2017

NPC Natural Product Communications Vol. 12

No. 3
Phytoconstituents and Biological Activities of Garcinia dulcis 453 - 460
(Clusiaceae): A Review
Nanthaphong Khamthong and Nongporn Hutadilok-Towatana*

College of Oriental Medicine, Rangsit University, Pathum Thani 12000, Thailand

nongporn.t@rsu.ac.th

Received: November 30th, 2016; Accepted: January 5th, 2017

Garcinia dulcis (Roxb.) Kurz is a tropical fruit tree native to Southeast Asia where it has a long history of use as a traditional medicine for the treatment of
ailments such as lymphatitis, parotitis, struma, scurvy, cough, and sore throat. Despite its medicinal values, this plant is not well known and rarely found
nowadays. Research on the phytochemical constituents and biological activities of G. dulcis have demonstrated that various parts of the plant contain an
abundance of bioactive compounds mainly xanthones and flavonoids, with significant pharmacological properties such as anti-atherosclerosis, anti-bacterial,
anti-cancer, anti-hypertension, and anti-malarial. In the present review, current knowledge of the phytochemistry of G. dulcis and biological activities of its
active constituents based on the available literature are summarized in order to explore application potentials and prospective research works on this plant.

Keywords: Garcinia dulcis, Bioactivities, Chemical Constituents, Flavonoids, Xanthones.

Garcinia dulcis (Roxb.) Kurz, commonly called gourka or egg tree, Ngot in Vietnam, and Ma-Phut in Thailand. Scientific classification
is a sub-woody plant belonging to the Clusiaceae (Guttiferae), which of this plant is shown below:
is the same botanical family as the famous mangosteen (G.
mangostana), also known as “the Queen of Fruits” [1]. Although, G. Kingdom Plantae
dulcis very much resembles mangosteen in the size of the tree and Subkingdom Tracheobionta
general growth, the phylogenetic relationship between both plants is Superdivision Spermatophyta
very distant. Parsimonious analysis based on sequence data of the Division Magnoliophyta
internal transcribed spacer (ITS) region of nuclear ribosomal DNA Class Magnoliopsida
among 17 Garcinia species has revealed that G. dulcis is closely Subclass Dilleniidae
related to G. tinctoria and G. xanthochymus. Neighbor joining Order Theales
analysis also shows that it has a different evolutionary process from Family Clusiaceae
that of mangosteen [2]. Since G. dulcis can adapt well to drought, it Genus Garcinia L.
has been used as rootstock for mangosteen which is less dry-tolerant, Species Garcinia dulcis (Roxb.) Kurz
to be planted in dry areas for commercial purposes [3]. In Southeast
Asia, G. dulcis is also known as a medicinal plant used in folklore
remedies. The leaves and seeds have been traditionally used against
lymphatitis, parotitis, and struma in Indonesia [4]. The crushed
extract from the stem bark has been used in Thai folk medicine as an
antiseptic, whereas the fruit juice, which is rather rich in vitamin C
(50 mg/kg of fruit), as an anti-scurvy, an expectorant for the relief of
cough and sore throat, as a mild laxative, and as a decongestant [5-
7]. The crushed extract from the root has also been used as an
antipyretic and as a detoxicant [5-7]. Extensive phytochemical and
pharmacological studies of this Garcinia species have revealed that
different parts of the plant contain diverse secondary metabolites,
and many of them exhibit pharmacological activities of potential
clinical relevance with a highlight on cardiovascular protective
effects of its biflavonoid content, morelloflavone. In order to
introduce G. dulcis as a source of medicinal ingredients and
stimulate research on this plant, we thus report the available
bioactivities of G. dulcis and its phytochemical compositions in the
present review. Figure 1: Garcinia dulcis (Roxb.) Kurz (A) Tree (B) Leaves, flower, and young
fruit (reproduced with permission from Elsevier) (C) Ripe fruit (available from
Botanical description www.botany.hawaii.edu).
G. dulcis is a tropical evergreen fruit tree widely distributed in
Southeast Asia. This species is believed to be native to the G. dulcis is a medium-sized, much-branched perennial tree, with a
Philippines or Borneo [4], and has been introduced into tropical short trunk (10-13 m high) (Figure 1A). The bark is dark brown and
islands of America such as Cuba and Puerto Rico [8]. It is called rough with white latex, and the branches are green. The leaves are
Mundu in Indonesia and Malaysia, Baniti in the Philippines, Búa opposite, lanceolate shaped, 10-30 cm long and 3-5 cm wide (Figure
1B). They are pale green when young and become dark green and
454 Natural Product Communications Vol. 12 (3) 2017 Khamthong and Hutadilok-Towatana

