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The Pharmacological Activities of (-)-Anonaine

  • Tzu Hui Institute of Technology

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Several species of Magnoliaceae and Annonaceae are used in Traditional Chinese Medicine. (-)-Anonaine, isolated from several species of Magnoliaceae and Annonaceae, presents antiplasmodial, antibacterial, antifungal, antioxidation, anticancer, antidepression, and vasorelaxant activity. This article provides an overview of the pharmacological functions of (-)-anonaine.
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Molecules 2013, 18, 8257-8263; doi:10.3390/molecules18078257
ISSN 1420-3049
The Pharmacological Activities of (−)-Anonaine
Hsing-Tan Li, Hui-Ming Wu, Hsin-Liang Chen, Chi-Ming Liu * and Chung-Yi Chen *
School of Medical and Health Sciences, Fooyin University, Kaohsiung 83102, Taiwan;
E-Mails: (H.-T.L.); (H.-M.W.); (H.-L.C.)
* Authors to whom correspondence should be addressed; E-Mails: (C.-M.L.); (C.-Y.C.); Tel.: +886-7-781-1151 (ext. 6200) (C.-M.L. & C.-Y.C.);
Fax: +886-7-783-4548 (C.-M.L. & C.-Y.C.).
Received: 13 May 2013; in revised form: 28 June 2013 / Accepted: 3 July 2013 /
Published: 12 July 2013
Abstract: Several species of Magnoliaceae and Annonaceae are used in Traditional
Chinese Medicine. ()-Anonaine, isolated from several species of Magnoliaceae and
Annonaceae, presents antiplasmodial, antibacterial, antifungal, antioxidation, anticancer,
antidepression, and vasorelaxant activity. This article provides an overview of the
pharmacological functions of ()-anonaine.
Keywords: ()-anonaine; magnoliaceae; annonaceae
1. Introduction
Various constituents of Michelia alba (Magnoliaceae) are used for medical purposes. In our
research, we have identified a series of compounds from Michelia alba, including (−)-anonaine
(Figure 1A) [1], an aporphine (isoquinoline) alkaloid also isolated from other plants (Table 1) with
interesting and varied biological and pharmacological activities, including vasorelaxant, antibacterial,
antifungal, antioxidative, anticancer and antidepressant effects, as summarized in Table 1 [132]. In
this article, we will focus on describing the pharmacological mechanisms of action of (−)-anonaine.
Molecules 2013, 18 8258
Figure 1. Chemical structure of ()-anonaine (A) and anonaine derivative (B).
Table 1. Anonaine isolated from plants and its pharmacological effects.
Pharmacological effects
1. Goniothalamus australis
2. aerial parts of Annona cherimola
3. bark of Annona salzmannii
4. Michelia champaca
5. Liriodendron tulipifera
6. leaves of Michlia alba
7. Magnolia grandiflora
8. Stephania yunnanensis
9. bark of Guatteria hispida
10. Fissistigma latifolium
11. Polyalthia longifolia
12. Rollinia leptopetala
13. fruit of Annona muricata
14. Annona cherimolia
15. Annona squamosa
16. Artabotrys maingayi
17. Chamanthera dependens
18. Nelumbo lutea
1. antoxidant activity
2. antidepression
3. anticancer activity
4. vasorelaxant activity
5. antiplasmodial activity
6. antibacterial activity
7. antifungal activity
2. Anticancer Activity
There are three different mechanisms by which a cell commits suicide by apoptosis. One is initiated
by signals arising within the cells. The second is triggered by death activators binding to receptors at
the cell surface. The third is triggered by reactive oxygen species (ROS).
