Chemical Constituents and Biological Activities of Adenium obesum ( Forsk. ) Roem. et Schult

REVIEW

Chemical Constituents and Biological Activities of Adenium obesum (Forsk. )Roem. et Schult.

by Muhammad Ali Versiani*a), Salman Khalid Ahmeda), Ambreen Ikrama), Syed Tahir Alia), KousarYasmeena), and Shaheen Faizib)

a) Department of Chemistry, Federal Urdu University of Arts, Sciences and Technology, Gulshan-e-IqbalCampus, Karachi-75300, Pakistan (phone: þ92-21-99244141-146, fax: þ92-21-99244272; e-mail:

[email protected])b) H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences,

University of Karachi, Karachi-75270, Pakistan

Contents1. Introduction2. Chemical Constituents

2.1. Cardiac Glycosides2.2. Pregnanes2.3. Triterpenes2.4. Flavonoids2.5. Carbohydrate

3. Biological Activities of Extracts and Pure Compounds3.1. As Biological Pesticides3.2. Pharmacological Activities

3.2.1. Antibacterial Activity3.2.2. Antitumor Activity3.2.3. Antiviral Activity3.2.4. Immunomodulatory Activity3.2.5. Toxicity3.2.6. Other Effects

4. Concluding Remarks

1. Introduction. – Adenium obesum, which is commonly known as desert rose,belongs to the family Apocynaceae, and occurs all over Africa and cultivated in Asia. Itis a xerophyte with thick stem and rather fleshy leaves and used as an ornamental plant.Name of its genus was derived from Aden, the former name of Yemen and nowadaysthe capital town of the country, while the term obesum refers to the swelling of the stemin its basal parts. The plant has several synonyms such as Nerium obesum Forssk., A.arabicum Balf.f., and A. tricholepis Chior, and more than one vernacular names like,Ombo gaduud, Obbe, Karya, and Locombolo based on different dialects used in thearea [1– 9]. Various parts of A. obesum had long been used as traditional medicines forthe treatment of skin problems, wound, ear ache, rhinitis, skin lumps, gonorrhea, andinfectious diseases. It is also a poisonous and toxic plant, and therefore used as a

CHEMISTRY & BIODIVERSITY – Vol. 11 (2014) 171

� 2014 Verlag Helvetica Chimica Acta AG, Z�rich

pesticide [1– 18]. Previous phytochemical studies on this plant revealed that it containstoxic cardiac glycosides (cardenolides), pregnanes, triterpenes, flavonoids, and acarbohydrate [19 – 28]. Some of the cardiac glycosides have antiviral, antitumor, andcytotoxic activities [19] [23] [24]. This review deals with the phytochemical studies onA. obesum and lists all the compounds reported so far (cf. Table 1). The biologicalactivities of the extracts and chemical constituents of this plant are also described (cf.Tables 2 –4).

2. Chemical Constituents. – A. obesum is a rich source of cardiac glycosides, whichexhibit a broad spectrum of biological activities. Fifty chemical constituents have beenisolated from different parts of this plant (Table 1). These compounds belong to theclass of cardenolides, 1 – 40 [19 – 25], pregnanes, 41 – 44 [21] [26], triterpenes, 45 and 46[19] [27], flavonoids, 47– 49 [19] [28], and one carbohydrate 50 [22].

2.1. Cardiac Glycosides. These are the glycosides of C23 steroids (cardenolides) andare the major constituents of this plant. So far, 38 such compounds and twocardenolides (aglycones), 31 and 40, have been isolated from the benzene, CHCl3,AcOEt, and BuOH fractions of the root, stem, leaves, and flowers extracts. Most of thecardiac glycosides are d-cymarosides, d-digitalosides, d-thevetosides, and d-sarmento-sides of digitoxigenin, gitoxigenin, or oleandrigenin (16-acetylgitoxigenin), whileoleandrigenin glycosides predominate over the two. The main glycoside is oleandri-genin b-d-glucopyranosyl-(1!4)-b-d-thevetoside (13) [19 –25]. From the stem of theplant D16-3-acetyldigitoxigenin (16-anhydro-3-acetylgitoxigenin; 40) was isolated as thegenuine compound [20].

