Dillenia species: A review of the traditional uses, active constituents and pharmacological properties from pre-clinical studies

Abstract

Context: Dillenia (Dilleniaceae) is a genus of about 100 species of flowering plants in tropical and subtropical trees of Southern Asia, Australasia, and the Indian Ocean Islands. Until now, only eight Dillenia species have been reported to be used traditionally in different countries for various medical purposes. Out of eight species, D. pentagyna (Roxb), D. indica (Linn.) and D. suffruticosa (Griffith Ex. Hook. F. & Thomsom Martelli) have been reported to be used to treat cancerous growth.

Objective: The present review explored and provided information on the therapeutic potential of Dillenia species.

Methods: Comprehensive and relevant literature on the therapeutic potential of Dillenia species was gathered through electronic databases including Google Scholar, Scopus, PubMed, and books, without limiting the dates of publication.

Results and conclusion: The review demonstrated that only a few Dillenia species have been proven scientifically for their therapeutic potential in pre-clinical studies, including D. pentagyna, D. indica, D. papuana (Martelli), D. meliosmifolia (Hook. F. Ex. Thomsom) and D. suffruticosa (Griffith Ex Hook. F. & Thomson). A few species of Dillenia have undergone isolation and characterization of compounds with lupeol and betulinic acids having tremendous pharmacological potential. Dillenia species warrant further studies on their therapeutic potential, which may eventually lead to the development of new drug candidates for treatment of various diseases.

• Active constituent(s)
• Dilleniaceae
• ethnomedicinal
• pharmacological

Introduction

Despite the increased amount of modern drugs in the pharmaceutical market, medicinal herbs have maintained their popularity as an alternative medicine due to low cost, their effectiveness, historical, cultural, and religious preferences (Alzweiri et al., 2011; Andel & Westers, 2010). The World Health Organization (WHO) estimated that approximately 80% of people in developing countries rely mainly on natural products for their primary healthcare (Azaizeh et al., 2003; Mukherjee & Wahil, 2006). The global market for medicinal herbs showed an upward trend from US$23 billion in 2002 (Crabb, 2004) to approximately US$83 billion in 2008 (WHO, 2011). Even though drug discovery from natural products has been historically and intensively carried out since World War 1, surprisingly only less than 10% from approximately 250 000 species of world biodiversity have been tested for medicinal properties (McChesney et al., 2007; Verpoorte, 1998), leaving many more waiting for discovery.

Dilleniaceae is a family of evergreen shrubs, sub-shrubs, or climbers comprising about 12 genera including Acrotrema, Curatella, Davilla, Didesmandra, Dillenia, Doliocarpus, Hibbertia, Pachynema, Pinzona, Schumacheria, Tetracera and Traxilisa. It is native to tropical and warm-temperate regions such as Australia and Asia. Most of the members of Dilleniaceae consist of woody plants including Dillenia. The leaves are simple, wide, well-developed, and alternate. The stipules are absent or wing-like. The flowers are mainly bisexual or rarely unisexual with colorful petal (white, yellow, or red) and visible reproductive component. The fruit is follicle or berrylike, sometimes edible, either dehiscent or indehiscent, and enclosed with fleshy calyx (Kerrigan et al., 2011).

Named after Johann Jacob Dillenius, a German botanist, Dillenia is a genus of about 100 species of flowering plants in tropical and subtropical trees of Southern Asia, Australasia, and the Indian Ocean Islands. However, up to now, only eight of Dillenia species have been reported to be used traditionally for different medical purposes including treatment of cancerous growth. As such, the present review explored and provided information on therapeutic potentials of Dillenia species.

Selection of studies for review

Comprehensive and relevant literature on the therapeutic potential of Dillenia species was gathered through electronic databases including Google Scholar, Scopus, PubMed, and books without limiting the dates of publication. The following combined terms were used: “(ethnomedicinal OR traditional properties) AND (pharmacological properties) AND (active constituents) AND Dillenia species”. Other publications were identified from the list of references from the above databases.

