combretum quadrangulare (combretaceae) - phytochemical constituents and biological activity

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Indo American Journal of Pharmaceutical Research, 2014 ISSN NO: 2231-6876

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INDO AMERICAN

JOURNAL OF

PHARMACEUTICAL

RESEARCH

Combretum quadrangulare (Combretaceae): Phytochemical Constituents and Biological

activity

Rajiv Roy1, Raj K. Singh

2, Shyamal K. Jash

3, Atasi Sarkar

4 and Dilip Gorai

1*

1Department of Chemistry, Kulti College, Kulti, Burdwan-713 343, West Bengal, India

2Department of Botany, Jhargram Raj College, Jhargram, Paschim Medinipur-721507, West Bengal, India

3Department of Chemistry, Saldiha College, Saldiha, Bankura-722173, West Bengal, India

4Department of Zoology, Kapastikuri S.S.K. Vidyapeeth, Sitapur-731235, Birbhum, West Bengal, India

Corresponding author

Dr. Dilip Gorai

Address: Department of Chemistry,

Kulti College, Kulti, Burdwan, West Bengal, India,

PIN-713 343,

E-mail: [email protected]/[email protected]

Copy right © 2014 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical

Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ARTICLE INFO ABSTRACT

Article history

Received 05/08/2014

Available online

31/08/2014

Keywords

Combretum quadrangulare,

Combretaceae,

Phytochemical constituents,

Biological activity.

The present work offers a review addressing the chemistry and pharmacology of Combretum

quadrangulare (belonging to Combretaceae family) regarded as one of the most significant

plant species in traditional system of medicine and is established as a source of terpenoids,

flavonoids, steroids etc. The isolated phytochemicals as well as different extracts exhibited

significant biological activities such as antimicrobial, anti-HIV, cytotoxic and

hepatoprotective activities. Exhaustive research regarding isolation of more phytochemicals

and pharmacology study on this medicinal plant is still necessary for the exploration the plant

regarding its medicinal importance. Therefore, the aim of this review is to boost up present

day researchers in this direction to undertake further investigation of this plant for searching

new phytochemicals for the development of new drugs. The present review covers literature

up to June 2014 and enlists 23 references.

Please cite this article in press as Dilip Gorai et al. Combretum quadrangulare (Combretaceae): Phytochemical Constituents and

Biological activity. Indo American Journal of Pharmaceutical Research.2014:4(08).

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Vol 4, Issue 08, 2014. hhhhet. al. ISSN NO: 2231-6876

Introduction

The Combretaceae family consists of as many as 600 species of trees, shrubs and lianas in about 18-20 genera. Plants

belonging to this family are found in tropical and sub- tropical regions, mostly in Africa and India. The largest genera are

Combretum and Terminalia, with about 370 and 200 species, respectively [1]. Combretum quadrangulare is the most investigated

species of this genus.

Combretum quadrangulare is a shrub or tree, indigenous to Southeast Asia, especially Burma to Laos. The plant is

commonly known as “tram bau” (Vietnam), “ke khao” (Laos) or “sang kae” (Cambodia). The tree grows wildly or is planted in

Vietnam, Cambodia, Laos, Myanmar and Thailand. The tree is planted

along the banks of rivers or arroyos for firing. It is found throughout

Thailand especially in open, wet places. Height of tree is 5-10

meters, having young branchlets acutely quadrangular or very narrowly

quadrialate. Leaves are simple, opposite, elliptic or obovate, which are 3-

8 cm wide and 6-16 cm long: petiole acutely ridged. Inflorescence in

terminal and axillary spike; flowers are small having yellowish white

colour. Fruit are dry, thinly quadrialate: seed brownish red, ellipsoid, 4-

angled [2]. Various terpenoids and flavonoids constituents have been

isolated from this plant and some significant biological activities are

reported by different plant parts, crude extracts as well as isolated

phytochemicals. Therefore, the aim of this review article is to stimulate

present day researcher to undertake more systematic research work on

this important medicinal plant so as to isolate more phytochemicals and

to discover other significant biological activities of the plant.