shiny on the upper surface at maturity. The lower leaves are often Table 1: Continued
hairy. The midrib is prominent with numerous veinlets arranged in Plant part Compound Category Reference
Flowers Cowaxanthone, 33 Xanthonoid [21]
parallel. The thick petiole is short being only 2 cm long. Flowers Xanthochymol, 34 Benzophenonoid
are borne in the axil. They are yellowish white with a sour smell BR-xanthone A, 35 Xanthonoid
1,3,6-Trihydroxy-7-methoxy-2,5-bis- Xanthonoid
(Figure 1B). Fruits are globose, 5-8 cm in diameter, with slightly (3-methyl-2-butenyl)xanthone, 36
pointed ends, often rather compressed and crowned by the persistent Guttiferone E, 37 Benzophenonoid
stigma. The fruit of this species, always mistaken for that of G. Rheediaxanthone A, 38 Xanthonoid
α-Mangostin, 39 Xanthonoid
xanthochymus [1], is soft with a thin and smooth green skin, which 1,7-Dihydroxy-3-methoxy-2-(3- Xanthonoid
turns orange when ripe (Figure 1C). The brown seeds (1-5 seeds, methyl-2-butenyl)xanthone, 40
each 2.5 cm long) are enveloped in an edible pulp of a darker color 3-Isomangostin, 41 Xanthonoid
Kaempferol 3-O-β-D-glucopyranosyl- Flavonoid
than the skin and have a pleasant taste [1, 9]. The fruit can be eaten 7-O-α-L-rhamnopyranoside, 42
fresh as a dessert, made into an excellent jam and as a flavoring Garcinone B, 43 Xanthonoid
Morusignin J, 44 Xanthonoid
agent in other foods [10]. The soft flesh of the ripe fruit has a butter- β-Mangostin, 45 Xanthonoid
like consistency and a pleasant acid flavor. Its bark gives a natural Fruits Desoxymorellin, 46 Xanthonoid [22]
yellow dye with potential applications for fabric dyeing and Morellic acid, 47 Xanthonoid
Morellin, 48 Xanthonoid
producing UV protective fabric [11]. The Javanese have used the Morelloflavone, 1 Biflavonoid [23]
bark also to dye mats [1]. The Kaulong people in Papua New Cowaxanthone*, 33 Xanthonoid
Guinea have applied orange sap of the bark of G. dulcis, locally BR-xanthone A, 35 Xanthonoid
l,3,6-Trihydroxy-7-methoxy-2,5-bis- Xanthonoid
called Kap, to treat tropical ulcer, which is an endemic polymicrobial (3-methyl-2-butenyl)xanthone**, 36
infection [12]. α-Mangostin, 39 Xanthonoid
l,7-Dihydroxy-3-methoxy-2-(3- Xanthonoid
methyl-2-butenyl)xanthone*, 40
Phytochemical constituents Kaempferol 3-O-β-D-glucopyranosyl- Flavonoid
Ninety compounds, mainly terpenoids, have been identified in the 7-O-α-L-rhamnopyranoside**, 42
Garcinone B**, 43 Xanthonoid
ripe-fruit aroma, of which, linalool, α-terpineol and hexadecanoic Xanthonoid
Morusignin J**, 44
acid are most abundant [13]. Apart from those volatile constituents, Dulcinoside*, 49 Flavonoid
a wide range of phenolic compounds, mainly belonging to the Dulcisisoflavone*, 50 Flavonoid
xanthonoid and flavonoid classes, have been isolated from other Dulcisxanthone A*, 51 Xanthonoid
parts of this plant as listed in Table 1 [14-29]. Their structures are Camboginol, 52 Benzophenonoid
Sphaerobioside acetate*, 53 Flavonoid
also illustrated in Figure 2. Octadecanoic acid-2,3-dihydroxy- Fatty acid
propyl ester, 54