2.2. Pregnanes. These are C21 steroids, and four compounds, 41 – 44, belonging to thisclass have been obtained from the root, stem, and leaves of the plant. Pregnanes arealso commonly found in other Apocynaceous and Asclepiadaceous plants [21] [26].

2.3. Triterpenes. Well-known bioactive pentacyclic triterpene betulin (46) [27] [29]and dihydroifflaionic acid (45) have been isolated from the plant [19].

2.4. Flavonoids. Flavonoids isolated were two flavonols, quercetin 3,3’-dimethylether (47) and kaempferol 3-methyl ether (48), and one anthocyanin, cyanindin 3-O-(4-O-a-l-rhamnopyranosyl)-b-d-galactopyranoside (49) [19] [28].

2.5. Carbohydrate. 4-O-b-d-Glucopyranosyl-d-cymaritol (50) was isolated from thepolar fraction of the MeOH extract of stem and root. Its structure was confirmed bycomparison with the authentic sample, which was obtained by reduction ofstrophanthobiose [22].

3. Biological Activities of Extracts and Pure Compounds. – 3.1. As BiologicalPesticides. Since A. obesum contains toxic constituents, its various parts have beenemployed as biological pesticides, and their use was mentioned in the literature toeradicate various pests and for the treatment of trypanosomiasis [4] [6 –8] [10– 15]. Itsextracts are also helpful in snail control (Table 2) [30] [31].

3.2. Pharmacological Activities. 3.2.1. Antibacterial Activity. In view of thetraditional use of A. obesum for the treatment of infectious diseases [4] [18] [36],systematic antimicrobial studies were performed on its various extracts [9] [32] [33].Preliminary antibacterial tests of the aqueous extract of the bark showed stronginhibitory activities against Proteus mirabilis and Pseudomonas aeruginosa, and weak

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activities against Staphylococcus aureus and Escherichia coli [32], while the MeOHextract of the stem bark exhibited higher sensitivity against E. coli, Salmonella typhiand Neisseria gonorrhea as compared to petroleum ether extract [33]. Synergisticactivity of the MeOH extract of the stem bark and oxytetracycline against eightdifferent clinical bacterial isolates has also been determined, which revealed thatGram-positive bacteria exhibited higher sensitivity to synergistic combination thanGram-negative ones [9].

3.2.2. Antitumor Activity. A. obesum is among the plants which are used in folkmedicine for the treatment of tumors [37] [38]. Moreover, there is also a correlationbetween the poisonous character and antitumor activity of the plants [12]. In 1977,Hoffmann and Cole reported that the EtOH extract of the aerial parts of the plantshowed cytotoxic activity against the human epidermoid carcinoma of the nasopharynxtest system. Fractionation and purification of the extract led to the isolation of fiveactive compounds of which four were cardiac glycosides, 1 – 4, and one flavonol, 47,while two constituents, a flavonol, 48, and a triterpene, 45, were found to be inactive[19]. In another work, the cytotoxic activity of the MeOH extract of the aerial parts ofthe plant was evaluated using three human cancer cell lines, namely, breast cancer(MCF7), hepatocellular carcinoma (HEPG2), and cervix cancer (HeLa) cells. Inaddition, human normal melanocyte (HFB4) was used as normal nonmalignant cells.The extract showed strong activity against all the cell lines (Table 3) [39]. Furthermore,it was reported that the aberrant hedgehog (Hh)/GLI signaling pathway causes theformation and progression of a variety of tumors. The MeOH extract of the leaves of A.obesum was found to inhibit Hh/GLI signaling, and bioassay-directed fractionation ofthe extract led to the isolation of 17 cardiac glycosides, 4, 6, 7, 12 –16, 27, 28, and 31 –37,which showed potent activities, especially 12 with the IC50 value of 0.11 mm. Theinhibition of GL-I-related protein expression with 12, 13, 32, 36, and 37 was observed inhuman pancreatic cancer cells (PANC1). These compounds also showed selectivecytotoxicities against two cancer cell lines, with less effect against normal cells(C3 H10T1/2). The structure�activity relationships of these Hh inhibitors disclosedthat the 16b-OH, AcO, and HCOO moieties decreased the activity, however,compound 36 showed inhibitions comparable with that of 4. Moreover, a modificationof aglycone with a C¼C bond also decreased the activity [24]. Importantly, recent



Table 1. Compounds Isolated from Different Parts of A. obesum

No. Compound class and name Parts of plant Ref.