Ethnopharmacological uses of Dillenia species

Among the Dillenia species, only a few have been reported to be used traditionally in different countries for different medical purposes (Table 1).

Table 1. Ethno-medicinal properties of different species of Dillenia.

Country	Species	Plant part	Ethno-medicinal practice	Reference
India	Dillenia pentagyna	Bark	Treatment for cuts and burns	Rao et al. (2003)
			Treatment for cancer	Sharma et al. (2001)
			Pain relief	Ghimire and Bastakoti (2009)
			Tonic for women after delivery	Dubey et al. (2009)
			Treatment for diabetes, diarrhea and dysentery	Dubey et al. (2009)
		Leaf	Treatment for chest pain	Sharma et al. (2001)
			Treatment for wounds	Prasad et al. (2008) and Sharma et al. (2001)
			Treatment for cancer	Dubey et al. (2009)
		Fruit	Dropsy therapy	Nyman et al. (1998)
			Body pain relief	Dubey et al. (2009)
	Dillenia indica	Fruit	Laxative	Prasad et al. (2008)
			Abdominal pain relief	Kritikar and Basu (2003)
			Increase appetite or treatment for weakness	Poonam and Singh (2009)
			As cosmetic to prevent dandruff	Saikia et al. (2006)
			Treatment for diabetes mellitus	Tag et al. (2012)
India	Dillenia indica	Fruit	Treatment for jaundice	Rai and Lalramnghinglove (2010)
			Treatment for fever and fatigue	Shome et al. (1980)
		Leaf	Treatment for fever, cough and constipation	Poonam and Singh (2009)
			Treatment for diabetes mellitus	Tarak et al. (2011) and Sood et al. (2005)
		Flower	Treatment for dysentery	Purkayastha et al. (2005)
		Mixed of fruit, bark, and leaf	Treatment of cancerous growth and diarrhea	Sharma et al. (2001)
	Dillenia andamanica	Stem bark	Treatment for leucoderma (skin diseases)	Prasad et al. (2008)
Indonesia	Dillenia meliosmifolia	Root	Treatment for food poisoning	Grosvenor et al. (1995a)
Thailand	Dillenia parviflora	Bark	Treatment for diarrhea	Srithi et al. (2009)
Vietnam	Dillenia Indica	Leaf	Treatment for intestinal diseases	Dung and Loi (1991)
			Treatment for malaria and malaria-like symptoms	Nguyen-Pouplin et al. (2007)
Malaysia	Dillenia suffruticosa	Fruit	Treatment for cancerous growth	Ahmad and Holdsworth (1995)
	Dillenia suffruticosa	Leaf	Promote wound healing, treatment for fever	Mat Salleh and Latiff (2002)
			Relief rheumatism	Hanum and Hamzah (1999)
Papua New Guinea	Dillenia papuana	Not stated	Treatment of asthma, chest pain and support in child delivery	Holdsworth (1987) and Balun and Holdsworth (1988)
Laos	Dillenia ovata	Bark	Treatment for itches, rash and wound	De-Boer et al. (2012)

Dillenia suffruticosa Griffith Ex. Hook. F. & Thomson Martelli

D. suffruticosa is a medium-sized tree up to 6 m in height, with 8–10 cm large five thin petals of yellow flower with no scent and nectar, and large oval leaves (15–35 cm). The pink star-shaped fruit capsule is fully expended long before sunrise, displaying its purple seeds with fleshy bright red aril (Corners, 1997). It grows naturally in the moist and evergreen forest from West Malaysia to Philippines, Indonesia, and Brunei Darussalam. In Peninsular Malaysia, the large rooted leaves are used widely to wrap “Tempe” or fermented soybean, one of the local foods. It is planted in the Heritage Garden of Badan Warisan Malaysia as an ornamental plant together with D. excelsa (Jalaluddin, 2009).

Locally known as “Simpoh air”, D. suffruticosa leaves are traditionally used by the Temuan Tribe of Ayer Hitam Forest, Selangor to relieve rheumatism (Hanum & Hamzah, 1999). The leaves are also used to promote wound healing and to treat fever (Mat-Salleh & Latiff, 2002), whereas the fruit is used for the treatment of cancerous growth among Rungus people of Kudat, Sabah (Ahmad & Holdsworth, 1995). The name “Simpoh” is derived from the hissing sound made when the tree trunk is cut (Corners, 1988).

