Gaultheria: Phytochemical and Pharmacological Characteristics

Liu, Wei-Rui; Qiao, Wen-Lin; Liu, Zi-Zhen; Wang, Xiao-Hong; Jiang, Rui; Li, Shu-Yi; Shi, Ren-Bing; She, Gai-Mei

doi:10.3390/molecules181012071

Open AccessReview

Gaultheria: Phytochemical and Pharmacological Characteristics

by

Wei-Rui Liu

,

Wen-Lin Qiao

,

Zi-Zhen Liu

,

Xiao-Hong Wang

,

Rui Jiang

,

Shu-Yi Li

,

Ren-Bing Shi

and

Gai-Mei She

^*

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)

Download

Browse Figure

Versions Notes

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.

Keywords:

Gaultheria; chemical components; pharmacological activity; methyl salicylate glycosides; anti-rheumatic effects

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 1–109 from Gaultheria

Table 1. Chemical Constituents from Genus Gaultheria.

**Table 1.** Chemical Constituents from Genus Gaultheria.
No.	Name	Resource	Plant part	Ref.
1	Methyl salicylate	G. yunnanensis	Aerial part	[6]
2	Methyl salicylate 2-O-β-d-glucopyranoside	G. yunnanensis	Seed	[7]
3	Gaultherin	G. yunnanensis	Aerial part	[3,6]
		G. yunnanensis	Seed	[7]
4	Methyl salicylate 2-O-β-d-lactoside	G. yunnanensis	-	[8]
5	MSTG-A	G. yunnanensis	Aerial part	[3]
6	MSTG-B	G. yunnanensis	Aerial part	[3]
7	Kaempferol	G. hispida	Leaf	[9]
		G. miqueliana	Leaf	[9]
		G. procumbens	Leaf	[9]
		G. trichophylla	Leaf	[9]
8	Quercetin	G. cuneata	Leaf	[9]
		G. depressa	Leaf	[9]
		G. hispida	Leaf	[9]
		G. hookeri	Leaf	[9]
		G. itoana	Leaf	[9]
		G. miqueliana	Leaf	[9]
		G. mucronata	Leaf	[9]
		G. procumbens	Leaf	[9]
		G. shallon	Leaf	[9]
		G. tasmanica	Leaf	[9]
		G. trichophylla	Leaf	[9]
		G. yunnanensis	Roots	[10]
		G. nummularioides	Whole plant	[11]
9	Myricetin	G. yunnanensis	Seed	[7]
		G. shallon	Leaf	[9]
10	Quercitrin	G. yunnanensis	Whole plant	[10]
		G. nummularioides	Whole plant	[11]
11	Avicularin	G. nummularioides	Whole plant	[11]
12	Kaempferol-3-O-β-d-glucuronide	G. leucocarpa var. yunnanensis or var. crenulata	Aerial part	[6]
13	Quercetin-3-O-β-d-glucuronide	G. leucocarpa var. yunnanensis or var. crenulata	Aerial part	[6]
		G. miqueliana	Leaf	[12]
14	Rutin	G. yunnanensis	Root	[10]
15	Hyperin	G. nummularioides	Whole plant	[13]
16	Quercetin-3-O-α-l-rhamnopyranoside	G. nummularioides	Whole plant	[13]
17	Quercetin 3-galactoside	G. fragrantissima	Leaf	[14]
18	(+)-Homoeriodictyol	G. nummularioides	Whole plant	[11]
19	Hesperetin	G. nummularioides	Whole plant	[11]
20	Hesperidin	G. nummularioides	Whole plant	[11]
21	Ginkgetin	G. yunnanensis	Seed	[7]
22	(+)-Catechin	G. yunnanensis	Root	[10]
23	Proanthocyanidin A-2	G. yunnanensis	Root	[10]
24	Pavetannin A-1	G. nummularioides	Whole plant	[11]
25	(+)-Lyoniresinol-2α-O-β-l-arabinopyranoside	G. yunnanensis	Root	[15]
			Root, stem and leaf	[16]
		G. griffithiana	Root, stem and leaf	[16]
		G. tetramera	Root, stem and leaf	[16]
		G. leucocarpa var. cumingiana	Root, stem and leaf	[16]
		G. fragrantissima	Root, stem and leaf	[16]
26	(+)-Lyoniresinol-2α-O-β-d-glucopyranoside	G. yunnanensis	Root	[15]
			Root, stem and leaf	[16]
		G. griffithiana	Root, stem and leaf	[16]
		G. tetramera	Root, stem and leaf	[16]
		G. leucocarpa var. cumingiana	Root, stem and leaf	[16]
