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Review

Gaultheria: Phytochemical and Pharmacological Characteristics

School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China
*
Author to whom correspondence should be addressed.
Molecules 2013, 18(10), 12071-12108; https://doi.org/10.3390/molecules181012071
Submission received: 26 August 2013 / Revised: 22 September 2013 / Accepted: 24 September 2013 / Published: 30 September 2013
(This article belongs to the Section Natural Products Chemistry)

Abstract

:
The genus Gaultheria, comprised of approximately 134 species, is mostly used in ethnic drugs to cure rheumatism and relieve pain. Phytochemical investigations of the genus Gaultheria have revealed the presence of methyl salicylate derivatives, C6-C3 constituents, organic acids, terpenoids, steroids, and other compounds. Methyl salicylate glycoside is considered as a characteristic ingredient in this genus, whose anti-rheumatic effects may have a new mechanism of action. In this review, comprehensive information on the phytochemistry, volatile components and the pharmacology of the genus Gaultheria is provided to explore its potential and advance research.

1. Introduction

The genus Gaultheria (Ericaceae) is widely distributed around the Pacific Ocean, westwards to western slopes of the Himalayas and the southern areas of India [1]. Most Gaultheria species growing in Southwest China are regarded as traditional herbal medicines. Parts of plants in this genus are used by nine minority nationalities for the treatment of wind-damp, as well as relieving pain. Additionally, G. procumbens is used as a folk remedy in America and Canada, and G. fragrantissima is employed in India [2]. Modern research has demonstrated that these plants exhibit anti-inflammatory, anti-oxidative, antibacterial and analgesic activities. To the best of our knowledge, about 109 compounds were reported from this genus, including methyl salicylate derivatives, C6-C3 constituents, terpenoids, and steroids. In particular methyl salicylate (1) and three methyl salicylate glycosides, methyl salicylate 2-O-β-d-glucopyranoside (2), gaultherin (3) and methyl benzoate-2-O-β-d-xylopyranosyl(1-2)[O-β-d-xylopyranosyl(1-6)]-O-β-d-glucopyranoside (5), from the aerial parts of G. yunnanensis, display notable analgesic and anti-inflammatory activities, which has impelled a number of studies on the phytochemistry and biology of this genus [3]. Meanwhile, it’s worth mentioning that methyl salicylate glycoside when used in animal experiments to explore its pharmacological effects could overcome the side-effects caused by aspirin in the clinic [3,4,5]. Herein, we summarize the phytochemical and biological studies on the genus Gaultheria. What’s more, all the compounds reported in the essential oils of Gaultheria are listed below, and the corresponding plants are included as well.