Taxonomical background

The taxonomical classification of the plant is presented below:

Kingdom Plantae

Order Myrtales

Family Combretaceae

Genus Combretum

Species C. quadrangulare

Medicinal use

The plant is reported to have traditional use as medicine. Its seeds, leaves, and the stem bark are used in Vietnamese traditional

medicine as an antipyretic, antidysenteric, and anthelmintic agent. The seeds are administered orally together with ripe bananas as

an anthelmintic for ascariasis and oxyuriasis. [3]

Materials and Methods

The chemical constituents isolated and identified from Combretum quadrangulare, pharmacological activities exhibited by the

isolated compounds as well as by the crude plant extracts were searched across the Medline (National Library of Medicine) and

Science Direct databases. The data were updated in June 2014, using the search terms Combretum quadrangulare, chemical

constituents, biological activities, pharmacological activities or properties of Combretum quadrangulare as keywords. In addition, the

reference lists of all papers identified were thoroughly reviewed.

Results and discussion

Phytochemical constituents isolated from Combretum quadrangulare

Chemical constituents isolated so far from this plant are presented in Table 1. Most of the isolated compounds belong to the class of

triterpenoids and flavonoids. As per literature survey upto June 2014, ninety-seven chemical constituents (Structure No. 1-97, Table-

1) have been isolated so from this plant.

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Table 1: List of phytochemical constituents isolated from C. quadrangulare

Str.No. Compound Name Reference

Triterpenoids

1 Arjungenin [4]

2 Arjunglucoside I [4]

3 1α,3β-dihydroxy-cycloart-24-ene-30-carboxylic acid [5]

4 1α,3β-dihydroxy-cycloart-24-ene-30-carboxylic acid methyl ester [5]

5 (20ξ)-1α,3β,25-trihydroxy-cycloart-21-al-23-ene-30-carboxylic acid

methyl ester [5]

6 Quadrangularic acid F [6]

7 Quadrangularic acid J [6]

8 Quadrangularic acid G [6]

9 Methyl quadrangularate I [6]

10 24-epiquadrangularic acid M [6]

11 24-epiquadrangularic acid G [6]

12 Quadrangularic acid M [6]

13 Quadrangularic acid H [6]

14 Quadrangularic acid K [6]

15 Quadrangularic acid L [6]

16 24-epiquadrangularic acid L [6]

17 7β-hydroxy-23-deoxojessic acid

[6]

18 Norquadrangularic acid A [6]

19 Methyl quadrangularate A [7]

20 Methyl quadrangularate B [7,8]

21 Methyl quadrangularate C [7]

22 Methyl 24-epiquadrangularate C [7]

23 Methyl quadrangularate O [7]

24 Methyl quadrangularate D [7,8]

25 Quadragularol A [7]

26 Methyl quadrangularate N [7]

27 Quadragularol B [7]

28 Quadrangularic acid E [7]

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29 23-Deoxojessic acid [7]

30 1-O-acetyl-23-deoxojessic acid [7]

31 4β,14α-dimethyl-5α-ergosta-9β,19-cyclo-24(31)-en-3β-hydroxy-4α-

carboxylic acid [7]

32 Methyl 23-deoxojessate [7]

33 Methyl quadrangularate P [7]

34 Norquadrangularic acid B [7]

35 Norquadrangularic acid C [7]

36 Betulinic Acid [7]

37 2α,6β-dihydroxybetulinic acid [9]

38 6β-hydroxyhovenic acid [9]

39 Quadranoside II [9,10]

40 6β-hydroxyarjunic acid [9]

41 Arjunic acid [9]

42 Arjunolic acid [9,11]

43 Arjunglucoside II [9,11]

44 19α-hydroxyasiatic acid [9,10]