		G. fragrantissima	Root, stem and leaf	[16]
27	(+)-Lyoniresinol	G. yunnanensis	Root	[17]
28	(-)-5'-Methoxyisolariciresinol	G. yunnanensis	Root	[17]
29	(-)-Isolariciresinol-2α-O-β-d-xylopyranoside	G. yunnanensis	Root	[15]
			Root, stem and leaf	[16]
		G. griffithiana	Root, stem and leaf	[16]
		G. tetramera	Root, stem and leaf	[16]
		G. leucocarpa var. cumingiana	Root, stem and leaf	[16]
		G. fragrantissima	Root, stem and leaf	[16]
30	(-)-5'-Methoxyisolariciresinol-2α-O-β-d-xylopyranoside	G. yunnanensis	Root	[15]
31	Gaultherin A	G. yunnanensis	Root	[18]
		G. leucocarpa var. yunnanensis or var. crenualta	Aerial part	[6]
32	Gaultherin B	G. yunnanensis	Root	[18]
		G. leucocarpa var. yunnanensis or var. crenualta	Aerial part	[6]
33	Gaultherin D	G. yunnanensis	Root	[19]
34	Gaultherin C	G. yunnanensis	Root	[19]
35	Ferulic acid	G. 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]
36	Cinnamic acid	G. itoana	Whole plant	[21]
		G. procumbens.	Leaf	[22]
37	p-Coumaric acid	G. 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]
38	Caffeic acid	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	-	[20,24]
			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]
39	Sinapic acid	G. 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]
40	o-Coumaric acid	G. procumbens	Leaf	[23]
41	Chlorogenic acid	G. yunnanensis	Root	[10]
42	Gaultheronoterpene	G. yunnanensis	Root	[25]
43	Gaultheric acid	G. yunnanensis	Root	[25]
44	13-Acetyl-14,18-dihydroxy-podocarpa-8,11,13-triene	G. itoana	Whole plant	[21]
		G. itoana	Whole plant	[21]
45	14,18-Dihydroxyabieta-8,11,13-trien-7-one	G. itoana	Whole plant	[21]
46	3β-Acetyl-12,25-diene-dammarane	G. yunnanensis	Root	[26]
47	3β-Hydroxy-20(29)-lupen-28-aldehyde	G. yunnanensis	Root	[26]
48	Lupeol	G. paniculata	Aerial part	[27]
49	3β-Acetoxy-20(29)-lupen-28-aldehyde	G. yunnanensis	Root	[26]
50	Taraxerol	G. nummularioides	Whole plant	[11]
51	Maslinsaeure	G. nummularioides	Whole plant	[11]
52	3β-Acetyloleanolic acid	G. yunnanensis	Root	[26]
53	Oleanolic acid	G. nummularioides	Whole plant	[11]
54	α-Amyrin	G. nummularioides	Whole plant	[11]
55	3β-Acetoxy-urs-12-ene	G. nummularioides	Whole plant	[11]
56	Ursolic acid	G. yunnanensis	Seed	[7]
		G. yunnanensis	Root	[26]
		G. subcorymbosa	Twig	[28]
		G. yunnanensis	Aerial part	[29]
		G. fragrantissima	Leaf	[14]
		G. nummularioides	Whole plant	[13]
57	3β-Dihydroxy-urs-12-en-28-oic acid	G. nummularioides	Whole plant	[11]
58	Pomolic acid	G. nummularioides	Whole plant	[13]
59	Tormentic acid	G. nummularioides	Whole plant	[13]
60	Methyl ursolate	G. subcorymbosa	Twig	[28]
61	Uvaol	G. subcorymbosa	Twig	[28]
62	3β-Hydroxy-bauer-7-en-28-oic acid	G. nummularioides	Whole plant	[11]
63	Euscaphic acid	G. nummularioides	Whole plant	[11]
64	(22E,24R)-24-Methyl-5α-cholesta-7,22-diene-3β,5,6β-triol	G. nummularioides	Whole plant	[11]
65	Daucosterol	G. yunnanensis	Root	[7,11,17]
66	Benzoic acid	G. miqueliana	-	[30]
		G. procumbens.	Leaf	[31]
67	4-Hydroxybenzoic acid	G. 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]
68	Protocatechuic acid	G. 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]
69	o-Pyrocatechuic acid	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	-	[20,32,33]
			Leaf	[23]
		G. tetramera	-	[20]
