost all the vegetables and medicinal plants. Attention is required in testing this compound for the curative purposes of the human diseases.

CONFLICT OF INTERESTS

Declared None

REFERENCES

  1. Croteau R, Kutchan TM, Lewis NG. Natural products (secondary metabolites). In: Buchanan B, Gruissem R, Jones R. Editors. Biochemistry and molecular biology of plants. John Wiley & Sons Inc, Somerset, NJ, USA; 2000.
  2. Ziegler J, Facchini PJ. Alkaloid biosynthesis: Metabolism and trafficking. Annu Rev Plant Biol 2008;59:735-69.
  3. Kainsa S, Kumar P, Rani P. Medicinal plants of Asian origin having anticancer potential: Short review. Asian J Biomed Pharm Sci 2012;2:1-7.
  4. Marella A, Tanwar OP, Saha R, Ali MR, Srivastava S, Akhter M, et al. Quinoline: A versatile heterocyclic. Saudi Pharm J 2013;21:1-12.
  5. Frick S, Kramell R, Schmidt J, Fist AJ, Kutchan TM. Comparative qualitative and quantitative determination of alkaloids in narcotic and condiment Papaver somniferum. J Nat Prod 2005;68:666-73.
  6. Nassiri M. Simple, one-pot, and three-component coupling reactions of azaarenes (phenanthridine, isoquinoline, and quinoline), with acetylenic esters involving methyl propiolate or ethyl propiolate in the presence of nh-heterocyclic or 1,3-dicarbonyl compounds. Synth Commun 2013;43:157-68.
  7. Herman A, Herman AP. Caffeine’s mechanisms of action and its cosmetic use. Skin Pharmacol Physiol 2013;26:8-14.
  8. Li S, Lo CY, Pan MH, Lai CS, Ho CT. Black tea: Chemical analysis and stability. Food Funct 2013;4:10-8.
  9. Singh AK, Chawla R, Rai A, Yadav LDS. NHC-catalysed diastereoselective synthesis of multifunctionalised piperidines via cascade reaction of enals with azalactones. Chem Commun 2012;48:3766-8.
  10. Machado PA, Hilario FF, Carvalho LO, Silveira MLT, Alves RB, Freitas RP, et al. Effect of 3-alkylpyridine marine alkaloid analogues in Leishmania species related to American cutaneous Leishmaniasis. Chem Biol Drug Res 2012;80:745-51.
  11. Cronemberger S, Calixto N, Moraes MN, Castro ID, Lana PC, Loredo AF. Efficiency of one drop of 2% pilocarpine to reverse the intraocular pressure peak at 6:00 A. M. in early glaucoma. Vision Pan-Am Pan-Am J Ophthalmol 2012;11:14-6.
  12. Majik MS, Tilve SG. Pyrrolizidine alkaloids pyrrolams A-D: Survey on synthetic efforts, biological activities and studies on their stability. Synthesis 2012;44:2373-681.
  13. Parmar NJ, Pansuriya BR, Barad HA, Kant R, Gupta VK. An improved microwave assisted one-pot synthesis, and biological investigations of some novel aryldiacenyl chromeno fused pyrrolidines. Bioorg Med Chem Lett 2012;22:4075-9.
  14. Singh KS, Das B, Naik CG. Quinolizidines alkaloids: Petrosin and xestospongins from the sponge Oceanapia sp. J Chem Sci 2011;123:601-7.
  15. Tso TC, Jeffrey RN. Paper chromatography of alkaloids and their transformation products in Maryland tobacco. Arch Biochem Biophys 1953;43:269-85.
  16. Mangold HK. Thin-layer chromatography of lipids. J Am Oil Chem Soc 1961;38:708-27.
  17. Wu CY, Wittick JJ. Separation of five major alkaloids in gum opium and quantitation of morphine, codeine, and thebaine by isocratic reverse phase high performance liquid chromatography. Anal Chem 1977;49:359-63.