Studies have demonstrated that ()-anonaine has anticancer activity and cytotoxic effects in different
cancer cell lines [6,7,15]. The viability of cells treated with ()-anonaine decreased in a dose-dependent
manner on different cell lines including HeLa, HepG2, rat hepatocytes, and H1299 [6,7,15]. In human
cervical cancer cell (HeLa), ()-anonaine caused DNA damage associated with increased intracellular
nitric oxide, ROS, glutathione (GSH) depletion, disruptive mitochondrial transmembrane potential,
activation caspase 3, 7, 8 & 9 activation and poly ADP ribose polymerase cleavage [15]. Moreover,
()-anonaine also up-regulates the protein expression of p53 and Bax [15]. ()-Anonaine is a potential
Molecules 2013, 18 8259
anticancer agent against HepG2 (human liver carcinoma cell), rat hepatocyte with IC
values of 33.5,
70.3 μg/mL [7]. This compound also exhibits antiproliferation, antimigratory effects, DNA damage
and cell cycle arrest in human lung cancer cell (H1299) [6]. The above-mentioned results indicate that
()-anonaine has cytotoxic activity (Scheme 1).
Scheme 1. The possible mechanism of action of ()-anonaine-induced apoptosis and cell
cycle arrest in cancer cells.
3. Vasorelaxation Activity
Reports have shown that aporphine alkaloids display a variety of different pharmacological
activites in cardiovascular system [16,20,26]. ()-Anonaine has Ca
channel blocking activity through
voltage-operated channel and α
-adrenoceptor blocking activity in isolated rat thoracic aorta [20].
Recently, a study has shown that the affinities of (−)-anonaine for α
-adrenoceptor subtypes are in the
order α
without inhibition phosphodiesterase enzymatic activity [16]. Further, this study
confirms that α
-adrenoceptor subtypes selectivity of aporphine alkaloids can be modulated by the position
of free hydroxyl (R2) and N-methyl (R1) substituents on the aporphine structure (Figure 1B) [16].
4. Antioxidative Activity
Oxidative stress is an imbalance of prooxidants and antioxidants in the organism. The oxidative
stress can contribute to inflammation, heart disease, hypertension, various neurodegenerative diseases,
and cancers. Anti-oxidative capacity of anonaine has been studied as a potential inhibitor of lipid
peroxidation stimulated by Fe
/cysteine in rat liver microsomal fractions [25]. The antioxidation
activity of anonaine was also evaulated monitoring inhibition of microsomal lipid peroxidation induced
by Fe
/ascorbate, CCl
/NADPH or Fe
ADP/NADPH [21]. However, one study demonstrated that
anonaine increased deoxyribose degradation by generated hydroxyl radical. This effect was determined by
thiobarbituric acid method in the incubation medium Fe
-EDTA and H
Molecules 2013, 18 8260
5. Central Nervous System (CNS) Activity
Depression is a common mental disorder all over the World. Several species of Annonaceae are
used in traditional medicine because of their anti-anxiety, anticonvulsant, and tranquilizing properties [2].
Previous study has shown that ()-anonaine has good selectivity for
H-dopamine uptake. The affinity
of ()-anonaine at dopamine D
H-SCH 23390 and D
H-raclopride binding sites was low [19].
()-Anonaine displays dopamine uptake inhibitory properties. 5-HT
receptor plays an important role in
depressive disorders. One study has shown that 1,2-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzoquinoline-
3,8,9,10-tetraol, ()-anonaine, liriodenine, and nornuciferine are the main constituents of the aerial parts of
Annona cherimola [2]. These main constituents produced antidepression-like effects due to the 5-HT
receptor agonistic activity of ()-anonaine and nornuciferine [2]. These results indicate that (−)-anonaine
displays dopamine uptake inhibitory and 5-HT
agonistic activity with anti-depressant activity.
Another study reported that ()-anonaine at 0.05 μM reduced tyrosine hydroxylase (TH) and
aromatic L-amino acid decarboxylase (AADC) activity [13]. In addition, ()-anonaine at 0.05 μM
reduced L-DOPA (50 μM and 100 μM)-induced increase in dopamine content without enhancing
L-DOPA-induced cell death in PC12 cells at 24 h [13].
6. Antiparasitic Activity and Antimicrobial Activity
Plasmodium falciparum is the cause of malaria, a life-threatening disease for thousands of years all
around the World, particularly in Africa. The drug resistance is reducing the therapeutic efficiency for the
treatment malarial and parasite. The in vitro antiplasmodial activity of ()-anonaine was examined [5,32].