Dillenia indica Linn.

D. indica or elephant apple is a medium-sized tree native to the forests of India, and the Indo-Malaysian region up to Tropical Australia. It is an evergreen tree, up to 15 m in height, consisting of five white petals and yellow stamen (flowers) (15–20 cm diameter), 15–36 cm large oval green leaves and 5–12 cm of edible large and hard greenish yellow fruits (CSIR, 1952; Huxley, 1992). The fruits (calyx) of D. indica are well known by the Indian communities as a flavoring agent for curries, and preparation of jam and jelly (CSIR, 1952).

Shome et al. (1980) reported the medicinal properties of the fruit juices of D. indica as a cooling beverage to treat fever and to relieve fatigue. Although mainly a source of food for elephant and monkey, the ripped fruits are taken orally to increase appetite and overcome weakness (Poonam & Singh, 2009), as laxative (Prasad et al., 2008) and medication for abdominal pain (Kritikar & Basu, 2003). Native communities in Mizoram, India, have used the fruit of the plant as a remedy for jaundice (Rai & Lalramnghinglove, 2010).

Recently, Tag et al. (2012) documented the use of the fruit of D. indica as a treatment for diabetes mellitus among the Khamptis traditional healers (“Chau yau”) in Arunachal Himalaya, Northeast of India. In contrast, the rural community of the Dhemaji district of Assam, Northeast India, use the leaves of the plant, locally known as “Outenga”, for the same purposes (treatment of diabetes) (Sood et al., 2005; Tarak et al., 2011). Besides that, the mucilaginous substance from the fruit is traditionally used as a cosmetic product to reduce dandruff among Assamese people in the North East of India (Saikia et al., 2006). The ethnic communities of Dibru-Saikhowa Biosphere Reserve of Northeast India were reported to use the decoction of the floral body of D. indica as a treatment for dysentery (Purkayastha et al., 2005).

Furthermore, the leaves juice (mixed with sugar) and decoction of the leaves of D. indica are taken orally to treat fever and cough, and constipation, among the Taungya community in Terai Arc Landscape, India (Poonam & Singh, 2009). The juices from the leaves, bark, and fruits are mixed together and taken orally (2–5 times daily) as a treatment for cancer and diarrhea among the native people of Mizoram, India (Sharma et al., 2001). In South Vietnam, the leaves of D. indica, locally known as “So ba” are traditionally used to treat intestinal diseases (Dung & Loi, 1991) and malaria-like symptoms (Nguyen-Pouplin et al., 2007).

Dillenia pentagyna Roxb.

Commonly known as Nepali elephant apple, D. pentagyna, is a large deciduous evergreen tree that grows up to 20 m in height with grayish white bark. It consists of five fragrant yellowish petals of flower, which arise from the nodes of fallen leaves. The leaves are broadly oblanceolate and crowded at the end of branches. The fruit is globosely shaped and acidic (Dubey et al., 2009). As one of the native plants in India, many parts of the plant have been documented to be used traditionally for medicinal purposes. For instance, the root and fruit of the plant are consumed for body pain relief (Dubey et al., 2009) and dropsy therapy (Nyman et al., 1998), respectively. Locally known as “Sambu”, the leaf juice is applied externally for its wound healing properties among the native people in the North Andaman, India (Prasad et al., 2008; Sharma et al., 2001).

Sharma et al. (2001) reported that decoction of the leaves is taken orally (2–3 times daily) for the treatment of chest pain. Dubey et al. (2009) reported that the leaf powder (5–10 g) is taken daily among women with breast cancer. Other than that, decoction of the bark is taken orally (3–5 times daily) as a medication for cancer (Sharma et al., 2001), and cuts and burns (Rao et al., 2003). The bark decoction is also taken orally as a tonic and used for bath among women after delivery (Dubey et al., 2009). Ghimire and Bastakoti (2009) reported the pain relief properties of the bark juice of the plant taken orally by the people of the Tharus of Nawalparasi District, Nepal. Also, the bark powder is used traditionally as a treatment for diabetes, diarrhea, and dysentery (Dubey et al., 2009). In Central Kerala, India, besides for medicinal purposes, the bark of plant is used for charcoal production (Kumar, 2011).