Table 1: Chemical constituents isolated from G. dulcis. Derriscannoside A*, 55 Flavonoid
Plant part Compound Category Reference l,6-Dihydroxy-3,7-dimethoxy-2-(3- Xanthonoid
Leaves Morelloflavone, 1 Biflavonoid [14] methyl-2-butenyl)xanthone*, 56
GB-2a, 2 Biflavonoid Cowanin*, 57 Xanthonoid
Volkensiflavone, 3 Biflavonoid 1,5,8-Trihydroxy-3-methoxy-2-(3- Xanthonoid
Amentoflavone, 4 Biflavonoid methyl-2-butenyl)xanthone, 58
I-4,I-5,II-5,I-7,II-7-Pentahydroxy- Flavonoid- Chandalone*, 59 Flavonoid
flavanone[I-3,II-8]chromone, 5 chromonoid Lupalbigenin*, 60 Flavonoid
Dulxanthone E, 6 Xanthonoid [15] Isolupalbigenin*, 61 Flavonoid
Dulxanthone F, 7 Xanthonoid [16] 6,8,12-Trihydroxy-7-(3-methyl-2-bu- Xanthonoid
Dulxanthone G, 8 Xanthonoid tenyl)-2-methyl-2-(4-methyl-3-pent-
Dulxanthone H, 9 Xanthonoid enyl)pyrano(2,3:7,8)xanthone*, 62
Morelloflavone, 1 Biflavonoid [17] 2-Hydroxy-l,2,3-propanetricarboxylic Carboxylic acid
GB-2a, 2 Biflavonoid acid-1,3-dimethylester*, 63
Volkensiflavone, 3 Biflavonoid Vitexin*, 64 Flavonoid
Amentoflavone, 4 Biflavonoid Clusiaphenone B*, 65 Benzophenonoid
Dulcisbiflavonoid A, 10 Biflavonoid Mangostenol, 66 Xanthonoid
Morelloflavone-7-sulfate, 11 Biflavonoid Cratoxylone*, 67 Xanthonoid
Branch 1,4,6-Trihydroxy-5-methoxy-7-(3- Xanthonoid [18] Garcinone D*, 68 Xanthonoid
methylbut-2-enyl)xanthone, 12 Flavonoid
Dulcisflavan**, 69
Friedelin, 13 Terpenoid
Dulcisxanthone B**, 70 Xanthonoid
3-(3-Methylbut-2-enyl)naringenin, 14 Flavonoid
Isonormangostin**, 71 Xanthonoid
I3,II8-Biapigenin, 15 Biflavonoid
Podocarpusflavone A, 16 Biflavonoid l,6-Dihydroxy-7-methoxy-8-(3,7- Xanthonoid
Garciniaxanthone E, 17 Xanthonoid [19] dimethyl-2,6-octadienyl)-2,2-
2,5-Dihydroxy-1-methoxyxanthone, 18 Xanthonoid dimethylpyrano[3,2-b]xanthen-9-
2,6-Dihydroxy-1,5-dimethoxyxan- Xanthonoid one**, 72
thone, 19 Tovophyllin A**, 73 Xanthonoid
Dulcisxanthone H, 20 Xanthonoid [20] Betulinic acid**, 74 Terpenoid
Dulcisxanthone I, 21 Xanthonoid l,6-Dihydroxy-7-methoxy-8-(3- Xanthonoid
Garciniaxanthone C, 22 Xanthonoid methyl-2-butenyl)-2,2-dimethyl-
Flowers Morelloflavone, 1 Biflavonoid [21] chromeno[5,6:2,3]xanthone**, 75
GB-2a, 2 Biflavonoid 8-Desoxygartanin**, 76 Xanthonoid
Volkensiflavone, 3 Biflavonoid Gartanin**, 77 Xanthonoid
Podocarpusflavone A, 16 Biflavonoid Apigenin**, 78 Flavonoid
Dulcisxanthone C, 23 Xanthonoid Benzophenonoid
Cambogin**, 79
Dulcisxanthone D, 24 Xanthonoid
Kaempferol 3,7-di-O-α- Flavonoid
Dulcisxanthone E, 25 Xanthonoid
Dulcisxanthone F, 26 Xanthonoid rhamnopyranoside**, 80
Dulcinone, 27 Chromonoid (–)-Epicatechin**, 81 Flavonoid
1-Hydroxy-3,4,5-trimethoxyxanthone, Xanthonoid Seeds Morelloflavone, 1 Biflavonoid [24]
28 Morusignin J, 44 Xanthonoid
Rhamnazin, 29 Flavonoid Dulcisxanthone G, 82 Xanthonoid
Quercetin 3-O-β-galactopyranoside, 30 Flavonoid 4-Hydroxy-7-methoxyflavan, 83 Flavonoid
Xanthochymusside, 31 Biflavonoid 4,4-Dihydroxy-2-methoxychalcone, Chalconoid
Fukugeside, 32 Biflavonoid 84
Garcinia dulcis: phytochemicals and bioactivities Natural Product Communications Vol. 12 (3) 2017 455