		G. thymifolia	-	[20]
		G. yunnunense	-	[20]
		G. rengifoana	-	[20]
		G. wisleyensis	-	[20]
		G. eriophylla	-	[20]
		G. procumbens.	Leaf	[22]
70	β-Resorcylic acid	G. superba	-	[24]
71	Salicylic acid	G. yunnanensis	Root	[10]
		G. nummularioides	Whole 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. trichophylla	Leaf	[9]
72	Acetylsyringic acid	G. yunnanensis	Root	[17]
73	Syringic acid	G. shallon	-	[20]
		G. pyroloides	-	[20]
		G. procumbens	-	[20]
		G. hispida	-	[20]
		G. eriophylla	-	[20]
		G. procumbens.	Leaf	[22]
74	Vanillic acid	G. yunnanensis	Root	[10]
		G. itoana	Whole plant	[21]
		G. yunnanensis	Aerial part	[29]
		G. nummularioides	Whole 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]
75	3,4,5-Trimethoxy-benzoic acid	G. yunnanensis	Root	[17]
76	Gentistic acid	G. 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]
			-	[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]
77	Methyl gentisate	G. yunnanensis	Aerial part	[6]
78	Vanillin	G. procumbens.	Leaf	[22]
79	Hydroquinone	G. mucronata	Leaf	[9]
80	(+)-Catechol	G. nummularioides	Whole plant	[11]
		G. adenothrix	-	[20]
		G. ovatifolia	-	[20]
		G. humifusa	-	[20]
81	Catechol-β-d-glucopyranoside	G. ovatifolia	Leaf	[20]
82	Arbutin	G. adenothrix,	Leaf	[35]
83	Gaultheriadiolide	G. yunnanensis	Seed	[7]
84	6-Ethyl-5-hydroxy-2,7-dimethoxy-1,4-naphthoquinone	G. yunnanensis	Seed	[7]
85	Scopoletin	G. yunnanensis	Root	[17]
86	Fraxinellone	G. nummularioides	Whole plant	[11]
87	Fraxinellonone	G. nummularioides	Whole plant	[11]
88	3,5-Dihydroxy-2-hydroxymethyl-4H-pyran-4-one	G. leucocarpa Bl var. crenulata	Leaves and stem	[36]
89	(2S,3S,4R)-N-[(2R)-Hydroxytetracosanoyl]-1,3,4-trihydroxy-2-amino-6-octadecene	G. nummularioides	Whole plant	[13]
90	(2S,3S,4R,8Z),-2-[(2R)-Hydroxybehenoylamino]-8-octadecene-l,3,4-triol-1-O-β-d-glucopyranoside	G. nummularioides	Whole plant	[13]
91	Preskimmianine	G. nummularioides	Whole plant	[11]
92	Dictamine	G. nummularioides	Whole plant	[11]
93	Confusameline	G. nummularioides	Whole plant	[11]
94	Hirsutine	G. nummularioides	Whole plant	[11]
95	Gaultherialine A	G. nummularioides	Whole plant	[11]
96	Pentadecane	G. subcorymbosa	Leafsurface wax	[37]
		G. antipoda	Leafsurface wax	[37]
97	Hexadecane	G. subcorymbosa	Leafsurface wax	[37]
		G. antipoda	Leafsurface wax	[37]
98	Heptadecane	G. subcorymbosa	Leafsurface wax	[37]
		G. antipoda	Leafsurface wax	[37]
99	Octadecane	G. subcorymbosa	Leafsurface wax	[37]
		G. antipoda	Leafsurface wax	[37]
100	Nonadecane	G. subcorymbosa	Leafsurface wax	[37]
		G. antipoda	Leafsurface wax	[37]
101	Eicosane	G. subcorymbosa	Leafsurface wax	[37]
		G. antipoda	Leafsurface wax	[37]
102	Heneicosane	G. subcorymbosa	Leafsurface wax	[37]
		G. antipoda	Leafsurface wax	[37]
103	Docosane	G. subcorymbosa	Leafsurface wax	[37]
		G. antipoda	Leafsurface wax	[37]
104	Tricosane	G. subcorymbosa	Leafsurface wax	[37]
		G. antipoda	Leafsurface wax	[37]
105	n-Dotriacontane	G. yunnanensis	Aerial part	[29]
106	Squalene	G. nummularioides	Whole plant	[11]
107	Octadecanol	G. nummularioides	Whole plant	[13]
108	Palmitic acid	G. yunnanensis	Root	[17]
		G. itoana	Whole plant	[21]
		G. nummularioides	Whole plant	[13]
109	Stearic acid	G. itoana	Whole plant	[21]