  18. Brochmann-Hanssen E, Svendsen AB. Gas chromatography of alkaloids, alkaloidal salts, and derivatives. J Pharm Sci 1962;51:1095-8.
  19. Zhou Q, Liu Y, Wang X, Di X. Microwave-assisted extraction in combination with capillary electrophoresis for rapid determination of isoquinoline alkaloids in Chelidonium majus L. Talanta 2012;99:932-8.
  20. Ovadia ME, Skauen DM. Effect of ultrasonic waves on the extraction of alkaloids. J Pharm Sci 1965;54:1013-6.
  21. Ellington E, Bastida J, Viladomat F, Codina C. Supercritical carbon dioxide extraction of colchicines and related alkaloids from seeds of Colchicum autumnale L. Phytochem Anal 2003;14:164-9.
  22. Djilani A, Legseir B, Soulimani R, Dicko A, Younos C. New extraction techniques for alkaloids. J Braz Chem Soc 2006;17:518-20.
  23. Macek K, Vanecek S. Ergot alkaloids IV. Estimation of alkaloids in a single sclerotium by means of paper chromatography. Die Pharmazie 1955;10:422-9.
  24. Brochmann-Hanssen E, Svendsen AB. Gas chromatography of alkaloids, alkaloidal salts, and derivatives. J Pharm Sci 1962;51:1095-8.
  25. McLaughlin JL, Goyan JE, Paul AG. Thin-layer chromatography of ergot alkaloids. J Pharm Sci 1964;53:306-10.
  26. Trugo LC, MacRae R, Dick J. Determination of purine alkaloids and trigonelline in instant coffee and other beverages using high performance liquid chromatography. J Sci Food Agric 1983;34:300-6.
  27. Gupta MM, Verma RK. Combined thin-layer chromatography-densitometry method for the quantitative estimation of major alkaloids in poppy straw sample. Indian J Pharm Sci 1996;58:161-3.
  28. Kleimola TT. Quantitative determination of ergot alkaloids in biological fluids by radioimmunoassay. Br J Clin Pharmacol 1978;6:255-60.
  29. Mattocks AR. Spectrophotometric determination of unsaturated pyrrolizidine alkaloids. Anal Chem 1967;39:443-7.
  30. Sener B. Turkish Species of Fumaria L. and their alkaloids VI. Alkaloids of Fumaria capreolate L. Pharm Biol 1985;23:161-3.
  31. Lehner AF, Craig M, Fannin N, Bush L, Tobin T. Electrospray [+] tandem quadrapole mass spectrometry in the elucidation of ergot alkaloids chromatographed by HPLC: Screening of grass or forage samples for novel toxic compounds. J Mass Spectrom 2005;40:1484-502.
  32. Rudzinska E, Berlicki L, Kafarski P, Lammerhofer M, Mucha A. Cinchona alkaloids as privileged chiral solvating agents for the enantiodiscrimination of N-protected aminoalkanephosphonates-a comparative NMR study. Tetrahedron: Asymmetry 2009;20:2709-14.
  33. Gustafson T. Pharmacological control of muscular activity in the sea urchin larva. I. Effects of nicotinic and muscarinic agents. Comp Biochem Physiol C: Comp Pharmacol 1989;94:1-14.
  34. Das M, Vedasiromoni JR, Chauhan SPS, Ganguly DK. Effect of green tea (Camellia sinensis) extract on the rat diaphragm. J. Ethnopharmacol 1997;57:197-201.
  35. Sotnikova R, Kettmann V, Kostalova D, Taborska E. Relaxant properties of some aporphine alkaloids from Mahonia aquifolium. Methods Find Exp Clin Pharmacol 1997;19:589-97.
  36. Chung HS, Woo WS. A quinolone alkaloid with antioxidant activity from the aleurone layer of anthocyanin-pigmented rice. J Nat Prod 2001;64:1579-80.
  37. Herraiz T, Galisteo J. Endogenous and dietary indoles: A class of antioxidants and radical scavengers in the ABTS assay. Free Rad Res 2004;38:323-31.