Table 1: Continued guttiferone E (37) from the flowers showed potent antioxidant
Plant part Compound Category Reference activity producing scavenging values of 57%, 56%, 60% and 59%,
Seeds Methyl 2,4-dihydroxy-3,5,6- Benzoate [24]
trimethylbenzoate, 85 respectively, whereas that of the reference anti-oxidant, butylated
Benzyl 2,4-dihydroxy-6- Benzoate hydroxytoluene (BHT) was only 43% [21]. Among the 42
propylbenzoate, 86
Euxanthone (1,7-Dihydroxyxan- Xanthonoid
compounds isolated from the green and ripe fruits, morelloflavone
thone), 87 (1), camboginol (52), dulcisflavan (69), cambogin (79), and (–)-
Loureirin A, 88 Chalconoid epicathechin (81) were effective scavengers of the DPPH radical. At
Loureirin B, 89 Chalconoid
Loureirin C, 90 Chalconoid a concentration of 10 µM, they were able to trap the radical at 51%,
5,7-Dihydroxy-2,6,8-methyl- Chromonoid 74%, 87%, 69% and 82%, respectively, better than BHT (43%) [23].
chromone, 91 When 14 different compounds isolated from the seeds (1, 44, 82-93)
7-Hydroxy-3-(4-hydroxybenzyl)- Chromanoid
chroman, 92 (10 µM each) were tested for their anti-oxidant activity with the use
(2R)-7,4-Dihydroxylflavan, 93 Flavonoid of DPPH, only compound 1 strongly inhibited the radical (%
Bark Dulciol A, 94 Xanthonoid [25]
12b-Hydroxy-D-garcigerin (12b- Xanthonoid
scavenging not reported), while the others exhibited very weak
Hydroxy-des-D-garcigerrin A), 95 activity with percentages of scavenging less than 10% [24].
Toxyloxanthone B, 96 Xanthonoid
Dulxanthone A, 97 Xanthonoid [26]
Dulxanthone B, 98 Xanthonoid
Anti-bacterial activity
Dulxanthone C, 99 Xanthonoid
Dulxanthone D (1,3,6-Trihydroxy- Xanthonoid
From the leaves of G. dulcis, a biflavonoid named GB-2a (2)
8-isoprenyl-7-methoxyxanthone), inhibited the growth of Staphylococcus aureus and its methicillin-
100 resistant strain (MRSA) with minimal inhibitory concentrations
Garciniaxanthone E, 17 Xanthonoid [27]
1,7-Dihydroxyxanthone Xanthonoid
(MICs) of 128 and 64 µg/mL, respectively, while vancomycin and
(Euxanthone), 87 gentamicin were more active against both bacterial strains (MICs 0.5
12b-Hydroxy-des-D-garcigerrin A Xanthonoid µg/mL) [17]. When the dichloromethane extract of the green branch
(12b-Hydroxy-des-D-garcigerin),
95 along with the three xanthones (20-22) isolated from it were tested
1-O-Methylsymphoxanthone, 101 Xanthonoid against S. aureus, MRSA, Escherichia coli, and Pseudomonas
Symphoxanthone, 102 Xanthonoid
aeruginosa, only the crude extract displayed antimicrobial activity
Root 2,5-Dihydroxy-1- Xanthonoid [28]
methoxyxanthone, 18 against the four bacteria with MICs of 128 µg/mL [20].
1,3,6-Trihydroxy-8-isoprenyl-7- Xanthonoid Xanthochymol (34), a benzophenone obtained from the flowers,
methoxyxanthone (Dulxanthone
D), 100
showed its ability to act as an effective anti-bacterial agent by
Garciduol A, 103 Benzophenonoid- inhibiting S. aureus and MRSA with MICs of 8 µg/mL, whereas
xanthonoid rhamnazin (29), a flavonoid from the same source, exhibited only
Garciduol B, 104 Benzophenonoid-
xanthonoid weak activity with MICs greater than 128 µg/mL [21]. Recently,
Garciduol C, 105 Benzophenonoid- Suwantong and co-workers have demonstrated by the disc diffusion
xanthonoid
1,3,6-Trihydroxy-7-methoxy- Xanthonoid
assay that electrospun poly(L-lactic acid) (PPLA) fiber mats
xanthone, 106 containing an acetone extract of G. dulcis flowers were active
1,4,5-Trihydroxyxanthone, 107 Xanthonoid against some common pathogenic microorganisms found on burn
1,3,5-Trihydroxyxanthone, 108 Xanthonoid
1,3,6-Trihydroxy-5-methoxy- Xanthonoid wounds with the highest potency against Streptococcus pyogenes,
xanthone, 109 followed by P. aeruginosa, S. aureus, S. epidermidis, Acinetobacter
Garciduol A, 103 Benzophenonoid- [29] calcoaceticus, Streptococcus agalactiae, and Candida albicans. In
xanthonoid
Garciduol B, 104 Benzophenonoid- addition, they were non-toxic to the normal human fibroblasts
xanthonoid making their potential for use as wound dressings [30]. Among 15
Dulciol B, 110 Xanthonoid [25] different compounds isolated from the fruits of G. dulcis that were
Dulciol C, 111 Xanthonoid
Dulciol D, 112 Xanthonoid evaluated for their anti-bacterial activity (1, 33, 35-36, 39, 42-43, 51-
Dulciol E, 113 Xanthonoid 53, 57, 60, 68, 79-80), only cowaxanthone (33), -mangostin (39),
Garciniaxanthone A, 114 Xanthonoid
Garciniaxanthone B, 115 Xanthonoid camboginol (52), and lupabigenin (60) could inhibit S. aureus and
Garciniaxanthone D, 116 Xanthonoid MRSA but in moderate potency with MICs ranging from 4-16
Globuxanthone, 117 Xanthonoid µg/mL as compared with vancomycin (MICs 2 µg/mL), whereas the
Subelliptenone C, 118 Xanthonoid
Subelliptenone D, 119 Xanthonoid others showed either weak or no activity [23]. Apart from benzyl
Subelliptenone F, 120 Xanthonoid 2,4-dihydroxy-6-propylbenzoate (86) that inhibited S. aureus and
* found in green fruit only; ** found in ripe fruit only MRSA with MICs of 64 µg/mL, the other 13 compounds from the
seeds displayed rather weak anti-bacterial activities (MICs 128
Biological activities µg/mL in all cases) [24]. The methanol extract of the bark showed
Among 120 compounds isolated from various parts of this plant anti-bacterial activity against B. subtilis by in-the-field anti-bacterial
(Table 1), 23 of them possess interesting biological/pharmacological testing of medicinal plants used by the Bulu and the inland Kaulong,
properties as listed in Table 2. They are elaborated in more detail the two geographically separated people groups in Papua New
below. Guinea. However, its hexane extract was highly active against both
S. aureus and MRSA when tested in controlled laboratory conditions
Anti-oxidant activity with MICs of 1 µg/mL compared with the control antibiotic,
nalidixic acid (MIC against S. aureus = 35 µg/mL). The same
G. dulcis is a rich source of anti-oxidants. Based on DPPH (2,2-
extract was also active against Streptococcus pneumoniae with a
diphenyl-1-picrylhydrazyl) assays, a variety of phenolic compounds
MIC of 8 µg/mL, which is less potent than penicillin and
obtained from the flower, fruit, and seed parts exhibited radical
erythromycin (MICs 0.06 µg/mL and less than 0.06 µg/mL,
scavenging activity. Ten µM each of quercetin 3-O-β-
respectively) [12].
galactopyranoside (30), fukugeside (32), xanthochymol (34), and
456 Natural Product Communications Vol. 12 (3) 2017 Khamthong and Hutadilok-Towatana