- no marked plant part.

2.1. Methyl Salicylate Derivatives

Methyl salicylate (1) and its glycoside derivatives 2–6, 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 7–24), mainly distributed in G. yunnanensis and G. nummularioides [6,7,9,10,11,12,13,14,29].

Compounds 7–17 are flavonols, with the C(5) and C(7) in ring-A, together with C(4′) in ring-B attached to hydroxyls. In compounds 9–17 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 25–34 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 35–41 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 42–45 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 47–49 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 51–53 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 54–63 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 66–109, 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 66–77 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—H^…O 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 89–95 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 96–105 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.	Name	Source	Plant part	Percentage (%)	Ref.
1	Methyl salicylate	G. yunnanensis	Stem and leaf	98.85	[43]
		G. yunnanensis	Rhizome	74.18	[46]
		G. leucocarpa Bl var. crenulata	Leaf	95.93	[47]
		G. yunnanensis	Stem, Leaf, Root	99.66	[48]
		G. yunnanensis	Whole plant	99.66	[49]
		G. yunnanensis	Root	89.82	[50]
		G. yunnanensis	Branch and leaf	99.62	[51]
		G. fragrantissima	Leaf	94.60	[52]
		G. fragrantissima	Leaf	97.00	[53]
		G. procumbens	-	96.90	[54]
2	Ethyl salicylate	G. yunnanensis	Stem and leaf	0.05	[43]
		G. leucocarpa Bl var. crenulata	Leaf	0.34	[47]
		G. yunnanensis	Branch and leaf	0.02	[51]
		G. fragrantissima	Leaf	5.36	[52]
3	Phenyl salicylate	G. yunnanensis	Stem and leaf	0.11	[43]
4	4-Methylene-1-( cis)-methyl ethyl-bicyclic(3,1,0)-normal Hexane	G. yunnanensis	Stem and leaf	0.17	[43]
5	2-Methyl-decane	G. yunnanensis	Rhizome	1.02	[46]
6	Tridecane	G. yunnanensis	Rhizome	0.24	[46]
7	Tetradecane	G. yunnanensis	Rhizome	0.37	[46]
8	Pentadecane	G. yunnanensis	Rhizome	1.38	[46]
9	Hexadecane	G. yunnanensis	Rhizome	1.59	[46]
10	4-Methyl-pentadecane	G. yunnanensis	Rhizome	0.24	[46]
11	Heptadecane	G. yunnanensis	Rhizome	0.93	[46]
12	2-Methyl-hexadecane	G. yunnanensis	Rhizome	0.20	[46]
13	3-Methyl-hexadecane	G. yunnanensis	Rhizome	0.24	[46]
14	Octadecane	G. yunnanensis	Rhizome	0.27	[46]
15	2,6,10,14-Teramethyl-pentadecane	G. yunnanensis	Rhizome	1.04	[46]
16	Eicosane	G. yunnanensis	Rhizome	0.28	[46]
17	Phytane	G. yunnanensis	Rhizome	0.29	[46]