2. Chemical Constituents

To date, extensive investigations on the chemical constituents from 34 species in the genus Gaultheria have led to the identification of 110 compounds, mostly assigned to five structural types, including methyl salicylate derivatives, C6-C3 constituents, terpenoids, steroids and other compounds. From an overall perspective, a majority of these compounds were found in two plants, G. yunnanensis and G. nummularioides. In this section, we summarize and classify all of the constituents in the genus Gautheria that have been reported. Their structures are shown below (see Figure 1), while the corresponding plant sources and references are collected in Table 1.
Figure 1. The structures of compounds 1109 from Gaultheria
Figure 1. The structures of compounds 1109 from Gaultheria
Molecules 18 12071 g001
Table 1. Chemical Constituents from Genus Gaultheria.
Table 1. Chemical Constituents from Genus Gaultheria.
No.NameResourcePlant partRef.
1Methyl salicylateG. yunnanensisAerial part[6]
2Methyl salicylate 2-O-β-d-glucopyranosideG. yunnanensisSeed[7]
3GaultherinG. yunnanensisAerial part[3,6]
G. yunnanensisSeed[7]
4Methyl salicylate 2-O-β-d-lactosideG. yunnanensis-[8]
5MSTG-AG. yunnanensis Aerial part[3]
6MSTG-BG. yunnanensis Aerial part[3]
7Kaempferol G. hispidaLeaf[9]
G. miquelianaLeaf[9]
G. procumbensLeaf[9]
G. trichophyllaLeaf[9]
8QuercetinG. cuneataLeaf[9]
G. depressaLeaf[9]
G. hispidaLeaf[9]
G. hookeriLeaf[9]
G. itoanaLeaf[9]
G. miquelianaLeaf[9]
G. mucronataLeaf[9]
G. procumbensLeaf[9]
G. shallonLeaf[9]
G. tasmanicaLeaf[9]
G. trichophyllaLeaf [9]
G. yunnanensis Roots[10]
G. nummularioidesWhole plant[11]
9MyricetinG. yunnanensisSeed[7]
G. shallonLeaf[9]
10QuercitrinG. yunnanensisWhole plant[10]
G. nummularioidesWhole plant[11]
11AvicularinG. nummularioidesWhole plant[11]
12Kaempferol-3-O-β-d-glucuronideG. leucocarpa var. yunnanensis or var. crenulataAerial part[6]
13Quercetin-3-O-β-d-glucuronideG. leucocarpa var. yunnanensis or var. crenulataAerial part[6]
G. miqueliana Leaf[12]
14RutinG. yunnanensis Root[10]
15HyperinG. nummularioidesWhole plant[13]
16Quercetin-3-O-α-l-rhamnopyranosideG. nummularioidesWhole plant[13]
17Quercetin 3-galactosideG. fragrantissimaLeaf[14]
18(+)-HomoeriodictyolG. nummularioidesWhole plant[11]
19Hesperetin G. nummularioidesWhole plant[11]
20HesperidinG. nummularioidesWhole plant[11]
21GinkgetinG. yunnanensisSeed[7]
22(+)-CatechinG. yunnanensis Root[10]
23Proanthocyanidin A-2G. yunnanensisRoot[10]
24Pavetannin A-1G. nummularioidesWhole plant[11]
25(+)-Lyoniresinol-2α-O-β-l-arabinopyranosideG. yunnanensis Root[15]
Root, stem and leaf[16]
G. griffithianaRoot, stem and leaf[16]
G. tetrameraRoot, stem and leaf[16]
G. leucocarpa var. cumingianaRoot, stem and leaf[16]
G. fragrantissimaRoot, stem and leaf[16]
26(+)-Lyoniresinol-2α-O-β-d-glucopyranosideG. yunnanensis Root[15]
Root, stem and leaf[16]
G. griffithianaRoot, stem and leaf[16]
G. tetrameraRoot, stem and leaf[16]
G. leucocarpa var. cumingianaRoot, stem and leaf[16]
G. fragrantissimaRoot, stem and leaf[16]
27(+)-LyoniresinolG. yunnanensisRoot[17]
28(-)-5'-MethoxyisolariciresinolG. yunnanensisRoot[17]
29(-)-Isolariciresinol-2α-O-β-d-xylopyranosideG. yunnanensis Root[15]
Root, stem and leaf[16]
G. griffithianaRoot, stem and leaf[16]
G. tetrameraRoot, stem and leaf[16]
G. leucocarpa var. cumingianaRoot, stem and leaf[16]
G. fragrantissimaRoot, stem and leaf[16]
30(-)-5'-Methoxyisolariciresinol-2α-O-β-d-xylopyranosideG. yunnanensisRoot[15]
31Gaultherin AG. yunnanensisRoot[18]
G. leucocarpa var. yunnanensis or var. crenualtaAerial part[6]
32Gaultherin BG. yunnanensis Root[18]
G. leucocarpa var. yunnanensis or var. crenualtaAerial part[6]
33Gaultherin DG. yunnanensis Root[19]
34Gaultherin CG. yunnanensis Root[19]
35Ferulic acidG. yunnanensis Root[10]
G. nummularioides -[20]
G. shallon -[20]
G. fragrantissima -[20]
G. cuneata -[20]
G. griffithiana -[20]
G. pyroloides -[20]
G. procumbens -[20]
G. depressa -[20]
G. hispida -[20]
G. tetramera -[20]
G. thymifolia -[20]
G. yunnunense -[20]
G. rengifoana -[20]
G. hispida -[20]
G. wisleyensis-[20]
G. eriophylla -[20]
36Cinnamic acid G. itoana Whole plant[21]
G. procumbens.Leaf[22]
37p-Coumaric acidG. nummularioides-[20]
G. nummularioides -[20]
G. shallon -[20]
G. fragrantissima -[20]
G. cuneata -[20]
G. griffithiana -[20]
G. hookeri -[20]
G. itoana -[20]
G. pyroloides -[20]
G. procumbens -[20]
Leaf[23]
G. depressa -[20]
G. tetramera -[20]
G. thymifolia -[20]
G. yunnunense -[20]
G. rengifoana -[20]
G. hispida -[20]
G. wisleyensis-[20]
G. eriophylla -[20]
G. procumbens.Leaf[22]
38Caffeic acidG. nummularioides -[20]
G. nummularioides -[20]
G. shallon -[20]
G. adenothrix-[20]
G. ovatifolia -[20]
G. humifusa-[20]
G. fragrantissima -[20]
G. cuneata -[20]
G. griffithiana -[20]
G. hookeri -[20]
G. itoana -[20]
G. pyroloides -[20]
G. procumbens -[20,24]
Leaf[23]
G. depressa -[20]
G. hispida-[20]
G. tetramera -[20]
G. thymifolia -[20]
G. yunnunense-[20]
G. rengifoana -[20]
G. hispida -[20]
G. wisleyensis-[20]
G. eriophylla -[20]
G. procumbens.Leaf[22]
39Sinapic acidG. nummularioides -[20]
G. shallon -[20]
G. griffithiana -[20]
G. itoana -[20]
G. hispida-[20]
G. tetramera -[20]
G. thymifolia -[20]
G. rengifoana -[20]
G. wisleyensis-[20]
G. eriophylla -[20]
40o-Coumaric acidG. procumbens Leaf[23]
41Chlorogenic acidG. yunnanensis Root[10]
42GaultheronoterpeneG. yunnanensis Root[25]
43Gaultheric acidG. yunnanensisRoot[25]
4413-Acetyl-14,18-dihydroxy-podocarpa-8,11,13-trieneG. itoana Whole plant[21]
G. itoana Whole plant[21]
4514,18-Dihydroxyabieta-8,11,13-trien-7-oneG. itoana Whole plant[21]
463β-Acetyl-12,25-diene-dammaraneG. yunnanensisRoot[26]
473β-Hydroxy-20(29)-lupen-28-aldehydeG. yunnanensisRoot[26]
48LupeolG. paniculata Aerial part[27]
493β-Acetoxy-20(29)-lupen-28-aldehydeG. yunnanensis Root[26]
50TaraxerolG. nummularioidesWhole plant[11]
51MaslinsaeureG. nummularioidesWhole plant[11]
523β-Acetyloleanolic acidG. yunnanensisRoot[26]