Cardiac glycosides and cardenolides1 Digitoxigenin b-d-cymaroside (somalin) Aerial parts, stem, roots [19] [21]2 Oleandrigenin b-d-cymaroside (hongheloside A) Aerial parts, stem, roots [19] [21]3 Oleandrigenin b-d-digitaloside (16-O-acetylstrospeside, ner-

italoside)Aerial parts, stem, roots [19] [21]

4 Digitoxigenin b-d-thevetoside (honghelin) Aerial parts, stem, roots [19] [21] [24]5 D16-Digitoxigenin b-d-cymaroside (D16-somalin) Stem, roots [21]6 Oleandrigenin b-d-thevetoside (obeside B) Leaves, roots [21] [24]7 Gitoxigenin-b-d-thevetoside (obeside C) Leaves, stem, roots [21] [24]8 D16-Digitoxigenin b-d-thevetoside (obeside D) Stem, roots [21]9 Gitoxigenin b-d-digitaloside (strospeside) Roots [21]

10 Oleandrigenin glucoside Stem, roots [21]11 Oleandrigenin b-d-glucopyranosyl-(1!4)-b-d-cymaroside

(hongheloside C )Stem, roots [21]

12 Digitoxigenin b-d-glucopyranosyl-(1!4)-b-d-thevetoside(obebioside A)

Stem, roots [21] [24]

13 Oleandrigenin b-d-glucopyranosyl-(1!4)-b-d-thevetoside(obebioside B)

Stem, roots [21] [24]

14 Gitoxigenin b-d-glucopyranosyl-(1!4)-b-d-thevetoside(obebioside C)

Roots [21] [24]

15 D16-Digitoxigenin b-d-glucopyranosyl-(1!4)-b-d-theveto-side (obebioside D)

Leaves, stem, roots [21] [24]

16 Digitoxigenin b-d-glucopyranosyl-(1!4)-b-d-digitalose(odorobioside G)

Roots [21]

17 Oleandrigenin b-d-glucopyranosyl-(1!4)-b-d-digitalose Aerial parts, stem, roots [21] [23]18 Gitoxigenin b-d-glucopyranosyl-(1!4)-b-d-digitalose Roots [21]19 D16-Digitoxigenin b-d-glucopyranosyl-(1!4)-b-d-digitalose Stem, roots [21]20 Digitoxigenin b-gentiobiosyl b-d-cymaroside (echujin) Stem, roots [21]21 Oleandrigenin b-gentiobiosyl b-d-cymaroside (honghelotrio-

side A)Stem, roots [21]

22 D16-Digitoxigenin b-gentiobiosyl b-d-cymaroside (D16-echu-jin)

Roots [21]

23 Digitoxigenin b-gentiobiosyl(1!4)-b-thevotoside (obetrio-side A)

Stem, roots [21]

24 Oleandrigenin b-gentiobiosyl(1!4)-b-d-thevotoside (obe-trioside B)

Stem, roots [21]

25 Digitoxigenin b-gentiobiosyl-b-d-digitaloside (odoroside G) Stem, roots [21]26 Oleandrigenin b-gentiobiosyl-b-d-digitaloside (16-O-acetyl-

neogitostin)Stem, roots [21]

27 Oleandrigenin 2’-O-acetyl b-d-thevetoside (2’-O-acetylobe-side B)

Roots, leaves [22] [24]

28 Digitoxigenin 2’-O-acetyl b-d-thevetoside (2’-O-acetylhong-helin)

Roots, leaves [22] [24]

29 Oleandrigenin b-d-glucopyranosyl-(1!4)-2’-O-acetyl-b-d-thevetoside

Stem, roots [22]

30 Digitoxigenin b-d-glucopyranosyl-(1!4)-2’-O-acetyl-b-d-thevetoside

Stem, roots [22]

31 Digitoxigenin (3b,14-dihydroxy-5b-card-20(22)-enolide) Leaves [24]32 Gitoxigenin b-d-sarmentoside Leaves [24]33 16-Formylgitoxigenin b-d-sarmentoside Leaves [24]

studies revealed that 3b-O-(b-d-monoglycosidic) compounds possessing the cardeno-lide structure with or without an AcO group at C(16) are the most effective cytotoxiccompounds isolated from Nerium oleander [40]. Two pregnanes, 41 and 43, possessing a16-en-20-one system, were also isolated from the MeOH extract of the leaves of A.obesum, and they exhibited cytotoxic activities against murine leukemia P388/S cells.The 16,17-dihydro derivatives 42 and 44 were inactive (Table 4) [26].