  38. Kolak U, Ozturk M, Ozgokce F, Ulubelen A. Norditerpene alkaloids from Delphinium linearilobum and antioxidant activity. Phytochemistry 2006;67:2170-5.
  39. Moura DJ, Richter MF, Boeira JM, Pegas Henriques JA, Saffi J. Antioxidant properties of beta-carboline alkaloids are related to their antimutagenic and antigenotoxic activities. Mutagenesis 2007;22:293-302.
  40. El-Desouky SK, Kim KH, Ryu SY, Eweas AF, Gamal-Eldeen AM, Kim YK. A new pyrrole alkaloid isolated from Arum palaestinum Boiss. and its biological activities. Arch Pharmacal Res 2007;30:927-31.
  41. Correche ER, Andujar SA, Kurdelas RR, Gomez Lechon MJ, Freile ML, Enriz RD. Antioxidant and cytotoxic activities of canadine: biological effects and structural aspects. Bioorg Med Chem 2008;16:3641-51.
  42. Tari C, Fournier N, Briand C, Ducet G, Crevat A. Action of vinca alkaloides on calcium movements through mitochondrial membrane. Pharmacol Res Commun 1986;18:519-28.
  43. Wani MC, Ronman PE, Lindley JT, Wall ME. Plant antitumor agents. 18. Synthesis and biological activity of camptothecin analogues. J Med Chem 1980;23:554-60.
  44. Goto S, Okutomi T, Suma Y, Kera J, Soma G, Takeuchi S. Induction of tumor necrosis factor by a camptothecin derivative, irinotecan, in mice and human mononuclear cells. Anticancer Res 1996;16:2507-11.
  45. Likhitwitayawuid K, Angerhofer CK, Chai H, Pezzuto JM, Cordell GA, Ruangrungsi N. Cytotoxic and antimalarial alkaloids from the tubers of Stephania pierrei. J Nat Prod 1993;56:1468-78.
  46. Angerhofer CK, Guinaudeau H, Wongpanich V, Pezzuto JM, Cordell GA. Antiplasmodial and cytotoxic activity of natural bisbenzylisoquinoline alkaloids. J Nat Prod 1999;62:59-66.
  47. Gul W, Hamann MT. Indole alkaloid marine natural products: An established source of cancer drug leads with considerable promise for control of parasitic, neurological and other diseases. Life Sci 2005;78:442-53.
  48. Wada K, Hazawa M, Takahashi K, Mori T, Kawhara N, Kashiwakura I. Inhibitory effects of diterpenoid alkaloids on the growth of A172 human malignant cells. J Nat Prod 2007;70:1854-8.
  49. Bringmann G, Lang G, Muhlbacher J, Schaumann K, Steffens S, Rytik PG, et al. Sorbicillactone a: a structurally unprecedented bioactive novel-type alkaloid from a sponge-derived fungus. Prog Mol Subcell Biol 2003;37:231-53.
  50. Rahman S, Akbor MM, Howlader A, Jabbar A. Antimicrobial and cytotoxic activity of the alkaloids of Amlaki (Emblica officinalis). Pakistani J Biol Sci 2009;12:1152-5.
  51. Mohamed SM, Hassan EM, Ibrahim NA. Cytotoxic and antiviral activities of aporphine alkaloids of Magnolia grandiflora L. Nat Prod Res 2010;24:1395-402.
  52. Umezawa K, Taniguchi T, Toi M, Ohre T, Tsutsumi N, Yamamoto T, et al. Growth inhibition of K-ras expressing tumors by a new Vinca alkaloid, conophylline in nude mice. Drugs Exp Clin Res 1996;22:35-40.
  53. Frederich M, Bentires-Alj M, Tits M, Angenot L, Greimers R, Gielen J, et al. Isostrychnopentamine–an Indolomonoterpenic alkaloid from Strychnos usambarensis, induces cell cycle arrest and apoptosis in Human colon cancer cell. J Pharmacol Exp Therapeut 2003;304:1103-10.
  54. Wang TS, Chen LJ, Wang ZY, Zhang ST, Lin JM. Purified alkaloid extract of Scutellaria barbata inhibits proliferation of hepatoma HepG-2 cells by inducing apoptosis and cell cycle arrest at G2/M phase. Afr J Pharm Pharmacol 2011;5:1046-53.