18	1-Ethyl-2-methyl cyclododecane	G. yunnanensis	Rhizome	0.30	[46]
19	Pregnane	G. yunnanensis	Rhizome	0.19	[46]
20	Methylcyclopentane	G. yunnanensis	Root	6.53	[50]
21	Cyclohexane	G. yunnanensis	Root	2.69	[50]
22	1,8-Cineole	G. leucocarpa Bl var. crenulata	Leaf	1.40	[47]
		G. yunnanensis	Branch and leaf	0.09	[51]
23	Bornyl acetate	G. leucocarpa Bl var. crenulata	Leaf	0.01	[49]
		G. yunnanensis	Branch and leaf	0.07	[51]
24	Cedrol	G. yunnanensis	Stem, Leaf, Root	trace amount	[48]
		G. yunnanensis	Whole plant	trace amount	[49]
25	2-Methyl-5-(1,5-dimethyl-4-hexenyl)-1,3-cyclohexadiene	G. yunnanensis	Stem and leaf	trace amount	[43]
26	β-Caryophyllene	G. yunnanensis	Rhizome	0.56	[46]
		G. leucocarpa Bl var. crenulata	Leaf	0.01	[47]
27	β-Maaliene	G. yunnanensis	Rhizome	0.28	[46]
28	Calarene	G. yunnanensis	Rhizome	1.00	[46]
29	α-Humulene	G. yunnanensis	Rhizome	0.40	[46]
		G. fragrantissima	Leaf		[53]
30	Germacrene D	G. yunnanensis	Rhizome	0.19	[46]
31	cis-α-Bisabolene	G. yunnanensis	Rhizome	0.30	[46]
32	β-Bisabolene	G. yunnanensis	Rhizome	0.38	[46]
33	7- Epi-α-selinene	G. yunnanensis	Rhizome	0.12	[46]
34	2-Hydroxy-4-methoxyacetophenone	G. yunnanensis	Rhizome	1.09	[46]
35	4-Methyl-2,6-ditertbutylphenol	G. yunnanensis	Rhizome	0.15	[46]
36	Elemicine	G. yunnanensis	Stem, Leaf, Root	trace amount	[48]
		G. yunnanensis	Whole plant	trace amount	[49]
37	m-Cymene	G. yunnanensis	Branch and leaf	0.04	[51]
38	1-Hexadecene	G. yunnanensis	Rhizome	0.13	[46]
39	Nonanal	G. yunnanensis	Stem and leaf	0.12	[43]
40	2-Decenal	G. yunnanensis	Stem and leaf	0.05	[43]
41	6-Methyl-5-heptene-2-one	G. yunnanensis	Stem and leaf	0.26	[43]
42	6,10-Dimethyl-5,9-undecadien-2-one	G. yunnanensis	Stem and leaf	0.29	[43]
43	Ethyl laurate	G. yunnanensis	Rhizome	0.42	[46]
44	Ethyl myristate	G. yunnanensis	Rhizome	0.60	[46]
45	Bornane-2,6-dione	G. yunnanensis	Rhizome	0.21	[46]
46	Ethyl pentadecanoate	G. yunnanensis	Rhizome	0.16	[46]
47	Ethyl palmitate	G. yunnanensis	Rhizome	0.43	[46]
48	Driman-3-ol	G. yunnanensis	Rhizome	0.18	[46]
49	Hexanol	G. yunnanensis	Stem, Leaf, Root	0.03	[48]
		G. yunnanensis	Whole plant	0.03	[49]
50	Hexanal	G. yunnanensis	Stem, Leaf, Root	0.03	[48]
51	trans-2-Hexenal	G. yunnanensis	Stem, Leaf, Root	0.16	[48]
52	Hexenal	G. yunnanensis	Whole plant	0.03	[49]
53	Palmitic	G. yunnanensis	Root	0.18	[50]
54	9-Octadecenic acid	G. yunnanensis	Root	0.04	[50]
55	Hexaacetyl-mannitol	G. yunnanensis	Root	0.04	[50]
56	Sorbitol-hexaacetate	G. yunnanensis	Root	0.03	[50]
57	Benzyl salicylate	G. leucocarpa Bl var. crenulata	Leaf	0.07	[47]
58	p-Hydroxy-methyl salicylate	G. leucocarpa Bl var. crenulata	Leaf	0.04	[47]