Dillenia andamanica C.E. Parkinson

Locally known as “Chalta”, the stem bark of D. andamanica, is used to treat leucoderma (skin diseases) among native people of North Andaman Islands, India (Prasad et al., 2008).

Dillenia meliosmifolia Hook. F. Ex Thomson

Commonly known as “Simpuh bukit”, D. meliosmifolia or D. sumatrana, is a native plant of Sumatra Indonesia, Malaysia, and Northern Borneo. It is a medium-sized tree that can grow up to 20 m in height, consisting of reddish brown bark, yellow or orange-yellow hairy fruit and yellow petal flowers (Kochummen, 1972). According to Grosvenor et al. (1995a), the native people of Riau Province, Sumatera Indonesia, have been consuming the decoction of D. meliosmifolia root as a medication for food poisoning.

Dillenia parviflora Griff.

D. parviflora is a deciduous tree that can grow up to 40 m in height with five thick yellow petals. It can be found abundantly in Myanmar and Thailand. Locally known as “Piao Kub”, the decoction of the bark is taken orally for the treatment of diarrhea among Mien people in Nan province, Thailand (Srithi et al., 2009).

Dillenia papuana Martelli

D. papuana is a large canopy tree that grows up to 37 m in height with reddish brown bark. Abundantly used as commercial hardwood, the plant is native to Indonesia and Papua New Guinea. It consists of bisexual yellowish flower and 25–35 mm long of fruits. D. papuana is used traditionally among native people in Marobe Province, Papua New Guinea, for the treatment of asthma, chest pain, and support in child delivery (Balun & Holdsworth, 1988; Holdsworth, 1987).

Dillenia ovata Wallich Ex. Hook. F. & Thomson

Commonly known as “Simpur minyak” (Indonesia), “Simpuh beludu” (Malaysia) and “Tonokkot” (Thailand), D. ovata, is a medium-sized tree native to Peninsular Malaysia, Indonesia, and Thailand. The plant can grow up to 30 m in height, consisting of five yellow petals (16 cm in diameter), green flesh indehiscent capsule and leaves that are ovate to elliptical in shape. In fact the name ovata refers to the egg shape of the leaf (Lemmens et al., 1995). Recently, De-Boer et al. (2012) documented that native people in Laos, mainly Brou and Saek, have applied externally the bark decoction of D. ovata to treat infected skin due to itches, rashes, and wounds. Alternatively, the poultice of dry bark is applied on the skin for the same purpose.

Pharmacological properties of Dillenia species

Up to now, only five of the Dillenia species, namely, D. pentagyna, D. indica, D. papuana, D. meliosmifolia, and D. suffruticosa, have been scientifically reported to have pharmacological potential based on pre-clinical (in vitro and in vivo) studies (Table 2).

Table 2. Pharmacological properties of different species of Dillenia.

Species	Plant part	Pharmacological property	Reference
Dillenia indica	Fruit	Antioxidant	Das et al. (2012); Singh et al. (2012); Abdille et al. (2005)
		Antitumor	Kumar et al. (2010)
	Leaf	Antimicrobial	Apu et al. (2010)
		Anti-inflammatory	Yeshwante et al. (2009)
		Anti-diabetic and cholesterol lowering	Kumar et al. (2011a,b,c)
		Antimalarial	Nguyen-Pouplin et al. (2007)
Dillenia pentagyna	Stem bark	Antitumor	Rosangkima and Prasad (2004)
		Antimicrobial	Haque et al. (2008)
	Fruit	Inhibit angiotensin-converting enzyme (ACE)	Nyman et al. (1998)
Dillenia papuana	Leaf and stem	Antimicrobial	Nick et al. (1995b)
Dillenia meliosmifolia	Leaf	Antimicrobial	Grosvenor et al. (1995b)
Dillenia suffruticosa	Leaf	Antimicrobial	Johnny et al. (2010) and Wiart et al. (2004)
		Antivirus of dengue	Muliawan (2008)
		Antitumor	Armania et al. (2013a,b), Husain (2010), and Said (2010)
		Antioxidant	Armania et al. (2013a)