53Oleanolic acidG. nummularioidesWhole plant[11]
54α-Amyrin G. nummularioidesWhole plant[11]
553β-Acetoxy-urs-12-ene G. nummularioidesWhole plant[11]
56Ursolic acidG. yunnanensis Seed[7]
G. yunnanensis Root[26]
G. subcorymbosa Twig[28]
G. yunnanensis Aerial part[29]
G. fragrantissimaLeaf[14]
G. nummularioidesWhole plant[13]
573β-Dihydroxy-urs-12-en-28-oic acidG. nummularioidesWhole plant[11]
58Pomolic acidG. nummularioidesWhole plant[13]
59Tormentic acidG. nummularioidesWhole plant[13]
60Methyl ursolateG. subcorymbosa Twig[28]
61UvaolG. subcorymbosa Twig[28]
623β-Hydroxy-bauer-7-en-28-oic acid G. nummularioidesWhole plant[11]
63Euscaphic acid G. nummularioidesWhole plant[11]
64(22E,24R)-24-Methyl-5α-cholesta-7,22-diene-3β,5,6β-triol G. nummularioidesWhole plant[11]
65DaucosterolG. yunnanensisRoot[7,11,17]
66Benzoic acidG. miqueliana -[30]
G. procumbens.Leaf[31]
674-Hydroxybenzoic acidG. itoana Whole plant[21]
G. nummularioides-[20]
G. shallon -[20]
G. fragrantissima -[20]
G. cuneata -[20]
G. griffithiana -[20]
G. itoana -[20]
G. pyroloides -[20]
G. depressa -[20]
G. hispida -[20]
G. tetramera -[20]
G. thymifolia -[20]
G. rengifoana -[20]
G. hispida -[20]
G. wisleyensis-[20]
G. procumbens -[24]
G. procumbens.Leaf[22]
68Protocatechuic acidG. yunnanensis Root[10]
G. nummularioides-[20]
G. nummularioides -[20]
G. shallon -[20]
G. adenothrix-[20]
G. ovatifolia-[20]
G. humifusa-[20]
G. fragrantissima -[20]
G. cuneata -[20]
G. griffithiana -[20]
G. hookeri -[20]
G. itoana -[20]
G. pyroloides -[20]
G. procumbens -[20]
Leaf[23]
G. depressa -[20]
G. hispida -[20]
G. tetramera -[20]
G. thymifolia -[20]
G. rengifoana -[20]
G. hispida -[20]
G. wisleyensis-[20]
G. eriophylla -[20]
G. procumbens.Leaf[22]
69o-Pyrocatechuic acidG. nummularioides -[20]
G. nummularioides -[20]
G. shallon-[20]
G. adenothrix-[20]
G. ovatifolia -[20]
G. humifusa-[20]
G. fragrantissima -[20]
G. cuneata -[20]
G. griffithiana -[20]
G. hookeri -[20]
G. itoana -[20]
G. pyroloides -[20]
G. procumbens -[20,32,33]
Leaf[23]
G. tetramera -[20]
G. thymifolia -[20]
G. yunnunense -[20]
G. rengifoana -[20]
G. wisleyensis-[20]
G. eriophylla -[20]
G. procumbens.Leaf[22]
70β-Resorcylic acidG. superba-[24]
71Salicylic acidG. yunnanensis Root[10]
G. nummularioidesWhole plant[11]
G. nummularioides-[20]
G. fragrantissima -[20]
G. cuneata -[20]
Leaf[9]
G. griffithiana -[20]
G. hookeri -[20]
Leaf[9]
G. itoana -[20]
Leaf[9]
G. pyroloides -[20]
G. procumbens -[20]
Leaf[23]
Leaf[9]
G. hispidula-[20]
G. tetramera -[20]
G. rengifoana -[20]
G. miqueliana Leaf[34]
G. procumbens.Leaf[22]
G. trichophyllaLeaf[9]
72Acetylsyringic acidG. yunnanensis Root[17]
73Syringic acidG. shallon -[20]
G. pyroloides -[20]
G. procumbens -[20]
G. hispida -[20]
G. eriophylla -[20]
G. procumbens.Leaf[22]
74Vanillic acidG. yunnanensis Root[10]
G. itoana Whole plant[21]
G. yunnanensisAerial part[29]
G. nummularioidesWhole plant[11]
G. nummularioides -[20]
G. nummularioides -[20]
G. shallon -[20]
G. adenothrix-[20]
G. humifusa-[20]
G. fragrantissima -[20]
G. cuneata -[20]
G. griffithiana -[20]
G. hookeri -[20]
G. itoana -[20]
G. pyroloides -[20]
G. procumbens-[20]
Leaf[23]
-[24]
G. depressa -[20]
G. tetramera-[20]
G. thymifolia -[20]
G. yunnunense -[20]
G. rengifoana-[20]
G. hispida -[20]
G. wisleyensis-[20]
G. eriophylla -[20]
753,4,5-Trimethoxy-benzoic acidG. yunnanensis Root[17]
76Gentistic acidG. yunnanensisRoot[10]
G. nummularioides -[20]
G. nummularioides -[20]
G. shallon -[20]
G. adenothrix-[20]
G. ovatifolia -[20]
G. humifusa-[20]
G. fragrantissima -[20]
G. cuneata-[20]
G. griffithiana -[20]
G. hookeri -[20]
G. itoana -[20]
G. pyroloides -[20]
G. procumbens -[20]
Leaf[23]
-[33]
G. depressa -[20]
G. hispida -[20]
G. tetramera -[20]
G. thymifolia -[20]
G. rengifoana-[20]
G. hispida-[20]
G. wisleyensis-[20]
G. eriophylla -[20]
G. procumbens.Leaf[22]
77Methyl gentisateG. yunnanensisAerial part[6]
78VanillinG. procumbens.Leaf[22]
79HydroquinoneG. mucronataLeaf[9]
80(+)-Catechol G. nummularioidesWhole plant[11]
G. adenothrix-[20]
G. ovatifolia -[20]
G. humifusa-[20]
81Catechol-β-d-glucopyranoside G. ovatifolia Leaf[20]
82ArbutinG. adenothrix,Leaf[35]
83GaultheriadiolideG. yunnanensisSeed[7]
846-Ethyl-5-hydroxy-2,7-dimethoxy-1,4-naphthoquinoneG. yunnanensisSeed[7]
85ScopoletinG. yunnanensisRoot[17]
86FraxinelloneG. nummularioidesWhole plant[11]
87FraxinellononeG. nummularioidesWhole plant[11]
883,5-Dihydroxy-2-hydroxymethyl-4H-pyran-4-oneG. leucocarpa Bl var. crenulataLeaves and stem[36]
89(2S,3S,4R)-N-[(2R)-Hydroxytetracosanoyl]-1,3,4-trihydroxy-2-amino-6-octadeceneG. nummularioidesWhole plant[13]
90(2S,3S,4R,8Z),-2-[(2R)-Hydroxybehenoylamino]-8-octadecene-l,3,4-triol-1-O-β-d-glucopyranosideG. nummularioidesWhole plant[13]
91PreskimmianineG. nummularioidesWhole plant[11]
92DictamineG. nummularioidesWhole plant[11]
93ConfusamelineG. nummularioidesWhole plant[11]
94Hirsutine G. nummularioidesWhole plant[11]
95Gaultherialine AG. nummularioidesWhole plant[11]
96PentadecaneG. subcorymbosa Leafsurface wax[37]
G. antipoda Leafsurface wax[37]
97HexadecaneG. subcorymbosaLeafsurface wax[37]
G. antipoda Leafsurface wax[37]
98HeptadecaneG. subcorymbosa Leafsurface wax[37]
G. antipoda Leafsurface wax[37]
99OctadecaneG. subcorymbosa Leafsurface wax[37]
G. antipoda Leafsurface wax[37]
100NonadecaneG. subcorymbosa Leafsurface wax[37]
G. antipoda Leafsurface wax[37]
101EicosaneG. subcorymbosaLeafsurface wax[37]
G. antipodaLeafsurface wax[37]
102HeneicosaneG. subcorymbosa Leafsurface wax[37]
G. antipoda Leafsurface wax[37]
103DocosaneG. subcorymbosa Leafsurface wax[37]
G. antipoda Leafsurface wax[37]
104TricosaneG. subcorymbosa Leafsurface wax[37]
G. antipoda Leafsurface wax[37]
105n-DotriacontaneG. yunnanensis Aerial part[29]
106SqualeneG. nummularioidesWhole plant[11]
107OctadecanolG. nummularioidesWhole plant[13]
108Palmitic acidG. yunnanensis Root[17]
G. itoana Whole plant[21]
G. nummularioidesWhole plant[13]
109Stearic acidG. itoana Whole plant[21]
- no marked plant part.