59	l,3,3-Trimethyl-tricyclo[2,2,1,O^2,6]-heptane	G. leucocarpa Bl var. crenulata	Leaf	0.14	[47]
60	Linalool	G. leucocarpa Bl var. crenulata	Leaf	0.03	[47]
61	Geraniol	G. leucocarpa Bl var. crenulata	Leaf	0.10	[47]
62	Citronellal	G. leucocarpa Bl var. crenulata	Leaf	0.05	[47]
63	Methyl geranate	G. leucocarpa Bl var. crenulata	Leaf	0.01	[47]
64	Neral	G. leucocarpa Bl var. crenulata	Leaf	0.01	[47]
65	α-Thujene	G. leucocarpa Bl var. crenulata	Leaf	0.02	[47]
66	p-Mentha-1(7),2-diene	G. leucocarpa Bl var. crenulata	Leaf	0.10	[47]
67	Carane	G. leucocarpa Bl var. crenulata	Leaf	0.01	[47]
68	α-phellandrene	G. leucocarpa Bl var. crenulata	Leaf	0.03	[47]
69	β-Elemene	G. leucocarpa Bl var. crenulata	Leaf	0.06	[47]
70	α-Terpinene	G. leucocarpa Bl var. crenulata	Leaf	0.01	[47]
71	1,8(9)-p-Menthadiene	G. leucocarpa Bl var. crenulata	Leaf	0.01	[47]
72	Myrcene	G. leucocarpa Bl var. crenulata	Leaf	0.18	[47]
		G. procumbens	-	0.09	[54]
73	Ocimene	G. leucocarpa Bl var. crenulata	Leaf	0.58	[47]
74	α-Pinene	G. leucocarpa Bl var. crenulata	Leaf	0.01	[47]
		G. fragrantissima	Leaf	trace amount	[53]
		G. procumbens	-	0.22	[54]
75	β-Pinene	G. leucocarpa Bl var. crenulata	Leaf	0.13	[47]
		G. fragrantissima	Leaf	trace amount	[53]
		G. procumbens	-	0.25	[54]
76	Isoeugenol	G. leucocarpa Bl var. crenulata	Leaf	0.01	[47]
77	Methyl isoeugenol	G. leucocarpa Bl var. crenulata	Leaf	0.01	[47]
78	Aromadendrene	G. leucocarpa Bl var. crenulata	Leaf	0.01	[47]
79	2,3,5,6-Tetramethyl- p-benzoquirione	G. leucocarpa Bl var. crenulata	Leaf	0.15	[47]
80	1,3,5-Trimcthyl-2-methoxy-benzene	G. leucocarpa Bl var. crenulata	Leaf	0.01	[47]
81	2,6-Dithydoxy-benzoicacid methylester	G. leucocarpa Bl var. crenulata	Leaf	0.02	[47]
82	Eugenol	G. leucocarpa Bl var. crenulata	Leaf	0.02	[47]
83	Methyl eugenol	G. leucocarpa Bl var. crenulata	Leaf	0.01	[47]
84	1-Undecene	G. leucocarpa Bl var. crenulata	Leaf	0.01	[47]
85	3-Methyl-2-butanol	G. leucocarpa Bl var. crenulata	Leaf	0.03	[47]
86	3-Hexen-1-ol	G. leucocarpa Bl var. crenulata	Leaf	0.15	[47]
87	γ-Ionone	G. leucocarpa Bl var. crenulata	Leaf	0.01	[47]
88	4-Acetoxy-1- p-menthene	G. leucocarpa Bl var. crenulata	Leaf	0.02	[47]
89	Geranyl acetate	G. leucocarpa Bl var. crenulata	Leaf	0.01	[47]
90	6-Methyl-1-heptanol	G. leucocarpa Bl var. crenulata	Leaf	0.01	[47]
91	△3-Carene	G. fragrantissima	Leaf	trace amount	[53]
92	Longifolene	G. fragrantissima	Leaf	0.80	[53]
93	Caryophylene oxide	G. fragrantissima	Leaf	trace amount	[53]
94	Limonene	G. procumbens	-	2.17	[54]
95	Sabinene	G. procumbens	-	0.08	[54]
96	Fenchone	G. procumbens	-	0.17	[54]
97	Menthone	G. 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.