Anticaner properties

D. suffruticosa, D. indica, and D. pentagyna have been scientifically evaluated for their in vitro and in vivo anticancer activities. Recently, Kumar et al. (2010) reported the cytotoxicity of methanol extract of D. indica fruits towards human leukemic cell lines (U937, HL60, and K562), which was likely due to induction of apoptosis. Further sequential solvent extraction (based on polarity) of the methanol extract showed that the ethyl acetate (EtOAc) fraction was the most cytotoxic among others (n-butanol and aqueous). Elucidation of betulinic acid as the major compound in the EtOAc fraction showed that it was likely responsible for the anti-leukemic properties of the fruits of D. indica. The finding was further supported by quantification of the highest amount of betulinic acid in the respective fraction (EtOAc) as compared to others. In addition, from the acute toxicity analysis, the methanol extract (1.5 g/kg) (in Swiss albino male mice for 24 h) was found to be non-toxic with absence of mortality (Kumar et al., 2010).

Other than D. indica, the root methanol extract of D. suffruticosa was found to be the most cytotoxic toward colon cancer (HT29), estrogen receptor positive and negative breast carcinoma (MCF-7 and MDA-MB-231), ovarian carcinoma (CaOV3), lung carcinoma (A549), and cervical carcinoma (HeLa) cell lines compared to other parts of the plant including the flower, leaf, and fruit. The methanol extract was more cytotoxic compared to the water extract. Dichloromethane (DCM) and EtOAc extracts obtained from sequential solvent extraction (based on polarity) of the root of D. suffruticosa exhibited higher cytotoxic activity (p < 0.05) to the selected cancer cells (HeLa, MCF-7, MDA-MB-231, A549, HT29, and CaOV3) compared to other extracts (Armania et al., 2013a).

The active fractions designated as D/F4, D/F5, and EA/P2, derived from the chromatographic fractionation of D. suffruticosa extracts (DCM and EtOAc), were found to be the most cytotoxic against selected cancer cells (MCF-7, MDA-MB-231, CaOV3, HeLa, and A549) among others. Cytotoxicity of the active fractions of D. suffruticosa extract toward the breast cancer cell lines was postulated to be due to induction of apoptosis and G₂/M cell cycle arrest (Armania et al., 2013b). Recently, Tor et al. (2014) suggest that the induction of apoptosis by D. suffruticosa in MCF-7 cell lines was by modulating numerous genes including SOD1, SOD2, NF-?B, p53, p38 MAPK, and catalase that manly involve in oxidative stress pathway. In addition, root aqueous extract of D. suffruticosa exhibited anticaner properties in azoxymethane (AOM)-induced colon cancer in male Sprague Dawley rats (Husain, 2010). Besides that, the aqueous extract also suppressed the progression of cervical cancer in diethylstilbestrol (DES)-induced cervical carcinogenesis in female Balb/c mice model (Said, 2010).

Rosangkima and Prasad (2004) documented the antitumor properties of the methanol extract of stem bark of D. pentagyna against murine ascites Dalton’s lymphoma (DL) via reduction of glutathione level. Nick et al. (1995a) reported that the methanol extract of D. papuana exhibited the highest inhibitory activities toward two protein kinases, namely, protein kinase C (PKC) and tyrosine-specific protein kinase of epidermal growth factor (PTK), among others (petroleum ether and DCM extract). Inhibition of both the enzymes is believed to inhibit the promotion of tumors as these enzymes play an important role in cell growth and differentiation (Nick et al., 1995a).