  55. Marshall KM, Andeljic CD, Tasdemir D, Concepcion GP, Ireland CM, Barrows LR. Deoxyamphimedine, a Pyridoacridine alkaloid damages DNA via the production of reactive oxygen species. Marine Drugs 2009;7:196-209.
  56. Yin HQ, Kim YH, Moon CK, Lee BH. Reactive oxygen species mediated induction of apoptosis by a plant alkaloid 6-methoxydihydrosanguinarine in HepG2 cells. Biochem Pharmacol 2005;70:242-8.
  57. Slunska Z, Gelnarora E, Hammerova J, Taborska E, Slaninova I. Effect of quaternary benzo (c) phenanthridine alkaloids sanguilutine and chelilutine on normal and cancer cells. Toxicol In Vitro 2010;24:699-706.
  58. Gohda J, Inoue J, Umezawa K. Downregulaton of TNF-alpha receptors by conophylline in human T-cell leukemia cells. Int J Oncol 2003;23:1373-9.
  59. Yui S, Mikami M, Mimaki Y, Sashida Y, Yamazaki M. Inhibition effect of Amaryllidaceae alkaloids, Lycorine and Lycoricidinol on macrophage TNF-α production. Yakugaku Zasshi 2001;121:167-71.
  60. Lamoral-Theys D, Decaestecker C, Mathieu V, Dubois J, Kornienko A, Kiss R, et al. Lycorine and its derivatives for anticancer drug design. Mini Rev Med Chem 2010;10:41-50.
  61. Jarvis WD, Grant S. The role of ceramide in the cellular response to cytotoxic agents. Curr Opinion Oncol 1998;10:552-9.
  62. Senchenkov A, Litvak DA, Cabot MC. Targetting caramide metabolism–a strategy for overcoming drug resistance. J Natl Cancer Inst 2001;93:347-57.
  63. Kim JB, Han AR, Park EY, Kim JY, Cho W, Lee J, et al. Inhibition of LPS-induced iNOS, COX-2 and cytokinins expression by poncirin on the NF-κB inactivation in RAW 264.7 macrophage cells. Biol Pharm Bull 2007;30:2345-51.
  64. Jin HZ, Lee JH, Lee D, Lee HS, Hong YS, Kim YH, Lee JJ. Quinoline alkaloids with inhibitory activity against nuclear factor of activated T cells from the fruits of Evodia rutaecarpa. Biol Pharm Bull 2004;27(6):926-8.
  65. Martinez LA, Rios J, Paya M, Alcarz MJ. Inhibition of non-enzymatic lipid peroxidation by benzylisoquinoline alkaloids. Free Radical Biol Med 1992;12:287-92.
  66. Takajashi S, Matsunaga T, Hasegawa C, Saito H, Fujita D, Kiuchi F, et al. Martefragin A: a novel indole alkaloid isolated from red alga, inhibits lipid peroxidation. Chem Pharm Bull (Tokyo) 1998;46:1527-9.
  67. Nambiar D, Rajamani P, Singh RP. Effects of phytochemicals on ionization radiation-mediated carcinogenesis and cancer therapy. Mutat Res 2011;728:139-57.
  68. Meng F, Zuo G, Hao X, Wang G, Xiao H, Zhang J, et al. Antifungal activity of the benzo[c]phenanthridine alkaloids from Chelidonium majus Linn. against resistant clinical yeast isolates. J Ethnopharmacol 2009;125:494-6.
  69. De Luca L. Naturally occurring and synthetic imidazoles: Their chemistry and their biological activities. Curr Med Chem 2006;13:1-23.
  70. Lohombo-Ekomba ML, Okusa PN, Penge O, Kabongo C, Choudhary MI, Kasende OE. Antibacterial, antifungal, antiplasmodial, and cytotoxic activities of Albertisia villosa. J Ethnopharmacol 2004;93:331-5.
  71. Gonzalez-Coloma A, Guadano A, Gutierrez C, Cabrera R, de La Pena E, de La Fuente G, et al. Antifeedant delphinium diterpenoid alkaloids. Structure-activity relationships. J Agric Food Chem 1998;46:286-90.