References

Mabberiey, D.J. The Plant-Book, 2nd ed.; Cambridge University Press: Cambridge, UK, 1997; p. 295. [Google Scholar]
Simon, J.E.; Chadwick, A.F.; Craker, L.E. Herbs: An Indexed Bibliography, 1st ed.; Archon Books: Hamden, CT, USA, 1984. [Google Scholar]
Zhang, B.; Li, J.B.; Zhang, D.M.; Ding, Y.; Du, G.H. Analgesic and anti-inflammatory activities of a fraction rich in Gaultherin isolated from Gaultheria yunnanensis (Franch.) Rehder. Biol. Pharm. Bull. 2007, 30, 465–469. [Google Scholar]
Hirsh, J.M.D. Progress review: The relationship between dose of Aspirin, side-effects and antithrombotic effectiveness. Stroke 1985, 16, 1–4. [Google Scholar] [CrossRef]
Levy, M. Aspirin use in patients with major upper gastrointestinal bleeding and peptic-ulcer disease. N. Engl. J. Med. 1974, 290, 1158–1162. [Google Scholar] [CrossRef]
She, G.M.; Li, D.C.; Zhang, Y.; Guo, Z.Q.; Lv, H.N.; She, D.M. Chemical consitituent of aerial parts of Dianbaizhu (Gaultheria leucocarpa var. yunnanensis or var. crenulata). J. Beijing Univ. Tradit. Chin. Med. 2010, 33, 62–72. [Google Scholar]
Li, J.; Li, F.; Lu, Y.Y.; Su, X.J.; Huang, C.P.; Lu, X.W. A new dilactone from the seeds of Gaultheria yunnanensis. Fitoterapia 2010, 81, 35–37. [Google Scholar] [CrossRef]
Zhang, T.T.; Sun, L.; Liu, R.; Zhang, D.; Lan, X.; Huang, C.; Xin, W.Y.; Wang, C.; Zhang, D.M.; Du, G.H. A novel naturally occurring salicylic acid analogue acts as an anti-inflammatory agent by inhibiting nuclear factor-kappaB activity in RAW264.7 macrophages. Mol. Pharm. 2012, 9, 671–677. [Google Scholar]
David, J.; Middleton, F.L.S. A chemotaxonomic survey of flavonoids and simple phenols in the leaves of Gaultheria L. and related genera (Ericaceae). Bot. J. Linn. Soc. 1992, 110, 313–324. [Google Scholar] [CrossRef]
Zhang, Z.Z.; Koike, K.; Guo, D.A.; Li, C.L.; Zheng, J.H.; Jia, Z.H.; Nikaido, T. Studies on the chemical constituents of yunnan wintergreen root Gaulheria yunnanensis (II). Chin. Tradit. Herb. Drugs. 1999, 30, 167–169. [Google Scholar]
Yang, M.F.; Li, Y.Y.; Li, B.G.; Zhang, G.L. A novel alkaloid from Gaultheria nummularioides. J. Asian. Nat. Prod. Res. 2007, 9, 183–186. [Google Scholar] [CrossRef]
Sasaki, T.; Watanabe, Y. Components of the leaves of Gaultheria miqueliana Takeda. J. Pharm. Soc. Jpn. 1956, 76, 892–894. [Google Scholar]
Yang, M.F. Phytochemical investigation on three plants and Studies on synthesis and characterization of mesoporous silica materials. PhD thesis, Chengdu Institute of Organic Chemistry, the Chinese Academy of Sciences, Sichuan, China, 2004. [Google Scholar]
Murthy, K.S.; Babu, M.R. Chemical investigation of the leaves of Gaultheria fragrantissima Wall. Indian J. Pharm. 1972, 125, 34–38. [Google Scholar]
Zhang, Z.Z.; Guo, D.A.; Li, C.L.; Zheng, J.H.; Koike, K.; Jia, Z.H.; Nikaido, T. Studies on the lignan glycosides from Gaultheria yunnanensis. Acta. Pharm. Sin. 1999, 34, 128–131. [Google Scholar]
Ma, X.J.; Zhao, L.; Han, Z.T.; Zheng, J.H.; Chen, X.Z. Comparison of the contents of lignans in 5 medicinal plants of Gaultheia by HPLC. J. Plant Resour. Environ. 2002, 11, 61–62. [Google Scholar]
Zhang, Z.Z.; Guo, D.A.; Li, C.L.; Zheng, J.H.; Koike, K.; Jia, Z.H.; Nikaido, T. Studies on the chemical constituents of yunnan wintergreen (Gaultheria yuannanensis) (I). Chin. Tradit. Herb. Drugs 1998, 29, 508–511. [Google Scholar]
Zhang, Z.Z.; Guo, D.A.; Li, C.L.; Zheng, J.H.; Koike, K.; Jia, Z.H.; Nikaido, T. Gaultherins A and B, two lignans from Gaultheria yunnanensis. Phytochemistry 1999, 51, 469–472. [Google Scholar]
Zhang, Z.Z.; Guo, D.A.; Li, C.L.; Zheng, J.H.; Koike, K.; Jia, Z.H.; Nikaido, T. Gaultherins C and D, two new lignans from the roots of Gaultheria yunnanensis. Heterocycles 2000, 53, 675–679. [Google Scholar] [CrossRef]
Towers, G.H.N.; Tse, A.; Maass, W.S.G. Phenolic acids and phenolic glycosides of Gaultheria species. Phytochemistry 1966, 5, 677–681. [Google Scholar] [CrossRef]
Chen, C.Y.; Lin, R.J.; Huang, J.C.; Wu, Y.H.; Cheng, M.J.; Hung, H.C.; Lo, W.L. Chemical constituents from the whole plant of Gaultheria itoana Hayata. Chem. Biodivers. 2009, 6, 1737–1743. [Google Scholar] [CrossRef]