2.1. Methyl Salicylate Derivatives

Methyl salicylate (1) and its glycoside derivatives 26, namely the methyl salicylate derivatives obtained from Gautheria species, possess remarkable analgesic and anti-inflammatory activities [3,6,7,8,38,39]. Methyl salicylate (1) is the chief component in the ethanol extract of the aerial part of G. yunnanensis. It also represents a large percentage in the volatile oils of Gaultheria plants [3,6,7]. Methyl salicylate has a wide range of applications in flavors, organic synthesis intermediates and solvents [3,38]. Medically, it has an important role in the anti-inflammatory and analgesic effects for dental medicine [38,39]. Structurally, methyl salicylate 2-O-β-d-glucopyranoside (2), gaultherin (3), methyl salicylate 2-O-β-d-lactoside (4), methyl benzoate-2-O-β-d-xylopyranosyl(1-2)[O-β-d-xylo-pyranosyl(1-6)]-O-β-d-glucopyranoside (MSTG-A) (5) and methyl benzoate-2-O-β-d-glucopyranosyl-(1-2)[O-β-d-xylopyranosyl(1-6)]-O-β-d-glucopyranoside (MSTG-B) (6) have one glucopyranosyl unit connected by an O-glycosidic bond to the C(1) position in the parent salicylic acid nucleus, and the carboxylic acid group in the C(2) position contains a methyl group in a formate ester. Compound 3 has a xylopyranosyl bound to the C(6′) of compound 2, and in compound 4 it is one galactopyranosyl. Up to now, methyl salicylate 2-O-β-d-lactoside (4) and MSTG-A (5) were only found in the G. yunnanensis. Those ingredients are probably the dominant chemical constituents of the G. yunnanensis responsible for curing rheumatism in traditional ethno-medicinal applications [3]. Nowadays many researchers consider the methyl salicylate glycosides as characteristic marker components in this genus, and as non-steroidal anti-inflammation drug (NSAID) leads, devoting themselves to finding other examples of those types of components in the genus, and trying to elucidate their mechanism of action for fighting rheumatism.

2.2. C6-C3 Constituents

There are 19 flavonoids, 10 lignans and seven simple phenylpropanoids in the genus Gaultheria [6,7,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,29].

2.2.1. Flavonoids

The sorts and contents of flavonoid in Gaultheria are relatively fewer than that of the other genus in the family Ericaceae. It has 18 flavonoids (compounds 724), mainly distributed in G. yunnanensis and G. nummularioides [6,7,9,10,11,12,13,14,29].
Compounds 717 are flavonols, with the C(5) and C(7) in ring-A, together with C(4′) in ring-B attached to hydroxyls. In compounds 917 the flavonol-aglycone is linked with different glycosyl groups (e.g., glucosyl, rhamnosyl, mannosyl, arabinosyl and galactosyl) at the C(3) position through O-glycosidic linkages. Kaempferol-3-O-β-d-glucuronide (12) and quercetin-3-O-β-d-glucuronide (13) are the only two glucuronides reported in G. yunnanensis [6]. Quercetin-3-O-α-l-rhamnopyranoside (16) was isolated from G. nummularioides, while hyperoside (17) comes from the leaves of G. fragrantissima. (+)-Homoeriodictyol (18), hesperetin (19) and hesperidin (20), which all were detected in the G. nummularioides, belong to the flavonone class, [11,13,14].Another, ginkgetin (21), is a dimeric-flavone. Proanthocyanidin A-2 (23) was found in the roots of G. yunnanensis, and pavetannin A-1 (24) in G. nummularioides [10,11].

2.2.2. Lignans

Compounds 2534 are cyclolignans, in which the aromatic carbon atom at the C(6) position of one phenylpropanoid unit is directly linked with the aliphatic carbon at the C(7′) position in the other C6-C3 unit. These sorts of compounds were also regarded in the past as active components against rheumatism in this genus [15,16,17,18,19]. The ten abovementioned compounds were all found in G. yunnanensis [6,15,16,17,18,19]. (+)-Lyoniresinol-2α-O-β-l-arabinopyranoside (25), (+)-lyoniresinol-2α-O-β-d-glucopyranoside (26) and (−)-isolariciresinol-2α-O-β-d-xylopyranoside (29) occur in the plants G. griffithiana, G. tetramera and G. fragrantissima [15,16,40]. The three lignans 25, 26 and 29 do not possess anti-inflammatory effects, while the n-butanol fraction from the roots of G. yunnanensis is rich in these three compounds and shows outstanding anti-inflammatory activities [40]. Ma et al. measured the contents of these three lignans from different parts of five species, G. fragrantissima, G. leucocarpa var. yunnanensis, G. leucocarpa var. cumingiana, G. tetramera and G. griffithiana. The contents of compounds 25 and 29 are the highest in the stems and roots of G. leucocarpa var. yunnanensis, and the lowest in the stems of G. fragrantissima. Moreover, the content of (+)-lyoniresinol-2α-O-β-d-glucopyranoside (26) is the highest in the roots of G. fragrantissima and the lowest in the roots of G. leucocarpa var. yunnanensis. The former is 25 times the latter. The sequence of the total content of those three lignans in roots is G. fragrantissima > G. leucocarpa var. yunnanensis > G. leucocarpa var. cumingiana > G. tetramera > G. griffithiana [16].
5-Methoxy-(+)-isolariciresinol-9,9′-diacetate (31) and (+)-lyoniresinol-9,9′-diacetate (32) are novel cyclolignan esters with two acetyls connected with the C(9) and C(9′) positions in the two lignans. The phytochemical properties, spectral analyses and chemical degradation play important roles in the chemical structures elucidation of the two compounds [6,18]. The compounds gaultherin D (33) and gaultherin C (34) are found in the roots of G. yunnanensis, which are employed as a medicinal part by the Bai nationality living in Yunnan Province [19].