OH OH OH R4 O R1
OH
HO O HO O OH R HO O
R2 HO O
OH OH O O OCH3
HO O
R3 R2
OH O R 1 O OH O HO O OH O HO O
OH O 6 R 1 = H, R 2 = R 3 = R 4 = OCH3
4 R = OH
OH O
1 R 1 = R 2 = OH
2 OH O 16 R = OCH3 5 OH O 7 R 1 = R 2 = OC H3, R 3 = H, R 4 = OH
OH O
3 R 1 = OH, R 2 = H
8 R 1 = R 2 = R 3 = OCH3, R 4 = OH
11 R 1 = OS O3H, R 2 = OH
R6 O OH 9 R 1 = OH, R 2 = R 3 = R 4 = OCH3
R5 R1 OH

R4 O R2 HO O
OH OH
R3 OH H H H OH
OH
HO O 12 R 1 = R 2 = R 6 = H, R 3 = OC H3, R 4 = OH, R 5 = HO O
HO O OH O HO O
21 R 1 = , R 2 = R 3 = R 5 = H, R 4 = OCH3, R 6 = OH O
OH O 10 13 OH O 14 15
22 R 1 = R 5 = R 6 = H, R 2 = R 4 = , R 3 = OH OH O
OH O
58 R 1 = R 2 = R 3 = H, R 4 = OC H3, R 5 = , R 6 = OH O OH
R2 R1
R4 O OH O OC H3 O OH O OH
O OH
R3 OH R1 HO O OH
O

R2 O OH R2 O O R3 O OCH3
HO O O
R1 R1 OH O R2 OC H3
17 R 1 = R 2 = OH, R 3 = , R4 = 18 R 1 = OH, R 2 = H 20 23 R 1 = R 3 = OCH3, R 2 = H 24 25 R 1 = , R 2 = OH

94 R 1 = , R 2 = R 3 = OH, R 4 = 19 R 1 = OC H3, R 2 = OH 28 R 1 = R 3 = H, R 2 = OCH3 36 R 1 = , R 2 = OCH3

108 R 1 = OH, R 2 = R 3 = R 4 = H R3 OH R2 O OH
109 R 1 = OCH3, R 2 = OH, R 3 = R 4 = H R1 O OH
HO O H 3C O R1
R2 R2 O
O OH
OH HO O OH
O R3 O CH3 OH
R1 OH O OH
R4 OH O O 33 R 1 = , R2 = H
HO
R3 O R1 O O
27 R 1 = H, R 2 = R 4 = OH, R 3 = CH3 29 R 1 = OH, R 2 = R 3 = OCH3 HO
R2 OH R1 39 R 1 = R 2 =