Anti-diabetic and cholesterol lowering properties

Kumar et al. (2011a) have reported the anti-diabetic properties of petroleum ether extract of the leaves of D. indica in alloxan-induced diabetic Wistar rats. Daily oral administration of 250 and 500 mg/kg of the extract significantly reduced the blood glucose level compared to untreated group. The reduction of the glucose level was in accordance with increase in serum insulin and increase in the body weight. Besides that, Kumar et al. (2011a) also reported the cholesterol-lowering potential of the extract. It has shown to reduce the cholesterol and triglyceride level in diabetic rats after oral administration with the extract for 21 d. The anti-diabetic and antihyperlipidemic effect of methanol extract of D. indica was also reported in STZ-induced diabetic rats (Kumar et al., 2011b).

Subsequently, further studies were conducted by the same group of researchers (Kumar et al., 2011c) on the antidiabetic and cholesterol-lowering properties of the bioactive fraction derived from solvent–solvent extraction of methanol extract of D. indica. Oral administration of 400 mg/kg of EtOAc fraction showed prominent antidiabetic effect in Type-1 and Type-2 diabetic models in Wistar rats induced with single intraperitoneal injection of streptozotocin (STZ). The author also reported the reduction of serum cholesterol and triglycerides level in diabetic rats treated with the EtOAc fraction.

Anti-oxidant properties

Abdille et al. (2005) have reported the antioxidant activities of fruit extracts (methanol, EtOAc, and aqueous extract) of D. indica in in vitro models including β-carotene-linoleate model system, 2,2-diphenyl-2-picrylhydrazyl radical (DPPH) scavenging assay, and phosphomolybdenum method. The methanol extract exhibited the highest anti-oxidant activities among others in the following descending order: methanol > EtOAc > aqueous. The phenolics present in the extracts are believed to be responsible for the anti-oxidant activities. The finding was in agreement with Das et al. (2012) and Singh et al. (2012).

Other than D. indica, methanol extract of root of D. suffruticosa exhibited the highest anti-oxidant activities among others (hexane, DCM, and EtOAc extract) as determined by DPPH, 2′2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), ferric ions (Fe³⁺) reducing antioxidant power (FRAP) and β-carotene bleaching assays. The anti-oxidant activity significantly correlated (p < 0.05) with total phenolic content (TPC), suggesting the important contribution of phenolic compounds to the anti-oxidant activity (Armania et al., 2013a).

Anti-microbial properties

Up to now, many plants from Dillenia species have been documented to possess antimicrobial properties. For instance, Nick et al. (1995a) reported that petroleum ether extract of D. papuana exhibited the highest antimicrobial properties against Gram positive (Escherichia coli) and Gram negative bacteria (Bacillus subtilis and Micrococcus luteus) among others (petroleum ether, DCM and methanol extract). Grosvenor et al. (1995b) reported the anti-microbial properties of the methanol extract of D. meliosmifolia leaves against Saccharomyces cerevisiae.

Wiart et al. (2004) reported the antimicrobial and antifungal properties of methanol extract of D. suffruticosa leaves toward Bacillus cereus, B. subtilis, Candida albicans, and Pseudomonas aeruginosa. Recently, Johnny et al. (2010) demonstrated the antifungal properties of acetone extract of the leaves in inhibiting the radial growth of Colletotrichum gloeosporioides. Apu et al. (2010) reported the antimicrobial properties of leaves extract of D. indica against Gram positive (B. cereus, Bacillus megaterium, B. subtilis, Staphylococcus aureus, and Sarcina lutea) and Gram negative bacteria (E. coli, P. aeruginosa, Salmonella paratyphi, Salmonella typhi, Shigella boydii, Shigella dysenteriae, Vibrio mimicus, and Vibrio parahemolyticus). The extract also demonstrated antifungal properties against C. albicans, Aspergillus niger, and Saccharomyces cerevisiae. The stem bark extract (petroleum ether and EtOAc) of D. pentagyna exhibited antimicrobial properties against Gram positive and Gram negative bacteria (Haque et al., 2008).