2.2.3. Simple Phenylpropanoids

The seven simple phenylpropanoids 3541 are phenylacrylic acid derivatives. Ferulic acid (35), p-coumaric acid (37), caffeic acid (38) and sinapic acid (39) are widely reported in many plants of the genus Gaultheria [10,20,21,22,23,24].

2.3. Terpenoids

There are four diterpenes and 18 triterpenoids in the genus Gaultheria [7,11,13,14,21,25,26,27,28,29]. Compounds 4245 are diterpenes with tricyclic podocarpane-type skeletons, which were firstly reported in the genus Gaultheria. As new diterpenes, they might be useful as chemotaxonomic markers [21,25]. Among them, gaultheronoterpene (42) and gaultheric acid (43) are wildly distributed in the roots of G. yunnanensis [25].
Eighteen triterpenoids (from 46 to 63) include one dammarane tetracyclic triterpene, as well as lupane, oleanane, and ursane pentacyclic triterpanes. Among them, 3β-acetyl-dammarane-12,25-diene (46) was the first dammarane-type compound discovered in the family Ericaceae. Compounds 4749 are lupine triterpenoids. Both 47 and 48 display a hydroxyl functional-group at the C(3) position, while 49 has an acetoxy group instead. The methyl is joined to C(28) in compounds 48 and 49, and it is replaced by an aldehyde group in 47. As for the four oleanane-triterpenoids, taraxerol (50), maslinsaeure (51), 3β-acetyloleanoic acid (52) and oleanolic acid (53), the C-17 position is attached to a methyl (C-28) in 50, while in 5153 it has a carboxyl (C-28). The C-3 location of 52 is an acetoxy group, and the other oleanane-type triterpenoids have a hydroxyl in the same place. Compounds 5463 belong to the α-amyrane type triterpenoids. Ursolic acid (56) from G. yunnanensis, G. subcorymbosa, G. fragrantissima and G. nummularioides is used in the cosmetics industry [7,11,13,14,26,28,29,41]. Compounds 60 and 61 were obtained from the twigs of G. subcorymbosa, and the plant G. nummularioides contains compounds 54, 55, 57, 58 59, 62 and 63 [11,13,28].

2.4. Steroids

Only two steroids were reported in the genus Gaultheria. They are (22E,24R)-24-methyl-5α-cholesta-7,22-diene-3β,5α,6β-triol (64) and daucosterol (65), obtained from G. yunnanensis and G. nummularioides, respectively [7,11,17].

2.5. Other Compounds

Compounds 66109, which include benzoic acid derivatives, alkaloids, anthraquinones, dilactones and hydrocarbons, were obtained from G. yunnanensis, G. nummularioides, G. shallon, G. adenothrix, G. ovatifolia, G. humifusa, G. fragrantissima, G. cuneata, G. griffithiana, G. hookeri, G. itoana and G. pyroloides [6,7,9,10,11,13,17,20,21,22,23,24,29,30,31,32,33,34,35,36,37].
Compounds 6677 are benzoic acid derivatives, with several hydroxyl-, methoxyl- and formoxyl- groups connected to different positions of the benzoic acid. Methyl gentisate (77) from the aerial part of G. yunnanensis, is usually used as a skin-lightener and antioxidant. It appears to be more efficient than the free acid as well as other well-known hypopigmentation agents [6,42].
Gaultheriadiolide (83), a new dilactone from the seeds of G. yunnanensis, exhibited medium cytotoxic effect against HEp-2 and HepG2 cells, with IC50 of 23.337 μM and 29.4497 μM, respectively [43]. 6-Ethyl-5-hydroxy-2,7-dimethoxy-1,4-naphthoquinone (84) in the seeds of G. yunnanensis, was the only reported anthraquinone in the genus Gaultheria [7].
Fraxinellone (86) and fraxinellonone (87) are degradation products of the limonoids in G. nummularioides, which have obvious pharmacological activities [11]. Compound 86 possessed neuroprotective and vasorelaxing effects [17,44]. Fraxinellonone (87) exhibited moderate insect-antifeeding activity and ichthyotoxicity [45]. 3,5-Dihydroxy-2-hydroxymethyl-4H-pyran-4-one (88), is referred to as 3-hydroxykojic acid and 3-oxykojic acid. Structurally speaking, as the asymmetric unit, it consists of two nearly parallel molecules connected with a strong intermolecular O—HO hydrogen bond. This compound is only derived from G. leucocarpa, and is used for the treatment of rheumatoid arthritis, swelling pain, trauma, chronic tracheitis, cold and vertigo [36].
The alkaloid compounds 8995 were only found in G. nummularioides [11,13]. They possess several novel structural features, in which (2S,3S,4R,8Z),-2-[(2R)-hydroxybehenoylamino]-8-octadecene-l,3,4-triol-1-O-β-d-glucopyranoside (90) is the mono-glycoside of compound 89. Preskimmianine (91), dictamine (92), and confusameline (93) are quinoline derivatives. Hirsutine (94) is an indole alkaloid and gaultherialine A (95) was reported in the genus Gaultheria as a novel alkaloid [11].
Compounds 96105 are all alkanes having no branched chains, and they are derived from the leaf surface waxes of G. subcorymbosa and G. antipoda in addition to n-dotriacontane (105) [29,37]. Squalene (106) and octadecanol (107) occur in G. nummularioides. Palmitic acid (108) and stearic acid (109) are two saturated fatty acids found in the genus Gaultheria [13,17,21].