One study has reported that (−)-anonaine has antiplasmodial activity against both chloroquine sensitive
D10 strain (IC
values of 25.9 ± 0.2 μM) and chloroquine resistant D12 strain of Plasmodium
falciparum (IC
values of 19.6 ± 1.1 μM) with low cytotoxicity in a Chinese Hamster Ovarian cell
line (CHO) [5]. Another study indicated that ()-anonaine has antiplasmodial activity by in vitro
radiometric Plasmodium falciparum growth inhibition assay (IC
values of 7 ± 2 μM) [32].
The antimicrobial effects of (+)-anonaine have been described in several studies, however, the exact
mechanism of action remains unclear [24,27,28]. Studies have shown that (+)-anonaine has strong
inhibitory activities against Bacillus cereus, Escherichia coli, Micrococcus sp., Staphylococcus aureus
and S. epidermidis and displays anti-fungus activities against Trichophyton rubrum and Microsporum
gypseum growth [24,27,28].
7. Conclusions
With the current information, it is evident that anonaine has interesting pharmacological functions,
including vasorelaxant, antbacterial, antifungal, antioxidative, anticancer and antidepressant effects. In
addition, one approved U.S. patent reports that anonaine also has utility in the prevention and
treatment of gastrointestinal dyskinetic diseases (US patent number US7198804) [33]. However, there
is lack of correlation between in vitro and in vivo studies on the effects of anonaine Toxicity studies
are missing too. For this reason, extensive pharmacological, chemical experiments and metabolism
studies should be undertaken. Last but not least, this article aims to provide useful information about
anonaine for researchers in this field.
Molecules 2013, 18 8261
This investigation was supported by a grant from the Fooyin University.
Conflict of Interest
The authors declare no conflict of interest.
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© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
... (6aS)-1,10-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2, 9- 3.77 (s, 3H). 13 (15), 278 (15), 265 (45), 252 (40), 236 (15), 222 (10). (20), 107 (8). ...
... As mentioned, studies on the insecticidal activity of alkaloids of type BIAs are scarce. It is described that anonaine 5, which is present in members of the plant families Magnoliaceae and Annonaceae, acts as an effective insecticide against aphids with activity comparable to rotenone [45,46]. Similar alkaloids have shown larvicidal and development regulatory activities for the malaria vector Anopheles stephensi [47]. ...
... This receptor belongs to the family of G-protein-coupled receptors (GPCR) and is orthologous to vertebrate β-adrenergic receptors [28,29]. The Octβ3R genetic knockdown produces an arrest in metamorphosis, which demonstrates the importance of this receptor in the metamorphosis process [45]. Moreover, 20-hydroxyecdysone enables an increased activity of tyrosine decarboxylase (TDC), which is the first enzyme responsible for the OA synthesis [33]. ...
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The white champaca ( Magnolia alba ) plant has been reported possess antioxidant and antimicrobial activity. The aim of this study was to investigate the antibacterial activities of n -hexane, ethyl acetate, and methanolic Magnolia alb a flower extracts on Staphylococcus epidermidis and Staphylococcus aureus. In this study, we also determined the secondary metabolites of the extracts by the phytochemical screening assay. The antibacterial activity of the Magnolia alb a flower extracts was determined by the Kirby-Bauer diffusion method. The phytochemical screening assay showed that n -hexane extract contained of flavonoids, terpenoids, and steroid, while the ethyl acetate and methanolic extracts contains of alkaloids, flavonoids, terpenoids, and steroid. The antibacterial activity of the n -hexane, ethyl acetate, and methanolic Magnolia alb a flower extracts was determined at four different concentrations of 5, 10, 20, and 50%. Results indicated that n -hexane extract had no activity against Staphylococcus epidermidis and Staphylococcus aureus . Meanwhile, ethyl acetate and methanolic extracts had antibacterial activities against Staphylococcus epidermidis and Staphylococcus aureus . The diameter zones of inhibition exhibited by the ethyl acetate extract against Staphylococcus epidermidis and Staphylococcus aureus ranged between 10.45 - 21.03 mm and 10.26 - 26.13 mm respectively. Meanwhile, the diameter zones of inhibition exhibited by the methanolic extract against Staphylococcus epidermidis ranged between 11.96 - 18.01 mm and against Staphylococcus aureus ranged between 7.23 - 13.9 mm. In conclusion, the ethyl acetate Magnolia alb a flower extracts gave higher antibacterial activity against Staphylococcus epidermidis and Staphylococcus aureus.