Others

Muliawan (2008) reported the inhibitory potential of aqueous extract of D. suffruticosa leaves against replication of dengue virus type 2 through down-regulation of the expression of the non-structural protein 1 (NS1) protein. Yeshwante et al. (2009) reported that oral administration of 200 and 400 mg/kg of D. indica leaves methanol extract showed significant anti-inflammatory activity in the carrageenan-induced edema and acetic acid-induced capillary permeability models. Nguyen-Pouplin et al. (2007) reported the anti-malarial properties of leaves extract of D. indica against Plasmodium falciparum. Nyman et al. (1998) showed the ability of fruit extract of D. pentagyna to inhibit the angiotensin-converting enzyme (ACE).

Isolated active constituent(s) from Dillenia species

Until now, there are only a few species of Dillenia that have undergone isolation and characterization of their compounds including D. pentagyna (Srivastava, 1981; Tiwari et al., 1980), D. indica (Banerji et al., 1975) and D. papuana (Nick et al., 1994, 1995b) (Table 3). Among the isolated compounds, lupeol and betulinic acid have tremendous pharmacological potential (Table 4).

Table 3. Isolated compounds from genus Dillenia.

Species	Group of compound	Compound	Property	Reference
Dillenia pentagyna (stem)	Saponin	α-l-Rhamnopyranosyl-3β-hydroxy-lup-20(29)-en-28-oic acid	Not stated	Tiwari et al. (1980)
	Flavonoid glycosides	Naringenin 7-galactosyl (1–4) glucoside	Not stated	Srivastava (1981)
		Dihydroquercetin, 5-galactoside
		Rhamnetin 3-glucoside
Dillenia indica (stem bark)	Pentayclic triterpenes	Betulinaldehyde	Not stated	Banerji et al. (1975)
		Betulin: (Lup-20(29)-ene-3β,28-diol)
		Lupeol
		β-Sitosterol
		Betulinic acid: (3β-hydroxy-20(29)-lupen-28-oic acid)
	Flavanoid	Flavonol myricetin
Dillenia papuana (stem bark and leaf)	Oleanene triterpenoids	2a-Hydroxy-3-oxoolean-12-en-30-oic acid	Antibacterial	Nick et al. (1994)
		Betulin aldehyde
		Dillenic acid A: (2 alpha-hydroxy-3-oxoolean-12-en-30-oic acid)
		Dillenic acid B: (2-oxo-3 beta-hydroxyolean-12-en-30-oic acid)
		Dillenic acid C: (1 alpha-hydroxy-3-oxoolean-12-en-30-oic acid)
		Betulinic acid: (3β-hydroxy-20(29)-lupen-28-oic acid)	Antibacterial	Nick et al. (1995b)
		Dillenic acid D: (2,3-seco-2-oxoolean-12-en-3-methylester-30-oic acid)
		Dillenic acid E: (1α-3β dihydroxyolean-12-en-30-oic acid)

Table 4. Pharmacological properties of the active constituent(s) of Dillenia sp.

Species	Compound	Pharmacological property^a
Dillenia indica Dillenia papuana	Betulin aldehyde	Antitumor (Pathak et al., 1988)
Dillenia indica	Betulin	Converted into active betulinic acid (pharmacological properties as shown below) (Kim et al., 1997)
Dillenia indica Dillenia papuana	Betulinic acid	Anti-human deficiency virus (HIV) agent (Qian et al., 2007) Anti-tumor (Nakagawa-Goto et al., 2009; Santos et al., 2011) Antiprotozoal (Dominguez-Carmona et al., 2010)
Dillenia indica	Lupeol	Antitumor (Nigam et al., 2007; Saleem, 2009) Anti-inflammatory (Nguemfo et al., 2009; Saleem, 2009) Antimicrobial (Abd-Alla et al., 2009; Ahmed et al., 2010) Antidiabetic (Na et al., 2009; Ortiz-Andrade et al., 2007)
Dillenia indica	β-Sitosterol	Cholesterol-lowering effect (Hac-Wydro, 2012)

^aThe same properties could also be produced by similar compounds from Dillenia species.