3. Volatile Chemical Constituents

The plants of the genus Gaultheria were first studied for their aromatic character. The essential oils of this genus were usually obtained by hydrodistillation, and their structures elucidated by gas chromatography-mass spectrometry (GC-MS) or solid-phase micro-extraction gas chromatography-mass spectrometry (SPME-GC-MS) [43,46,47,48,49,50,51,52,53,54]. Ninety seven chemical constituents were recently reported from the essential oils of four Gaultheria plants: G. yunnanensis, G. leucocarpa Bl var. crenulata, G. fragrantissima and G. procumbens (see Table 2). These essential oils are composed primarily of methyl salicylate (five compounds), alkanes (19 compounds), monoterpenes (22 compounds), sesquiterpenes (14 compounds) and aromatic derivatives (nine compounds). Methyl salicylates are major components found at fairly high concentrations (70–99%) in contrast with other components present in only trace amounts. Through odor-evaluation and blending, it was determined that essential oils of G. yunnanensis a sweet and long staying, and thus more suitable to make gum essence and tooth-paste fragrances. They have been the subject of extensive studies due to their economic importance. The constituents showed good prospects for application in the fragrance industry [47].

4. Biological Activities

Many studies have verified that the extracts and compounds derived from Gaultheria plants exhibit a wide spectrum of pharmacological activities in vitro and in vivo, covering anti-inflammatory, analgesic, anti-oxidative and antibacterial properties.