Annona squamosa is most widely distributed in tropical and subtropical region native to tropical America comes under the Annonaceae family. It is a widely used tree having edible fruits called as custard apple which is eatable. Annona squamosa plant also contains 35-42 mg/100 g of vitamin C and significant value of nutrient like thiamine, amino acid, riboflavin, niacin, calcium, potassium and dietary fibers. It also contains the phytoconstituents like diterpenes, alkaloids, cyclopeptides and annonaceous acetogenins proved by phytochemistry investigations. The plant Annona squamosa show a number of pharmacological activities like insecticidal, anticancer, hypoglycemic, antioxidant, antimalarial, analgesic and wound healing activity. The vermicidal effect of leaves is responsible for the treatment of tumors, wounds and other skin infections. A number of alkaloids were isolated from the leaves of plant. Most of them belong to aporphine group of alkaloids. Among all the phytoconstituents an alkaloid Annonaine, plays a vital role for its biological activity. The present review represents the phytochemical constituents, biological action, traditional as well as medicinal uses of Annona squamosa. Sugar apple might be the better explored plant part used in treatment of many disorders and the present critical study will hopefully provide a disease free and healthy life to the human society.
The agroindustrial sector is highly concerned with regards to the reducing the environmental impact of waste from pruning activities (leaves, branches and bark) and from food industry processes (peels and seeds). In this sense, the wastes generated by cherimoya cultivation and processing industries should be contemplated as a valuable source of biologically active compounds. In this work we have studied the bioactivity of alkaloid-rich Annona cherimola Mill. extracts obtain by means of supercritical fluid extraction techniques. The extracts were obtained from the peel and leaves using the following optimal conditions: 100 bar of pressure, 75 ºC and 15% methanol as co-solvent. High antioxidant capacity (5304.23±73.60 to 21705.20±1069.31 μmol Trolox equivalent/100 g), and acetylcholinesterase (IC50 = 87.69±3.42 to 515.02±29.25 g mL⁻¹) and α-glucosidase (IC50 = 1097.76±121.12 to 3206.88±97.06 g mL⁻¹) inhibitory activities were exhibited by both peel and leaf extracts. Larger alkaloid contents were determined by UHPLC-ESI-MS analysis, with peel extracts presenting high concentration of N-trans-feruloyl phenethylamine, while leaf extracts were rich in anonine. This work reports novel data on bioactivity of cherimoya peel and leaves and on their potential as source of bioactive compounds. Keywords: cherimoya by-products, bioactivity, supercritical fluid extraction, alkaloids, experimental design.
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The antioxidant capacity by oxygen radical absorbance capacity (ORAC)-FL method and antimicrobial activity using the broth microdilution method of aporphinoids (liriodenine 1, anonaine 2 and asimilobine 3) and other alkaloids (reticuline 4 and cleistopholine 5) isolated from the bark of Annona salzmannii A. DC. (Annonaceae) were evaluated. For antioxidant activity, the most active alkaloid was asimilobine with ORAC value of 2.09 relative trolox equivalents. For antimicrobial activity, some alkaloids showed significant minimal inhibitory concentration (MIC) values in the range of 25-100 µg mL(-1). The most active compounds were the aporphinoids liriodenine, anonaine and asimilobine, some of them more active than the positive control.