26 R 1 = OC H3, R 2 = H, R 3 = OH 91 R 1 = R 3 = OH, R 2 = R 4 = CH3 30 R 1 = O--D-galactose, R 2 = R 3 = OH R2

57 R 1 = , R2 =
OH O
HO
43 R 1 = R 3 = OH, R 2 = H 42 R 1 = O--D-glucose, R 2 = O--L-rhamnose, R 3 = H 31 R 1 = -H, R 2 = H 66 R 1 = , R2 =
OH
51 R 1 = OH, R 2 = H, R 3 = 80 R 1 = R 2 = O--L-rhamnose, R 3 = H 32 R 1 + R 2 = double bond 67 R 1 = , R2 =
OH
73 R 1 = R 3 = OH, R 2 = 68 R 1 = , R2 =
R1 O OH HO OH
OH O O OH R2 82 R 1 = , R2 =
O
OH 100 R 1 = H, R 2 =
R3 O OC H3
HO O O
O O OH O O O R4 R5 106 R 1 = R 2 = H
34 R = 35 OH 38
40 R 1 = R 3 = R 4 = R 5 = H, R 2 = OH
O OH 37 R =
R 45 R 1 = , R 2 = OCH3, R 3 = OH, R 4 = R 5 = H

56 R 1 = R 4 = R 5 = H, R 2 = OC H3, R 3 = OH
R OH
O R2
70 R 1 = , R 2 = R 3 = OH, R 4 = R 5 = H
O O O HO O
OH O OH O OH
98 R 1 = R 2 = H, R 3 = R 4 = OH, R 5 = OH
OC H3
R1
HO O O
OH O OH O HO O
O O OH O O
41 OH 44 46 R = CH3 49 R 1 = -D-glucose-(6 1)--L-rhamnose, R 2 = H
O OH
H3C OR 3 47 R = CO2H 64 R 1 = H, R 2 = -D-glucose O O
R 3O O O
48 R = CHO R2 50 52
R 3O 78 R 1 = R 2 = H
HO O
O
R1 O OH
R 3O O O OH
O O O O OH O O O O
R 3O O OH
OR 3
HO O OH H 3C O OCH3
53 R 1 = OH, R 2 = R 3 = Ac HO O 16 OH
60 R 1 = , R2 = H
R1 O OH OH O 62 63
OR 2 OH
55 R 1 = R 3 = H, R 2 = CH3 54 59 61 R 1 = H, R 2 =

OH R O OH
O OH
OH OH
R O O R O OH H HO O O
HO O O H3C O OH
H O OH
HO OH
O OH
R OH HO O OH HO O O H O O
OH
65 HO
69 R = OH 71 72 R = H 74 76 R = H 79

81 R = H 75 R = 77 R = OH

OH O O OH R1 R2
OH OH OH O
H3C HO HO HO O OH
R O HO OCH3 O

HO O R3
HO CH3
C H3 O
H3CO O 92
83 R = OCH3 84 85 86 87 88 R 1 = R 2 = OC H3, R 3 = H

93 R = OH 89 R 1 = R 2 = R 3 = OCH3

90 R 1 = H, R 2 = OH, R 3 = OC H3
O OH O OH R1 O OH O R1 H3CO OH O OH R O OH
R O OH O OH OH HO
R
O HO O OH R2 O OCH3 R2 O OH O O HO O
OH OH 96 OH OH O OH OH
OH OH H3CO OH
95 R = 97 R 1 = H, R 2 = OH 101 R 1 = OCH3, R 2 = OH 103 R = H 105 110 R =
OH
107 R = H 99 R 1 = , R 2 = OCH3 102 R 1 = R 2 = OH 104 R = OH 111 R =
OH O

117 R 1 = OH, R 2 = H
OH O
OH O O O OH O OH O OH O R1

O O
OH
O O O R O O R2 OH
OH 112 O OH 113 OH OH OH OH 115 O OH 116 O

OH 118 R 1 = , R 2 = OH
114 R =
120 R = OH 119 R 1 = OH, R 2 =

Figure 2: Chemical structures of metabolites isolated from G. dulcis.

Garcinia dulcis: phytochemicals and bioactivities Natural Product Communications Vol. 12 (3) 2017 457

Table 2: Biological activities of G. dulcis.

Plant Part Test Material Activity Experimental Model Reference
Leaves Compound 1 Anti-cancer Tumor angiogenesis assay [31]
Compound 2 Anti-bacterial S. aureus, MRSA [17]
Ethyl acetate fraction Anti-atherosclerosis Diet-induced hypercholesterolemic rabbits ]53]
Compound 1 Anti-restenosis Vascular smooth muscle cell migration assay [54[
Compound 1 Anti-atherosclerosis Ldlr-/-Apobec1-/- mice [55[
Compound 1 Anti-hypercholesterolemia HMG-CoA reductase assay [56]
Green branch Dichloromethane extract Anti-bacterial S. aureus, MRSA, E. coli, P. aeruginosa [20]
Flowers Compounds 30, 32, 34, 37 Anti-oxidant DPPH assay [21]
Compound 34 Anti-bacterial S. aureus, MRSA [21]
Acetone extract-loaded- Anti-oxidant DPPH assay [30]
PLLA fiber mats Anti-microbial S. pyogenes, P. aeruginosa, S. aureus, S. epidermidis, A. calcoaceticus, [30]
S. agalactiae, C. albicans
Whole fruit Compounds 1, 52, 69, 79, 83 Anti-oxidant DPPH assay [23]
Compounds 33, 39, 52, 60 Anti-bacterial S. aureus, MRSA [23]
Compounds 46-48 Anti-cancer L1210 cancer cell line [22]
Compounds 1, 52 Anti-atherosclerosis Human LDL-oxidation [52]
Compound 1 Anti-hypertension Rat thoracic aorta relaxation assay [57]
Flesh of fruit Methanol extract Anti-cancer HepG2 liver cancer cell line [32]
Seeds Compound 1 Anti-oxidant DPPH assay [24]
Compound 86 Anti-bacterial S. aureus, MRSA [24]
Stem bark Hexane extract Anti-bacterial S. aureus, MRSA, S. pneumonia (lab testing) [12]
Methanol extract Anti-bacterial B. subtilis (in-the-field testing) [12]
Compounds 17, 87, 95, 101-102 Anti-malarial P. falciparum culture [27]
Compounds 95, 117 Anti-cancer Luciferase assay of androgen receptors on prostate carcinoma LNCaP cells [33]
Ethyl acetate extract Anti-malarial P. berghei induced mice [34]
Root Ethanol extract Anti-malarial P. berghei infected mice [35]