4.1. Anti-Inflammatory Activities

It was found that the H2O, EtOAc and n-butanol extracts of G. leucocarpa had remarkable anti-inflammatory activity by significantly reducing the level of joint swelling in a rat adjuvant-induced arthritis model [40].
A salicylate derivative fraction (SDF), which is rich in gaultherin (3) reported from G. yunnanensis, exhibited a significant inhibition of pain and inflammatory processes. Beyond that, compared with indomethacin, a positive control, SDF has strong inhibitory activity on the hind paw edema (200, 400 mg/kg body wt., p.o.) and ear swelling tests in mice (200, 400, 800 mg/kg body wt., p.o.) caused by carrageen and croton oil, respectively [3].
Table 2. Essential Oils of Genus Gaultheria.
Table 2. Essential Oils of Genus Gaultheria.
No.NameSourcePlant partPercentage (%)Ref.
1Methyl salicylateG. yunnanensisStem and leaf98.85[43]
G. yunnanensisRhizome74.18[46]
G. leucocarpa Bl var. crenulataLeaf95.93[47]
G. yunnanensisStem, Leaf, Root99.66[48]
G. yunnanensisWhole plant99.66[49]
G. yunnanensisRoot89.82[50]
G. yunnanensisBranch and leaf99.62[51]
G. fragrantissima Leaf94.60[52]
G. fragrantissima Leaf97.00[53]
G. procumbens -96.90[54]
2Ethyl salicylateG. yunnanensisStem and leaf0.05[43]
G. leucocarpa Bl var. crenulataLeaf0.34[47]
G. yunnanensisBranch and leaf0.02[51]
G. fragrantissima Leaf5.36[52]
3Phenyl salicylateG. yunnanensisStem and leaf0.11[43]
44-Methylene-1-( cis)-methyl ethyl-bicyclic(3,1,0)-normal HexaneG. yunnanensisStem and leaf0.17[43]
52-Methyl-decaneG. yunnanensisRhizome1.02[46]
6TridecaneG. yunnanensisRhizome0.24[46]
7TetradecaneG. yunnanensisRhizome0.37[46]
8PentadecaneG. yunnanensisRhizome1.38[46]
9HexadecaneG. yunnanensisRhizome1.59[46]
104-Methyl-pentadecaneG. yunnanensisRhizome0.24[46]
11HeptadecaneG. yunnanensisRhizome0.93[46]
122-Methyl-hexadecaneG. yunnanensisRhizome0.20[46]
133-Methyl-hexadecaneG. yunnanensisRhizome0.24[46]
14OctadecaneG. yunnanensisRhizome0.27[46]
152,6,10,14-Teramethyl-pentadecaneG. yunnanensisRhizome1.04[46]
16EicosaneG. yunnanensisRhizome0.28[46]
17PhytaneG. yunnanensisRhizome0.29[46]
181-Ethyl-2-methyl cyclododecaneG. yunnanensisRhizome0.30[46]
19PregnaneG. yunnanensisRhizome0.19[46]
20MethylcyclopentaneG. yunnanensisRoot6.53[50]
21CyclohexaneG. yunnanensisRoot2.69[50]
221,8-CineoleG. leucocarpa Bl var. crenulataLeaf1.40[47]
G. yunnanensisBranch and leaf0.09[51]
23Bornyl acetateG. leucocarpa Bl var. crenulataLeaf0.01[49]
G. yunnanensisBranch and leaf0.07[51]
24CedrolG. yunnanensisStem, Leaf, Roottrace amount[48]
G. yunnanensisWhole planttrace amount[49]
252-Methyl-5-(1,5-dimethyl-4-hexenyl)-1,3-cyclohexadieneG. yunnanensisStem and leaf trace amount[43]
26β-CaryophylleneG. yunnanensisRhizome0.56[46]
G. leucocarpa Bl var. crenulataLeaf0.01[47]
27β-MaalieneG. yunnanensisRhizome0.28[46]
28CalareneG. yunnanensisRhizome1.00[46]
29α-HumuleneG. yunnanensisRhizome0.40[46]
G. fragrantissimaLeaf [53]
30Germacrene DG. yunnanensisRhizome0.19[46]
31cis-α-BisaboleneG. yunnanensisRhizome0.30[46]
32β-BisaboleneG. yunnanensisRhizome0.38[46]
337- Epi-α-selineneG. yunnanensisRhizome0.12[46]
342-Hydroxy-4-methoxyacetophenoneG. yunnanensisRhizome1.09[46]
354-Methyl-2,6-ditertbutylphenolG. yunnanensisRhizome0.15[46]
36ElemicineG. yunnanensisStem, Leaf, Roottrace amount[48]
G. yunnanensisWhole planttrace amount[49]
37m-CymeneG. yunnanensisBranch and leaf0.04[51]
381-HexadeceneG. yunnanensisRhizome0.13[46]
39NonanalG. yunnanensisStem and leaf 0.12[43]
402-DecenalG. yunnanensisStem and leaf0.05[43]
416-Methyl-5-heptene-2-oneG. yunnanensisStem and leaf0.26[43]
426,10-Dimethyl-5,9-undecadien-2-oneG. yunnanensisStem and leaf0.29[43]
43Ethyl laurateG. yunnanensisRhizome0.42[46]
44Ethyl myristateG. yunnanensisRhizome0.60[46]
45Bornane-2,6-dioneG. yunnanensisRhizome0.21[46]
46Ethyl pentadecanoateG. yunnanensisRhizome0.16[46]
47Ethyl palmitateG. yunnanensisRhizome0.43[46]
48Driman-3-olG. yunnanensisRhizome0.18[46]
49HexanolG. yunnanensisStem, Leaf, Root0.03[48]
G. yunnanensisWhole plant0.03[49]
50HexanalG. yunnanensisStem, Leaf, Root0.03[48]
51trans-2-HexenalG. yunnanensisStem, Leaf, Root0.16[48]
52HexenalG. yunnanensisWhole plant0.03[49]
53PalmiticG. yunnanensisRoot0.18[50]
549-Octadecenic acidG. yunnanensisRoot0.04[50]
55Hexaacetyl-mannitolG. yunnanensisRoot0.04[50]
56Sorbitol-hexaacetateG. yunnanensisRoot0.03[50]
57Benzyl salicylateG. leucocarpa Bl var. crenulataLeaf0.07[47]
58p-Hydroxy-methyl salicylateG. leucocarpa Bl var. crenulataLeaf0.04[47]
59l,3,3-Trimethyl-tricyclo[2,2,1,O2,6]-heptaneG. leucocarpa Bl var. crenulataLeaf0.14[47]
60LinaloolG. leucocarpa Bl var. crenulataLeaf0.03[47]
61GeraniolG. leucocarpa Bl var. crenulataLeaf0.10[47]
62CitronellalG. leucocarpa Bl var. crenulataLeaf0.05[47]
63Methyl geranateG. leucocarpa Bl var. crenulataLeaf0.01[47]
64NeralG. leucocarpa Bl var. crenulataLeaf0.01[47]
65α-ThujeneG. leucocarpa Bl var. crenulataLeaf0.02[47]
66p-Mentha-1(7),2-dieneG. leucocarpa Bl var. crenulataLeaf0.10[47]
67CaraneG. leucocarpa Bl var. crenulataLeaf0.01[47]
68α-phellandrene G. leucocarpa Bl var. crenulataLeaf0.03[47]
69β-ElemeneG. leucocarpa Bl var. crenulataLeaf0.06[47]
70α-TerpineneG. leucocarpa Bl var. crenulataLeaf0.01[47]
711,8(9)-p-MenthadieneG. leucocarpa Bl var. crenulataLeaf0.01[47]
72MyrceneG. leucocarpa Bl var. crenulataLeaf0.18[47]
G. procumbens-0.09[54]
73OcimeneG. leucocarpa Bl var. crenulataLeaf0.58[47]
74α-PineneG. leucocarpa Bl var. crenulataLeaf0.01[47]
G. fragrantissimaLeaftrace amount[53]
G. procumbens-0.22[54]
75β-PineneG. leucocarpa Bl var. crenulataLeaf0.13[47]
G. fragrantissimaLeaftrace amount[53]
G. procumbens-0.25[54]
76IsoeugenolG. leucocarpa Bl var. crenulataLeaf0.01[47]
77Methyl isoeugenolG. leucocarpa Bl var. crenulataLeaf0.01[47]
78AromadendreneG. leucocarpa Bl var. crenulataLeaf0.01[47]
792,3,5,6-Tetramethyl- p-benzoquirioneG. leucocarpa Bl var. crenulataLeaf0.15[47]
801,3,5-Trimcthyl-2-methoxy-benzeneG. leucocarpa Bl var. crenulataLeaf0.01[47]
812,6-Dithydoxy-benzoicacid methylesterG. leucocarpa Bl var. crenulataLeaf0.02[47]
82EugenolG. leucocarpa Bl var. crenulataLeaf0.02[47]
83Methyl eugenolG. leucocarpa Bl var. crenulataLeaf0.01[47]
841-UndeceneG. leucocarpa Bl var. crenulataLeaf0.01[47]
853-Methyl-2-butanolG. leucocarpa Bl var. crenulataLeaf0.03[47]
863-Hexen-1-olG. leucocarpa Bl var. crenulataLeaf0.15[47]
87γ-IononeG. leucocarpa Bl var. crenulataLeaf0.01[47]
884-Acetoxy-1- p-mentheneG. leucocarpa Bl var. crenulataLeaf0.02[47]
89Geranyl acetateG. leucocarpa Bl var. crenulataLeaf0.01[47]
906-Methyl-1-heptanolG. leucocarpa Bl var. crenulataLeaf0.01[47]
91△3-CareneG. fragrantissimaLeaftrace amount[53]
92LongifoleneG. fragrantissimaLeaf0.80[53]
93Caryophylene oxideG. fragrantissimaLeaftrace amount[53]
94LimoneneG. procumbens-2.17[54]
95SabineneG. procumbens-0.08[54]
96FenchoneG. procumbens-0.17[54]
97MenthoneG. procumbens-0.12[54]
-no marked plant part.
Gaultherin (3), having a similar chemical structure to aspirin, inhibited the abdominal contractions in the acetic acid-induced writhing test in mice at a dosage of 200 mg/kg. Compared to aspirin, it did not show gastric ulcerogenic effects, which is the main clinical side-effect of aspirin. The possible reason is that gaultherin released salicylate in the intestine slowly, not in stomach and it left the cyclooxygenase-1 unaffected. It was the source of cytoprotective prostaglandin in gastric epithelium [55]. Methyl salicylate 2-O-β-d-lactoside (4) inhibits the IKK/NF-κB signal pathway to protect from LPS-induced inflammation [8]. MSTG-A (5) and MSTG-B (6) from G. yunnanensis display anti-inflammatory effects through inhibiting the production of pro-inflammatory cytokines, NO and ROS. The two methyl salicylate glycosides dose-dependently inhibited the production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6, respectively. They also can remarkably suppress the accumulation of NO, with an inhibitory rate of 56.20% and 51.72% at 3.0 μg/mL concentration, respectively [56].