Table 1 (cont.)

No. Compound class and name Parts of plant Ref.

34 Oleandrigenin b-d-sarmentoside Leaves [24]35 Digitoxigenin b-d-sarmentoside Leaves [24]36 16-Formylgitoxigenin b-d-thevetoside Leaves [24]37 Digitoxigenin b-d-digitaloside (odoroside H) Leaves [24]38 Gitoxigenin b-d-glucopyranosyl-(1!4)-b-d-thevetoside Stem, roots [21]39 Canariengenin b-d-glucopyranosyl-(1!4)-b-d-thevetoside Leaves [24]40 D16-3-Acetyldigitoxigenin (16-anhydro-3-acetylgitoxigenin) Stem [20]

Pregnanes41 12b-Hydroxypregna-4,6,16-triene-3,20-dione (neridienone A) Stem, roots, leaves [21] [26]42 12b-Hydroxypregna-4,6-diene-3,20-dione

(16,17-dihydroneridienone A)Stem, roots, leaves [21] [26]

43 12b-Hydroxpregna-4,16-diene-3,20-dione Leaves [26]44 12b-Hydroxypregn-4-ene-3,20-dione Leaves [26]

Triterpenoids45 Dihydroifflaionic acid Aerial parts [19]46 Lup-20(29)-ene-3,28-diol (betulin) Stem bark [27]

Flavonoids47 Quercetin 3,3’-dimethyl ether Aerial parts [19]48 Kaempferol 3-methyl ether Aerial parts [19]49 Cyanidin 3-O-(4-O-a-l-rhamnosyloxy)-b-d-galactopyrano-

sideFlower [27]

Carbohydrate50 4-O-b-d-Glucopyranosyl-d-cymaritol Stem, roots [22]

Table 2. Biological Activities of Extracts Obtained from Different Parts of A. obesum

S. No. Activity Part of plant Extract Ref.

1 Molluscicidal Leaves MeOH [30]Stem MeOH, Benzene [31]

2 Locusticidal Roots H2O, H2O/EtOH [14]3 Antibacterial Bark Aqueous [32] [18]

Stem bark MeOH [9] [33]Petroleum ether [9] [33]

4 Cytotoxic Stem, flower, leaves EtOH [19] [34]5 Antiviral Aerial part MeOH [23] [34]6 Immunomodulatory – CH2Cl2 [35]

MeOH25% EtOH

3.2.3. Antiviral Activity. The MeOH extract of the aerial parts of the plant showedantiviral activity against influenza virus A/PR/8/34 (H1N1) to the extent of 99.3%inhibition at the concentration of 10 mg/ml, while the CHCl3 fraction of the extractdisplayed the highest antiviral activity and lower toxicity at a concentration of 5 mg/ml.Cardiac glycoside 17 was isolated from the CHCl3 extract as the antiviral principle, andit led to the reduction of virus titre by 69.3% inhibition at a concentration of 1 mg/ml(IC50 0.86 mg/ml). Compound 17 had a considerable cytotoxicity against MDK cell atconcentrations of higher than 2.5 mg/ml (CC50 1.53 mg/ml) [23]. In an earlierinvestigation of antiviral activity of the plant, its various extracts were found to betoxic to HeLa cells (Table 2) [34].

3.2.4. Immunomodulatory Activity. The in vitro immunomodulatory effects ofdifferent extracts of A. obesum have also been investigated. These extracts exertedenhancing effects in a concentration-dependent manner on immune cells from threedifferent strains of mice. Its EtOH extract showed measurable enhancements of B andT cell proliferation. A. obesum could also enhance the LPS-induced synthesis of IgM bylymphocytes from the NMRI mouse strain. Its extracts were able to enhance the IgMantibody production without the addition of LPS. The CH2Cl2 fraction was inhibitory tolymphocytes at nontoxic concentrations (Table 2) [35].