Anti-cancer/tumor activity
In 2009, Pang and co-workers demonstrated that morelloflavone (1)
from G. dulcis leaves inhibited prostate cancer cell (PC-3) growth
in xenograft mouse model via inhibition of angiogenesis, the pivotal
step in growth, invasiveness, and metastasis of the tumor. They
also found that compound 1 exerted its anti-angiogenic action by
targeting the activation of Rho-GTPases and ERK signaling
pathways [31]. Three prenylated paraxanthonoids, desoxymorellin
(46), morellic acid (47), and morellin (48), isolated from the hexane
extract of the dried fruits, were cytotoxic against the murine
leukemic cell line L1210 with half maximal inhibitory
concentration (IC50) values of 26.6, 20.8 and 25.5 µg/mL,
respectively [22]. When the peel, flesh and seed extracts of G.
dulcis fruit were tested against the HepG2 liver cancer cell line in
MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide) assay, they induced cytotoxicity to the cells with IC50
values of 46.3, 38.3 and 7.5 µg/mL, respectively. Moreover, the
flesh extract, which contains hydroxymethylfurfural and 3-methyl-
2,5-furandione as the main components, showed its potential as a
liver cancer chemotherapeutic agent by inducing apoptosis in
HepG2 cells [32]. Two hydroxyxanthones, 2-(1,1-dimethyl-allyl)-
1,4,5-trihydroxyxanthone (12b-hydroxy-des-D-garcigerin) (95) and
4-(1,1-dimethyl-allyl)-1,2,5-trihydroxyxanthone (globuxanthone)
(117), isolated from the bark exhibited remarkable anti-androgenic
effects by inhibiting androgen receptor transcription in prostate
cancer LNCaP cells as compared with bicalutamide, a non-steroidal
anti-androgen used primarily in the treatment of prostate cancer
[33].
Anti-malarial activity
Five xanthones isolated from the stem bark, garciniaxanthone E
(17), 12b-hydroxy-des-D-garcigerrin A (95), 1,7-dihydroxy-
xanthone (87), 1-O-methylsymphoxanthone (101), and
symphoxanthone (102) exhibited in vitro anti-malarial activity by
inhibiting the growth of Plasmodium falciparum with IC50 values of
0.96, 2.08, 3.88, 3.71, and 3.75 µg/mL, respectively, comparable
with that of the commonly used anti-malarial drug, pyrimethamine
(IC50 2.80 µg/mL) [27]. When the anti-malarial activity of the ethyl
acetate extract of G. dulcis stem bark containing flavonoid, saponin
and tannin, was evaluated against P. berghei induced mice, oral
administration of the extract at a dosage of 50 mg/kg body weight
(BW) was more effective at decreasing % parasitemia as well as
leukocyte count than those of 25 and 75 mg/kg BW [34]. In another
study, oral treatment of P. berghei infected mice with ethanol
extract of the root at 1, 10, and 100 mg/kg BW for 4 days caused
more than 90% inhibition of the malaria parasite growth as
compared with the negative control group [35].
Cardiovascular protection
Morelloflavone (1) or 5,7,4,5,7,3,4-heptahydroxy-[3,8]-
flavonylflavanone was first isolated from the heartwood of G.
morella [36]. Chemically, it is indeed the same compound as
“fukugetin” [37], having a biflavonoid structure consisting of a
flavanone, naringenin, covalently linked to a flavone, luteolin.
During the past two decades, a wide range of health-beneficial
bioactivities of morelloflavone (also fukugetin), mostly derived
from Garcinia plants, has been reported. For example, the
compound acted as an anti-oxidant in different test systems [38-41],
exerted anti-analgesic and anti-inflammatory effects in animal
models [42-43], inhibited melanin production based on tyrosinase
and cell-based assays [44-45], and showed in vitro anti-parasitic
activity against malaria [46], Chagas disease [47], leishmaniasis
[48], and schistosomiasis [49]. In addition, this biflavonoid
exhibited anti-microbial activity against various types of pathogenic
microorganisms, including HIV-virus [50] and tumor-reducing
activity in a crown gall tumor assay [51].
In G. dulcis, morelloflavone (1) exists in almost all parts of the
plant [14, 17, 21, 23-24]. Due to the fact that this compound is a
good anti-oxidant [21, 23-24], its protective effects on the
cardiovascular system have received much attention from several
research groups. When compound 1 and an isoprenylated
benzophenone derivative, camboginol (52) isolated from the fruits,
were examined for their ability to protect LDL particles from
oxidation, which is known to set the stage for development of
atherosclerosis, the results showed that compound 1 was more
potent than compound 52 and the standard anti-oxidant, vitamin E,
at inhibiting human LDL oxidation by both the Fe2+- and the
AAPH [2,2-azobis(2-amidinopropane) dihydrochloride]-induced
oxidation systems [52]. Later, Decha-Dier and co-workers detected
anti-atherogenic effects of the morelloflavone-rich fraction prepared
from the ethyl acetate extract of the leaves in diet-induced
hypercholesterolemic rabbits. Four month consumption of the
fraction at 0.005% (w/w) and 0.01% (w/w) dosages, effectively
458 Natural Product Communications Vol. 12 (3) 2017 Khamthong and Hutadilok-Towatana