45 Nigaichigoside F1 [9,10]

46 Quadranoside IV [9,10,11]

47 2α,3β,23-trihydroxyurs-12,18-dienoic acid [9]

48 Glucosyl 2α,3β,23-trihydroxyurs-12,18-dien-28-oate [9]

49 Glucosyl 2α,3β,23-trihydroxyurs-12,19(20)-dien-28-oate [9]

50 Quadranoside I [10]

51 Quadranoside III [10]

52 Quadranoside V [10]

53 2α,3β,23-trihydroxyurs-12,19-dien-28-oic acid β-D-glucopyranosyl [4,10]

54 Pinfaensin [10]

55 Quadranoside VI [4]

56 Quadranoside VII [4]

57 Quadranoside VIII [4]

58 Quadranoside IX [4]

59 Rosamutin [4]

60 28-O-β-D-glucopyranosyl-6β,23-dihydroxytormentic acid [4]

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61 Quadranoside X [4]

62 Quadranoside XI [4]

63 Arjunetin [4]

64 Chebuloside II [4]

65 β-D-glucopyranosyl-2α,3β,6β-trihydroxyolean-12-en-28-oate [4,11]

66 Ursolic Acid [12]

67 Combretanone A [12]

68 Combretanone B [12]

69 Combretanone C [12]

70 Combretanone D [12]

71 Combretanone E [12]

72 Combretanone F [12]

73 Combretanone G [12]

74 Combretic acid A [12]

75 Combretic acid B [12]

Flavonoids

76 Kamatakenin [7]

77 Isokaempferide [7]

78 5,7,4′-trihydroxy-3,3′-dimethoxyflavone [7]

79 5,4′-dihydroxy-3,7,3′-trimethoxyflavone [7]

80 (+)-catechin [10]

81 (+)-gallocatechin [4]

82 (-)-epicatechin [4]

83 (-)-epigallocatechin [4]

84 Vitexin [10]

85 5,7,3′,5′-tetrahydroxy-3,4′-dimethoxyflavone [12]

86 Combretol [12]

87 3′,5-dihydroxy-3,4′,5′,7-tetramethoxyflavone [12]

88 Pachypodol [12]

89 Quercetin 3,4′-dimethyl ether [12]

90 Myricetin 3,3′,4′-trimethyl ether [12]

Miscellaneous

91 Gallic acid [10]

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92 Methyl gallate [10]

93 1-O-Galloyl-6-O-(4-hydroxy-3,5-dimethoxy)benzoyl-β-D-glucose [13]

94 β-sitosterol [7]

95 β-sitosterol glucoside [10]

96 5-methoxy-(-)-isolariciresinol [10]

97 5-methoxy-9β-xylopyranosyl-(-)-isolariciresinol [10]

Biological activity exhibited by the plant and phytochemicals isolated

Crude plant extracts as well as phytochemicals isolated from C. quadrangulare exhibited various biological activities as discussed

below:

Antibacterial activity

Crude methanolic extracts of C. quadrangulare seeds showed antibacterial activity against gram-positive cocci, methicillin-sensitive

S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) having MIC values of 1212 μg/mL and 606.25 μg/mL, respectively

[14]. The extract was also found to be active against non-fermentative gram-negative bacteria P. aeruginosa ATCC 27853 and

Acinetobacter baumanii, having MIC value 2425 μg/mL and 2425 μg/mL, respectively and fermentative gram-negative bacilli E. coli

having MIC value 9,700 μg/mL [14]. Somanabandhu et al. revealed t h a t ether and ethanolic extracts of dried root bark or dried

seeds of the plant are effective against earthworms when tested in vitro [15]. Dr ied leaf ex t rac t o f t he p lant was repor ted

to sho w a ntimicrobial activity against Helicobacter pylori [16]. Acetone, MeOH, and aqueous extracts of C. quadrangulare were

tested for their trypanocidal activity against epimastigotes of Trypanosoma cruzi, the causative agent of Chagas disease; acetone

extract being the most active [17].

