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The Pharmacological Activities of (-)-Anonaine

July 2013
Molecules 18(7):8257-63

DOI:10.3390/molecules18078257

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PubMed

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CC BY 4.0

Authors:

Chi-Ming Liu

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

molecules

ISSN 1420-3049

www.mdpi.com/journal/molecules

Review

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: htli9796@ms16.hinet.net (H.-T.L.); mt019@fy.edu.tw (H.-M.W.);

percy283@yahoo.com.tw (H.-L.C.)

* Authors to whom correspondence should be addressed; E-Mails: beagleliu@gmail.com (C.-M.L.);

xx377@fy.edu.tw (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 [1–32]. In

this article, we will focus on describing the pharmacological mechanisms of action of (−)-anonaine.

OPEN ACCESS

Molecules 2013, 18 8258

Figure 1. Chemical structure of (−)-anonaine (A) and anonaine derivative (B).

(A)

(B)

Table 1. Anonaine isolated from plants and its pharmacological effects.

Source

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

＞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

[22].

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

Acknowledgments

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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Antimicrobial Evaluation of Clerodane Diterpenes from Polyalthia Longifolia Var. Pendula

Article

Full-text available

Mar 2009
NAT PROD COMMUN

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.

Antioxidant and cytotoxic activities of canadine: Biological effects and structural aspects

Article

May 2008

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.

Effects of Various Isoquinoline Alkaloids on In Vitro 3 H-Dopamine Uptake by Rat Striatal Synaptosomes

Article

Oct 1995

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.

Antimicrobial activity of benzylisoquinoline alkaloids from Annona salzmanii D.C

Article

Feb 1992
J ETHNOPHARMACOL

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.

Pyridocoumarin, aristolactam and aporphine alkaloids from the Australian rainforest plant Goniothalamus australis

Article

Nov 2012

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.

Antiplasmodial Activity of Aporphine Alkaloids and Sesquiterpene Lactones from Liriodendron tulipifera L

Article

Jan 2011
J ETHNOPHARMACOL

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.

Norstephalagine et Atherospermidine, Deux Aporphines d'Artabotrys maingayi Relaxantes du Muscle Lisse

Article

Jun 2004
J NAT PROD

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.

Alkaloids of Nelumbo latea (Willd.) pers. (Nymphaeaceae)

Article

Nov 1977
J PHARM SCI-US

Steven G. Zelenski

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.

Iron-reducing and free-radical-scavenging properties of apomorphine and some related benzylisoquinolines

Article

Sep 1993
FREE RADICAL BIO MED

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.