4.2. Analgesic Activities

Zhang et al. reported that EtOAc and n-butanol fractions of G. yunnanensis roots (100 mg/kg and 200 mg/kg) have remarkable anti-inflammatory effects through significantly inhibiting murine peritoneal capillary permeability [57].

4.3. Anti-Oxidative Activities

Li et al analyzed the antioxidant capacity of different polar parts and furthermore, gradient elution samples obtained through macroporous resin column chromatography from an EtOH extract of G. leucocarpa were also tested. The ethyl acetate part and the 100% MeOH-elution part showed more striking ABTS and DPPH radical scavenging effects. The major constituent of the 100% MeOH is quercetin-3-O-β-d-glucuronide (13), which is suggested to be responsible for the efficacy [58]. In 2011, it was demonstrated that the fruit extracts of G. fragrantissima and G. tiliaefolia possessed anti-oxidative activities [59]. The EtOAc extract of G. shallon displayed a high anti-oxidative activity in scavenging DPPH with an IC50 value of 14.76 ± 0.85 μg/mL, compared to ascorbic acid (IC50 = 18.53 ± 1.58 µg/mL), as reference compound [60].

4.4. Antibacterial Activities

The 95% EtOH extract, the EtOAc, and n-butanol fractions of the stems or roots of G. leucocarpa significantly inhibited Staphylococcus aureus. Additionally, the EtOAc and n-butanol parts of G. leucocarpa stem revealed certain inhibitory effects towards Escherichia coli and Pseudomonas aeruginosa [61]. The essential oil from the leaves of G. yunnanens presented similar antibacterial effects as methyl salicylate. It has antibacterial activity against E. coli and S. aureus, but the essential oil is superior to methyl salicylate, and the lowest antimicrobial concentration is 0.3125% and 5%, respectively [38].

4.5. Others

13-Acetyl-14,18-dihydroxy-podocarpa-8,11,13-triene (44) and 14,18-dihydroxyabieta-8,11,13-trien-7-one (45) from G. itoana showed significant cytotoxicities against LNCaP. Compared with the relevant clinical chemotherapeutic drug taxol, compound 44 seemed to have lower IC50 value against LNCaP [21]. Gaultheriadiolide (83), a new dilactone from the seeds of G. yunnanensis, exhibited medium cytotoxic effect against HEp-2 and HepG2 cells, with IC50 of 23.337 μM and 29.4497 μM, respectively [43]. Fraxinellone (86) was reported to possess neuroprotective and vasorelaxing activities [17,44].

5. Conclusions

This article summarized a total of 109 compounds and abundant volatile components that have been reported from the genus Gaultheria, with 63 references cited. The genus Gaultheria is widely distributed all over the World, and many species have been used as traditional herbal medicines [62,63]. So far, phytochemical research on the genus has revealed the extensive presence of methyl salicylate derivatives, C6-C3 constituents, terpenoids, and other compound types, together with prolific essential oils. The pharmacological activities of pure compounds and crude extract from this genus were mainly focused on anti-inflammatory and analgesic properties. For their significantly anti-inflammatory activities, methyl salicylate glycoside is a research hotspot in the abovementioned plants. So far, some experiments point out the anti-rheumatic effects of methyl salicylate derivatives may be due to a new mechanism of action. As a whole, the phytochemical and biological investigations were mainly concentrated on the G. yunnanensis, with little or no attention being paid to other species. This species has several fractions with demonstrated anti-inflammatory and analgesic abilities. In view of this background, plenty of further studies are necessary in order to examine the other plants of the Gaultheria genus, together with the some fractions and different constituents of the G. yunnanensis to identify the medicine effects. The authors hope this review will provide valuable data for the exploration and advanced research on Gaultheria species.

Acknowledgments

Financial support of this work was provided by National Natural Science Foundation of China (No. 81001697), Beijing Nova Program (No. 2011070), Self-Selected Topic of Beijing University of Chinese Medicine (No. 2011JYB22XS-061), National Training Programs of Innovation and Entrepreneurship for Undergraduates (NO. 201210026051), Excellent Talents of Beijing (NO. 2012B009999000003), Innovative Research Team of Beijing University of Chinese Medicine (NO. 2011-CXTD-12) and Scientific Research Project of Beijing Educational Committee for Undergraduates (NO. BJGJ1114 and BJGJ1115).

Conflicts of Interest

The authors declare no conflict of interest.

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MDPI and ACS Style

Liu, W.-R.; Qiao, W.-L.; Liu, Z.-Z.; Wang, X.-H.; Jiang, R.; Li, S.-Y.; Shi, R.-B.; She, G.-M. Gaultheria: Phytochemical and Pharmacological Characteristics. Molecules 2013, 18, 12071-12108. https://doi.org/10.3390/molecules181012071

AMA Style

Liu W-R, Qiao W-L, Liu Z-Z, Wang X-H, Jiang R, Li S-Y, Shi R-B, She G-M. Gaultheria: Phytochemical and Pharmacological Characteristics. Molecules. 2013; 18(10):12071-12108. https://doi.org/10.3390/molecules181012071

Chicago/Turabian Style

Liu, Wei-Rui, Wen-Lin Qiao, Zi-Zhen Liu, Xiao-Hong Wang, Rui Jiang, Shu-Yi Li, Ren-Bing Shi, and Gai-Mei She. 2013. "Gaultheria: Phytochemical and Pharmacological Characteristics" Molecules 18, no. 10: 12071-12108. https://doi.org/10.3390/molecules181012071

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