Anti-HIV Activity The aqueous and EtOH extracts of C. quadrangulare were screened for their inhibitory activity against HIV-1 integrase (IN) - an

enzyme essential for viral replication. The investigators noted significant inhibitory activity against the tested enzyme for both the

aqueous and EtOH extract having IC50 values of 2.5 and 2.9 µg/mL, respectively [18].

Cytotoxic Activity

Cycloartane tritererpenoids and flavonoids isolated from the MeOH extract of leaves were subjected to cytotoxic activity against

highly liver metastatic murine colon 26-L5 carcinoma cells [7]. Methyl quadrangutarate B (20) and D (24) out of the tested terpenoids

exhibited strong cytotoxicity having ED50 values of 9.54 and 5.42 µM, respectively, whereas all the flavonoids (76-79) showed the

strong cytotoxicity having ED50 values less than 6 µM (Table-2)[7].

Table 2: Cytotoxic activity of the constituents isolated from C. quadrangulare

Compounds ED50 value

(µM)

Compound ED50 value

(µM)

Compound ED50 value

(µM)

19 43.8 27 17.6 32 65.7

20 9.5 28 58.6 34 65.9

21 18.9 78 5.2 36 59.7

23 52.6 79 4.5 76 3.0

24 5.4 29 49.6 77 1.8

25 49.7 30 57.7

26 61.4 31 62.4

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Hepatoprotective activity

Many plants are reported to exhibit hepatoprotective activity [19-21]. The hepatoprotective effect of MeOH, MeOH/H2O (1:1) and

aqueous extracts of C. quadrangulare seeds were examined on D-galactosamine (D-GalN)/tumor necrosis factor-α (TNF-α)-

induced cell death in primary cultured mouse hepatocytes [22]. The MeOH extract n o t o n l y showed the strongest

inhibitory effect on D-GalN/TNF-α-induced cell death (IC50 56.4 μg/mL) but also significantly lowered the serum GPT level in

mice with D-GalN/lipopolysaccharide (LPS)-induced liver injury [22].

Bio-guided separation of the MeOH extract led to the isolation of various classes of compound including triterpcne glucosides, lignans

and catechin derivatives. Among the isolated triterpene glucosides, lupane-type Quadranoside II (39), Quadranoside I (50) and

Quadranoside XI (62) exhibited hepatoprotective efficacy against n-GalN/TNF-α-induced cell death in primary cultured mouse

hepatocytes having IC50 values of 63.1, 59.8 and 76.2 μM, respectively whereas ursane-type Quadranoside V (52), mixture of

Glucosyl 2α,3β,23-trihydroxyurs-12,19(20)-dien-28-oate (49) and Glucosyl 2α,3β,23-trihydroxyurs-12,18-dien-28-oate acid (48),

and β-D-glucopyranosyl (53) exhibited strong hepatoprotective activity having IC50 values 30.2 and 34.6 μM, respectively. Other

isolated compounds like 1-O-galloyl-6-O-(4-hydroxy-3,5-dimethoxy)benzoyl-β-D-glucose (93), methyl gallate (92) and (-)-

epicatechin (82) were also found to exhibit potent hepatoprotective effect having IC50 values of 7.2, 19.9 and 71.2 μM, respectively

[22]. The compound 1 - O-galloyl-6-O-(4-hydroxy-3,5-dimethoxy)benzoyl-β-D-glucose (93), a gallic acid derivative isolated from C.

quadrangulare, demonstrated potent hepatoprotective activity against D-GalN/TNF-alpha-induced cell death in primary cultured

mouse hepatocytes with an IC50 of 3.3 μM [13].