3.2.5. Toxicity. A. obesum is also known to be a poisonous plant, and theconsumption of roots and stem-bark extracts were found to cause hyperthermia,hyperventilation, collapse, and atony leading to death, when tested against Musmusculus [16] [41]. The LD50 values within 24 h were found to be 9.69 and 22.10 g plant/kg body weight, for CH2Cl2 and H2O extracts of the root, respectively. No acutemortality was recorded in case of the MeOH extract of the roots, nor for any of the


Table 3. Cytotoxic Activities (IC50 [mg/ml]) of MeOH Extract of A. obesum and Its Fractions [39]

Fraction Cell linesa)

MCF 7 HFB4 HEPG2 HeLa

MeOH (extract) 11.6 5.2 18.7 6.9Petroleum ether 12.7 21.9 23.1 13.7CHCl3 3.15 7.01 4.78 3.15BuOH 3.56 3.96 4.17 3.15

a) Breast cancer (MCF 7), hepatocellular carcinoma (HEPG2), cervix cancer (HeLa), and humannormal melanocyte (HFB4).

Table 4. Cytotoxic Activities (IC50 [mg/ml]) of Compounds against Murine Leukemia Cancer Cell Lines[26]

Compound P388/S P388/ADR P388/VCR

41 2.75 2.0 2.042 1.25 0.9 0.943 >25 >25 20.044 >25 >25 12.5

three extracts of the bark [41]. The CH2Cl2, MeOH, and 25% EtOH extracts wereshown to be toxic against HeLa cell cultures at concentrations lower than 1 mg/ml (0.12,0.4, and 0.4 mg/ml, resp.) [34], on the other hand, they did not show brine shrimptoxicity [10].

3.2.6. Other Effects. The in vitro activity of the MeOH extract of A. obesum was alsoevaluated against Plasmodium falciparum, Trypanosoma brucei brucei, T. cruzi, andLeishmania infantum [42] [43]. In a DPPH antioxidant assay, compound 49 showedweak activity [28]. Moreover, its latex was reported as cordiotonic [44]. A cosmeticcomposition has also been prepared and patented, containing A. obesum extract. Thiscomposition can be used to strengthen the cutaneous barrier, to reinforce the cohesionof the dermal – epidermal junction, and to prevent or delay the effects of skin aging[45].

4. Concluding Remarks. – Adenium obesum, an ornamental and poisonous plant,occurs from Tanzania to Ethiopia, Somalia, and the Arabian Peninsula, and it is alsocultivated in Asia usually in Indo-Pakistan subcontinent, Thailand, and Philippines. Ithas a long history of its use as a medicinal plant in Africa, for treating infectious andvenereal diseases, and tumors. So far, 50 chemical constituents were isolated from thedifferent parts of the plant. Its extracts and isolated compounds have been reported tohave diverse biological features, such as antitumor, antimicrobial, anti-influenza,molluscicidal, locusticidal, and antiviral activities, including potential immunomodu-latory and cardiotonic activities. A. obesum extract has also been used in cosmetics. Itwas noted that much of the chemical and biological investigations on this plant havebeen focused on its moderately polar constituents. The nonpolar petroleum ether andhighly polar aqueous fractions of the extracts received little or no attention, and manyof highly nonpolar and polar constituents are still undiscovered. No work was carriedout on the essential oils of any part of the plant, as well as no GC, GC/MS studies wereconducted. Phytochemical investigation on this plant revealed that it is rich in cardiacglycosides which have cytotoxic and antitumor activities; however, no systematic studywas attempted regarding the cardiovascular properties of the extracts, fractions, andpure compounds. This review shows that various parts of A. obesum possess promisingbiological activities, while no in-depth phytochemical and pharmacological studies havebeen carried out, and it is necessary to further isolate and evaluate all of its chemicalconstituents systematically, employing bioassay-guided fractionation procedures forthe isolation of active principles, and to understand mechanisms of active components.The information presented in this review might help the scientific community to carryout further research on this plant with respect to its use in pharmaceutical,agrochemical, and cosmetics industries.

This work was supported by Higher Education Commission Government of Pakistan (P. No. 20-1-1480/R&D/09).


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Received July 21, 2012


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Chemical Constituents and Biological Activities of Adenium obesum ( Forsk. ) Roem. et Schult