reduced hyperlipidemia, serum TBARS (thiobarbituric acid-reactive
substances) levels or known markers for plasma lipoprotein
oxidation, as well as the extent of aortic atherosclerotic lesions in
the animals [53]. The purified compound 1, also from the leaves,
was found to block injury-induced neointimal hyperplasia in
endothelium-denuded mouse carotid artery by limiting the
migration of vascular smooth muscle cells (VSMC) through its
inhibition of multiple migration-related kinases such as focal
adhesion kinase, c-Src, ERK, and Rho, without inducing apoptosis
or neointimal cell cycle arrest [54]. These findings thus have
suggested that morelloflavone (1) is a promising alternative for
prevention of in-stent restenosis (re-narrowing within a coronary
stent leading to restricted blood flow), the most ominous
complication of percutaneous coronary intervention. When
compound 1 was studied in the Ldlr-/-Apobec1-/- mouse model of
human atherosclerosis, oral administration at 0.003% (w/w) for 8
months significantly reduced the aortic atherosclerotic areas and the
number of VSMC in the atherosclerotic lesion without changing the
density of macrophages in the lesion or the percentages of
proliferating and apoptotic cells [55]. The anti-cholesterolgenesis
effect of compound 1 was demonstrated in vitro. Compound 1
strongly inhibited the activity of HMG-CoA (hydroxymethyl
glutaryl coenzyme A) reductase, the rate-limiting enzyme of the
cholesterol biosynthesis pathway by competing with HMG-CoA
that resembles the action of contemporary cholesterol-lowering
drugs known collectively as statins, whereas it was non-competitive
towards its cofactor, NADPH (reduced nicotinamide adenine
dinucleotide phosphate). Also, the findings that naringenin and
luteolin equally competed with HMG-CoA and were also non-
competitive with NADPH, have suggested that each subunit of
compound 1 would occupy the active site of the enzyme molecule,
thereby blocking access of its native substrate (HMG-CoA) [56].
Most recently, the vasorelaxant effect of compound 1 obtained from
G. dulcis fruits, on vascular smooth muscle was observed in isolated
rat thoracic aorta pre-contracted with norepinephrine. The
vasorelaxation mechanism of compound 1, however, was
endothelium-dependent, mainly involving the nitric oxide signaling
pathway. Together, these results have suggested an alternative use
of morelloflavone (1) in the treatment of hypertension [57].
Conclusions
This review is the first to present a comprehensive view on
phytochemical constituents and biological activities of G. dulcis,
which has been used as a folk medicine in Southeast Asian
countries. From 120 secondary metabolites isolated from leaves,
branch, stem, bark, flowers, seeds and fruits of G. dulcis, 23 of them
(about 19% of the total) have significant pharmacological properties
that include anti-oxidant, anti-microbial, anti-cancer, and
cardiovascular protection. Thus, there is little doubt about the
potential of G. dulcis as an important resource for novel therapeutic
agents. However, more research is required to characterize its
active ingredients as well as to elucidate their underlying molecular
mechanisms of action. Hopefully, this literature review may
provide useful information and gain some interest to further
investigate this lesser known Garcinia species.
Acknowledgements - The authors wish to thank Dr Decha
Pinkaew at the University of Texas Medical Branch and Dr Decha
Sermwittayawong at Prince of Songkla University for critical
reading of this article. NHT feels deeply grateful to Dr Wilawan
Mahabusarakam for her kind support and continuous collaboration
on G. dulcis-derived morelloflavone research activities.

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