Dillenia pentagyna

Tiwari et al. (1980) have isolated a new triterpene glycoside, namely, α-l-rhamnopyranosyl-3β-hydroxy-lup-20(29)-en-28-oic acid, from the ethanol extract of D. pentagyna stem by acidic hydrolysis. The compound showed characteristics of saponin such as strong foam-forming properties in aqueous solution and hemolyse, the red blood cells. Further isolation and characterization on flavonoid glycosides namely naringenin 7-galactosyl (1–4) glucoside, dihydoquercetin 5-galactoside, and rhamnetin 3-glucoside were carried out. The compounds were characterized based on the UV and spectroscopy data as flavonone (naringenin and dihydoquercetin) and flavonol (rhamnetin) glycosides (Srivastava, 1981).

Dillenia indica

Banerji et al. (1975) have successfully identified and confirmed the presence of betulinaldehyde, betulin, lupeol, sitosterol, betulinic acid, and flavonol myricetin from the stem bark of D. indica. The presence of betulinic acid in the D. indica extracts has been also reported previously (Kumar et al., 2010; Pavanasasivam & Sultanbawa, 1974). Betulinic acid was distributed in the bark, timber, pericarp (Pavanasasivam & Sultanbawa, 1974) and fruit (Kumar et al., 2010), with the greatest amount in the pericarp (Pavanasasivam & Sultanbawa, 1974). In addition, based on the spectroscopy data and characteristic reaction including positive Liebermann–Burchard and Zimmerman’s test, a new hydroxylactone was isolated and identified as 3β-hydroxy-lupane-13β-28-lactone (Banerji et al., 1975). Flavonoids such as kaempherol, quercetin, naringenin, isohamnetin, dihydrokaempherol, dillenetin, sitosterol, and gallic acid have also been identified in the ethanol extract of bark, wood, and pericarp of D. indica (Pavanasasivam & Sultanbawa, 1974).

Dillenia papuana

Nick et al. (1994) have successfully isolated and elucidated the structure of the oleanene-type triterpenoid acids from the aerial part of D. papuana, namely, 2α-hydroxy-3-oxoolean-12-en-30-oic acid, 2-oxo-3 beta-hydroxyolean-12-en-30-oic acid, 1α-hydroxy-3-oxoolean-12-en-30-oic acid, 3-oxoolean-1, 12-dien-30-oic acid, and dillenic acid (A, B, and C). Further investigation on the leaves and stem of the plant has led to the isolation of another three oleanene triterpenoids, namely, dillenic acid D and E, with betulinic acid as the major compound (Nick et al., 1995b).

Others

Besides D. indica, Pavanasasivam and colleagues (1974) also reported the distribution of betulinic acid in the bark and timber of D. retusa. Gurni and Kubitzki (1981) reported the presence of flavonoids including quercetin, kaempherol, quercetin-3-galactoside, kaempherol 3-glucuronide and procyanidin in the D. retusa extracts. Other than that, flavonoids such as naringenin, gallic acid, sitosterol, dihyroquercetin, and dillenetin in the ethanol extract of bark and wood of D. retusa have been identified (Pavanasasivam & Sultanbawa, 1974). Gurni et al. (1981) showed the presence of kaempferol 3,7-disulfate in the ethanol extract of D. bracteata leaves.

Conclusion

In conclusion, only a few species of Dillenia have scientifically been shown to have therapeutic potential including D. pentagyna, D. indica, D. papuana, D. meliosmifolia, and D. suffruticosa, leaving many more for discovery. Among those, only three, namely, D. indica, D. suffruticosa, and D. pentagyna, have potential in vitro and in vivo anticancer activities. In addition, only a few species of Dillenia have undergone isolation and characterization of their compounds including D. pentagyna, D. indica, and D. papuana. Among the isolated compounds, lupeol and betulinic acid have tremendous pharmacological potential. Dillenia species warrant further studies on their therapeutic potential which may eventually lead to development of new drug candidate(s) for treatment of various diseases.

Declaration of interest

The authors declare that there was no conflict of interest with respect to the data collected and procedures used within the study.

Author’s contribution

All authors contributed equally to this project. All authors read and approved the final manuscript.