The triterpenes of the lupane type, 2α,6β-dihydroxybetulinic acid (37) and 6β-hydroxyhovenic acid (38), isolated from the

MeOH extract of C. quadrangulare seeds, also exhibited strong hepatoprotective activity [9]. Both MeOH and water extracts of the

leaves of Combretum quadrangulare showed hepatoprotective effect dose-dependently with cell survival rates of 88.2±8.8% and

60.0±6.7%, respectively, at 100 μg/mL concentration as compared to control (cell survival rate 43.7±5.7%). This result indicated that

the MeOH extract had stronger hepatoprotective effect than the water extract, which is parallel to that obtained from the in vivo

experiment.

The MeOH extract of leaves of the plant showed significant hepatoprotective effect on Dgalactosamine (D-

GalN)/lipopolysaccharide (LPS)-induced experimental liver injury in mice and on DGalN/tumor necrosis factor-α (TNF-α)-

induced cell death in primary cultured mouse hepatocytes [23]. The compounds isolated from MeOH extract showed various

potencies of hepatoprotective effect on D-GalN/TNF-α-induced cell death in primary cultured mouse hepatocytes. Quadrangularol B

(27), methyl quadrangularate I (9), kamatakenin (76), 5,7,4'-trihydroxy-3,3'dimethoxyflavone (78), 5,4'-dihydroxy-3,7,3'-

trimethoxyflavone (79) and isokaempferide (77) showed strong inhibitory effect on TNF-α-induced cell death with IC50 values of

34.3, 33.7, 13.3, 22.4, 13.4 and 22.8 μM, respectively whereas clinically-used silibinin had an IC50 value of 39.6 μM while

glycyrrhizin showed very weak inhibitory effect. Methyl quadrangularates A (19) and N (26), norquadrangularic acid B (34) and

vitexin (84) also showed potent inhibition on TNF-α-induced cell death with IC50 values of 45.7, 89.3, 67.6 and 40.1 μM,

respectively, however the other isolated constituents like 4β,14α-dimethyl-5α-ergosta-9β,19-cyclo-24(31)-en-3β-hydroxy-4α-

carboxylic acid (31), Methyl quadrangularate D (24), 24-epiquadrangularic acid M (10), Quadrangularic acid H (13), 24-

epiquadrangularic acid L (16), Norquadrangularic acid C (35) and epimeric mixture of Methyl quadrangularate C (21) and Methyl

24-epiquadrangularate C (22) exhibited weak hepatoprotective activity against O-GalN/TNF-α-induced cell death in primary cultured

mouse hepatocytes. All these compounds were found to have stronger hepatoprotective effect than glycyrrhizin [23].

Conclusion

The present article deals with an up-to-date review on the chemistry and pharmacology of Combretum quadrangulare, a useful

medicinal plant from Combretaceae family finding applications in indigenous systems of medicine. Its seeds, leaves, and the stem

bark are used in Vietnamese traditional medicine as an antipyretic, antidysenteric, and anthelmintic agent. The isolated

phytochemicals as well as different extracts exhibited significant biological activities such as antimicrobial, anti-HIV, cytotoxic and

hepatoprotective activities and is established as a source of terpenoids, flavonoids and other phytochemicals. Exhaustive research

regarding isolation of more phytochemicals and pharmacology study on this medicinal plant is still necessary so as to explore the plant

regarding its medicinal importance. Therefore, the aim of this review is to boost up present day researchers in this direction to

undertake further investigations of this plant and we do anticipate that this plant will be much effective in drug development

programme in near future; present day researcher will surely undertake further research work on this medicinal plant for the

betterment of mankind.

Acknowledgements

The authors are thankful to the Department of Chemistry, Kulti College and Department of Chemistry, Saldiha College for providing

necessary infrastructural facilities to carry out the review work.

Authors’ Statements

Competing Interests

The authors declare no conflict of interest.

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Figure-1: Structure of the chemical constituents isolated from C. quadrangulare

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combretum quadrangulare (combretaceae) - phytochemical constituents and biological activity

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