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Phytochemical investigation of the ethanolic extract of leaves of Polyalthia longifolia var. pendula has led to the isolation of seven clerodane diterpenoids and five alkaloids. (-)-14, 15-bisnor-3, 11E-kolavadien-13-one (1), (-)-16-oxocleroda-3,13(14)Edien-15-oic acid (2), (-)-16α-hydroxycleroda- 3,13 (14)Z-dien-15,16-olide (3), (+)-(4→2)-abeo-16(R/S)-2, 13Z-kolavadien-15, 16-olide-3-al (4), (-)-3β, 16α-dihydroxycleroda- 4(18), 13(14)Z-dien-15,16-olide (5), (-)-3, 12E-kolavadien-15-oic acid-16-al (6), (-)-labd-13E-en-8-ol-15-oic acid (7), liriodenine (8), (-)-anonaine (9), (+)-isoboldine (10), (-)-asimilobine (11) and hordenine (12) have been isolated. This is the first report of 1, 6 and 10 from this plant species while 12 is reported for first time from this genus. Clerodane derivatives 1-7 were evaluated for their antimicrobial activity. Diterpene 3 was found to be most potent agent with MIC value of 6.25 μg/mL against Staphylococcus aureus and Sporothrix schenckii.
The cytotoxic effects of four alkaloids, berberine, canadine, anonaine, and antioquine were evaluated using three different cell cultures, a primary culture (rat hepatocytes) and two cell lines (HepG2 and HeLa). Our results indicate that berberine, anonaine, and antioquine possess a significant the cytotoxic effect. In contrast, canadine does not possess cytotoxic effect at concentrations tested here. A molecular modeling study indicates that the quaternary nitrogen, the aromatic polycyclic and planar structure of berberine could be the pharmacophoric patron to produce the cytotoxic effect. In parallel our results demonstrated that canadine possess a significant antioxidant activity. Stereoelectronic aspects of this alkaloid were found to be closely related to those displayed by alpha-tocopherol and its water-soluble analogue trolox. The antioxidant activities of canadine, combined with its low-toxic effect, indicated that the potential of this alkaloid as a novel class of antioxidant agent is very interesting and deserves further research.
Various alkaloids having an isoquinoline skeleton from different species of the Annonaceae, Fumariaceae, and Aristolochiaceae (aporphine, cularine, benzylisoquinoline, and bisbenzylisoquinoline derivatives) were rested for their ability to inhibit in vitro H-3-dopamine uptake by rat striatal synaptosomes which was compared to their activity ac striatal dopamine D-1 H-3-SCH 23390 and D-2 H-3-raclopride binding sites. Except for some aporphine derivatives (anonaine [1], norstephalagine [2], isopiline [3]) and some bisbenzylisoquinoline alkaloids (dimethylgrisabine [27], antioquine [28], obaberine [29], isotetrandrine [30])that displayed affinities of the same order as reference compounds (nomifensine [38], amineptine [39], dexamphetamine [40]), the other tested products had low, or no, affinity on H-3-dopamine uptake. Only anonaine [1] appeared to display a goad selectivity for 3H-dopamine uptake since, in comparison, its affinity ac dopamine D-1 H-3-SCH 23390 and D-2 H-3-raclopride binding sites was low. These data suggest chat ir. could be possible to synthesize anonaine-like products displaying intense dopamine-uptake inhibitory properties, which could lead to a potential antidepressant activity.
Bark of Annona salzmanii D.C. (Annonaceae), used in Brazilian folk medicine, was found to contain four benzylisoquinoline alkaloids, namely reticuline, anonaine, laurelliptine and isoboldine. Only anonaine possesses some antibacterial property while all four alkaloids show some antifungal activity.
