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The Pharmacological Activities of (-)-Anonaine

Authors:
  • Tzu Hui Institute of Technology

Abstract and Figures

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 [132]. 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).
N
O
O
H
H
N
O
O
R
2
R
1
H
(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
50
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
2+
channel blocking activity through
voltage-operated channel and α
1
-adrenoceptor blocking activity in isolated rat thoracic aorta [20].
Recently, a study has shown that the affinities of (−)-anonaine for α
1
-adrenoceptor subtypes are in the
order α
1A
α
1D
α
1B
without inhibition phosphodiesterase enzymatic activity [16]. Further, this study
confirms that α
1
-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
2+
/cysteine in rat liver microsomal fractions [25]. The antioxidation
activity of anonaine was also evaulated monitoring inhibition of microsomal lipid peroxidation induced
by Fe
2+
/ascorbate, CCl
4
/NADPH or Fe
3+
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
3+
-EDTA and H
2
O
2
[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
3
H-dopamine uptake. The affinity
of ()-anonaine at dopamine D
1
3
H-SCH 23390 and D
2
3
H-raclopride binding sites was low [19].
()-Anonaine displays dopamine uptake inhibitory properties. 5-HT
1A
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
1A
receptor agonistic activity of ()-anonaine and nornuciferine [2]. These results indicate that (−)-anonaine
displays dopamine uptake inhibitory and 5-HT
1A
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
50
values of 25.9 ± 0.2 μM) and chloroquine resistant D12 strain of Plasmodium
falciparum (IC
50
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
50
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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