  72. Wright AE, Pomponi SA, Cross SS, McCarthy P. A new bis (indole) alkaloid from a deep-water marine sponge of the genus Spongosorites. J Org Chem 1992;57:4772-5.
  73. Bokesch HR, Pannell LK, McKee TC, Boyd MR. Coscinamides A, B and C, three new bis-indole alkaloids from the marine sponge Cosinoderma sp. Tetrahedron Lett 2000;41:6305-8.
  74. Wright CW, Marshall SJ, Russell PF, Anderson MM, Phillipson JD, Kirby GC, Warhurst DC, et al. PL. In vitro antiplasmodial, antiamoebic, and cytotoxic activities of some monomeric isoquinoline alkaloids. J Nat Prod 2000;63:1638-40.
  75. Hymete A, Iversen TH, Rohloff J, Erko B. Screening of Echinops ellenbeckii and Echinops longisetus for biological activities and chemical constituents. Phytomedicine 2005;12:675-9.
  76. Biavatti MW, Vieira PC, da Silva MFGF, Fernandes JB, Victor SR, Pagnocca FC, et al. Biological activity of quinoline alkaloids from Raulinoa echinata and X-ray structure of flindersiamine. J Braz Chem Soc 2002;13:66-70.
  77. Wirasathien L, Boonarkart C, Pengsuparp T, Suttisri R. Biological activities of alkaloids from Pseuduvaria setosa. Pharm Biol 2006;44:274-8.
  78. Nibret E, Sporer F, Asres K, Wink M. Antitrypanosomal and cytotoxic activities of pyrrolizidine alkaloid-producing plants of Ethiopia. J Pharm Pharmacol 2009;61:801-8.
  79. Cui G, Qin X, Zhang Y, Gong Z, Ge B, Zang YQ. Berberine differentially modulates the activities of ERK, p38 MAPK, and JNK to suppress Th17 and Th1 T cell differentiation in type 1 diabetic mice. J Biol Chem 2009;284:28420-9.
  80. Cottam HB, Shih H, Tehrani LR, Wasson DB, Carson DA. Substituted xanthines, pteridinediones, and related compounds as potential antiinflammatory agents. Synthesis and biological evaluation of inhibitors of tumor necrosis factor alpha. J Med Chem 1996;39:2-9.
  81. Farombi EO, Ogundipe O, Moody JO. Antioxidant and anti-inflammatory activities of Mallotus oppositifolium in model systems. Afr J Med Med Sci 2001;30:213-5.
  82. Barbosa-Filho JM, Piuvezam MR, Moura MD, Silva MS, Lima KVB, da Cunha EVL, et al. Anti-infl ammatory activity of alkaloids: A twenty-century review. Braz J Phcog 2006;16:109-39.
  83. Dias DA, Urban S. HPLC and NMR studies of phenoxazone alkaloids from Pycnoporus cinnabarinus. Nat Prod Commun 2009;4:489-98.
  84. Hansch C, Verma RP. 20-(S)-camptothecin analogues as DNA topoisomerase I inhibitors: A QSAR study. Chem Med Chem 2007;2:1807-13.
  85. Motiur Rahman AF, Liang JL, Lee SH, Son JK, Jung MJ, Kwon Y, et al. 2,2-dimethyl-2H-pyran-derived alkaloids I. Practical synthesis of acronycine and benzo[b]acronycine and their biological properties. Arch Pharmacol Res 2008;31:1087-93.


About this article

Title

ALKALOIDS-IMPORTANT THERAPEUTIC SECONDARY METABOLITES OF PLANT ORIGIN

Date

30-06-2015

Additional Links

Manuscript Submission

Journal

Journal of Critical Reviews
Vol 2, Issue 3, 2015 Page: 1-8

Online ISSN

2394-5125

Statistics

438 Views | Downloads

Authors & Affiliations

Rajbir Kaur
Department of Botany, Sri Guru Teg Bahadur Khalsa College, Sri Anandpur Sahib, Ropar 140118, Punjab, India
India

Saroj Arora
Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar 143005, Punjab, India


Refbacks

  • There are currently no refbacks.