Chemical investigation of the CH(2)Cl(2)/CH(3)OH extracts from aerial parts of the Australian plant Goniothalamus australis has resulted in the isolation of two pyridocoumarin alkaloids, goniothalines A (1) and B (2) as well as eight known natural products, aristolactam AII (3), enterocarpam II (4), caldensine (5), sauristolactam (6), (-)-anonaine (7), asimilobine (8), altholactone (9) and (+)-goniofufurone (10). The chemical structures of all compounds were determined by extensive spectroscopic and spectrometric analysis. Methylation of 2 using TMS-diazomethane afforded 1, which unequivocally established that both 1 and 2 possessed a 10-methyl-2H-pyrano[2,3-f]quinolin-2-one skeleton. These pyridocoumarin alkaloids are putatively proposed to arise biosynthetically from an aporphinoid precursor. Compounds 1-10 were evaluated for in vitro antimalarial activity against a chloroquine-sensitive Plasmodium falciparum line (3D7). Sauristolactam (6) and (-)-anonaine (7) exhibited the most potent antiparasitic activity with IC(50) values of 9 and 7μM, respectively.
Aim of the study: The objective of this study was to isolate and characterize the active constituents of the traditionally used antimalarial plant Liriodendron tulipifera by antiplasmodial-assay guided fractionation. Materials and methods: Bark and leaves were extracted with solvents of increasing polarity. Fractions were generated using flash chromatography, counter current chromatography and preparative HPLC and subjected to in vitro antiplasmodial and cytotoxicity assays. Active fractions were subjected to further fractionation until pure compounds were isolated, for which the IC(50) values were calculated. Results and discussion: Six known aporphine alkaloids, asimilobine (1), norushinsunine (2), norglaucine (3), liriodenine (4), anonaine (5) and oxoglaucine (6) were found to be responsible for the antiplasmodial activity of the bark. Leaves yielded two known sesquiterpene lactones, peroxyferolide (7) and lipiferolide (8) with antiplasmodial activity. The antiplasmodial activity of (2) (IC(50)=29.6 μg/mL), (3) (IC(50)=22.0 μg/mL), (6) (IC(50)=9.1 μg/mL), (7) (IC(50)=6.2 μg/mL) and (8) (IC(50)=1.8 μg/mL) are reported for the first time. Conclusion: This work supports the historical use of Liriodendron tulipifera as an antimalarial remedy of the United States and characterizes its antiplasmodial constituents.
Nine isoquinoline alkaloids have been isolated from the bark of Artabotrys maingayi: four noraporphines (norstephalagine [1], 3-hydroxynornuciferine, anonaine, and nornuciferine), one 7-hydroxyaporphine (ushinsunine), three oxoaporphines (atherospermidine [2], liriodenine, and lysicamine), and one protoberberine (discretamine). The effects of the main alkaloids, norstephalagine and atherospermidine, have been studied on the Ca-dependent contractile activity of smooth muscle (uterus). Both norstephalagine and atherospermidine show relaxing activity on rat uterine contractions induced by KCl or rhythmic contractions induced by oxytocin in the presence of Ca, but only atherospermidine can relax oxytocin- or vanadate-induced contractions in a Ca-free medium.
A phytochemical investigation of an alcoholic extract of the petioles of Nelumbo lutea resulted in the identification of the alkaloids N-methylasimilobine, anonaine, and roemerine. The alkaloids nuciferine, armepavine, N-nornuciferine, and N-norarmepavine, previously reported in the whole plant, were also identified.
The scavenging and iron-reducing properties of a series of benzylisoquinolines of natural and synthetic origin have been studied. Bulbocapnine, boldine, glaucine, and stepholidine acted as scavengers of hydroxyl radical in the deoxyribose degradation by Fe3+-EDTA + H2O2. On the contrary, laudanosoline, apomorphine, protopapaverine, anonaine, and tetrahydroberberine increased deoxyribose degradation by a mechanism related to generation of superoxide anion. Only apomorphine had a stimulating effect in the system using citrate instead of ethylenediaminetetraacetic acid (EDTA) as well as in the absence of chelator. Apomorphine also stimulated DNA damage by Cu2+. The iron-ion reducing ability of apomorphine and laudanosoline was confirmed using cytochrome c. Both compounds scavenged peroxyl radicals in an aqueous medium, while in Fe3+-induced microsomal lipid peroxidation apomorphine acted as an inhibitor and laudanosoline stimulated the process. It is suggested that in microsomes the chain-breaking antioxidant properties of apomorphine overcome its possible influence on redox cycling of iron, or prooxidant properties.