Grisebach, H.; Vollmer, K.O. On the biosynthesis of benzoic acids in Gaultheria procumbens L. II. Z. Naturforsch. B. 1964, 19, 781–783. [Google Scholar]
EL-Basyouni, S.Z.; Chen, D.; Ibraim, R.K.; Neish, A.C.; Towers, G.H.N. The biosynthesis of hydroxybenzoic acids in higher plants. Phytochemistry 1964, 3, 485–492. [Google Scholar]
Ibrahim, R.K.; Towers, G.H.N. The identification, by chromatography, of plant phenolic acids. Arch. Biochem. Biophys. 1960, 87, 125–128. [Google Scholar] [CrossRef]
Zhang, Z.Z.; Guo, D.A.; Li, C.L.; Zheng, J.H.; Koike, K.; Jia, Z.H.; Nikaido, T. Two diterpenoids from the roots of Gaultheria yunnanensis. J. Nat. Prod. 1999, 62, 297–298. [Google Scholar] [CrossRef]
Zhang, Z.Z.; Guo, D.A.; Li, C.L.; Zheng, J.H.; Koike, K.; Jia, Z.H.; Nikaido, T. Studies on the chemical constituents of yunnan wintergreen (Gaultheria yuannanensis)(III). Chin. Tradit. Herb. Drugs 1999, 30, 247–250. [Google Scholar]
Cambie, R.C.; Parnell, J.C. A New Zealand phytochemical survey, VII. Constituents of some dicotyledons. New Zealand Journal of Science 1969, 12, 453–466. [Google Scholar]
Alauddin, M.; Bryce, T.A.; Clayton, E.; Martin-Smith, M.; Subramanian, G. Triterpenoids from new zealand plants. isolation of ursolic acid from Gaultheria subcorymbosa Col. J. Chem. Soc. 1965, 4611–4612. [Google Scholar]
Ma, X.J.; Du, C.F.; Zheng, J.H.; Chen, X.Z. Studies on chemical constituents of Gaultheria leucocarpa var. yunnanensis (Franch.) T. Z. Hsu & R. C. Fang. Chin. J. Chin. Ma. Med. 2001, 26, 844–846. [Google Scholar]
Belousova, M.V.; Grakhov, V.P.; Berozovskaya, T.P.; Dmitruk, S.U.; Komissarenko, N.F. Free phenolic acids of ericaceous plants of Siberia and the Russian Far East. Rastitel'Nye Resursy 1999, 35, 74–81. [Google Scholar]
Vollmer, K.O.; Grisebach, H. Biosynthesis of benzoic acids in Gaultheria procumbens. III. Z. Naturforsch. B 1966, 21, 435–439. [Google Scholar]
Ibrahim, R.K. The distribution of o-pyrocatechuic acid in plants. Naturwissenschaften 1963, 50, 734. [Google Scholar] [CrossRef]
Ibrahim, R.K.; Towers, G.H.N. Conversion of salicylic acid to gentisic acid and o-pyrocatechuic acid, all labeled with carbon-14, in plants. Nature 1959, 184, 1803. [Google Scholar] [CrossRef]
Fujii, K.; Matsukawa, T. Constitution of Gaultheria miqueliana Takeda. Yakugaku Zasshi 1936, 56, 641–642. [Google Scholar]
Kariyone, T.; Hashimoto, Y. Microchemical detection of plant constituents. II. detection of arbutin. Yakugaku Zasshi 1943, 63, 120–121. [Google Scholar]
Yao, G.M.; Wang, Y.B.; Wang, L.Q.; Qin, G.W. 3,5-Dihydroxy-2-hydroxymethyl-4H-pyran-4-one. Acta. Cryst. 2005, E61, o1403–o1405. [Google Scholar]
Eglinton, G.; Hamilton, R.J.; Martin-Smith, M. The alkane constituents of some New Zealand plants and their possible taxonomic implications. Phytochemistry 1962, 1, 137–145. [Google Scholar]
Wang, Y.F.; Yao, N.; Tang, B. Studies on antimicrobial activity of essential oil from the leaves of Gaultheria yunnanensis. Shanxi J. Tradit. Chin. Med. 2005, 26, 1385–1386. [Google Scholar]
Li, R.Q. A research abstracting methyl salicylate from the leaves of purpurea. J. Sichuan Vocat. Tech. Coll. 2005, 15, 90–91. [Google Scholar]
Xiong, Y.L.; Xiao, B.; Ma, X.J.; Li, C.L.; Zheng, J.H.; Ye, J. Effects of Gaultheria yunnanensis on adjuvant arthritis in rats. Chin. J. Chin. Mat. Med. 2009, 34, 2516–2519. [Google Scholar]
Zhang, M.F.; Shen, Y.Q. Research advances on hepatoprotective activities of oleanolic acid and ursolic acid. Anti. Infect. Pharm. 2012, 9, 13–19. [Google Scholar]
Song, C.W.; Xiong, L.D.; Wang, Y.J.; Zhang, N.; Li, X.; Li, Y.; Li, L.; Yin, S.F. Synthesis and inhibition of tyrosinase acitivity of new gentisic acid derivatives. Chin. J. Org. Chem. 2012, 32, 1753–1758. [Google Scholar] [CrossRef]
Chen, S.Z. Analysis of chemical compositions of volatile oil from Gaultheria yunnanensis (Franch) Rehd. Chin. Tradit. Herb. Drugs 1990, 20, 42–43. [Google Scholar]
Kim, J.H.; Park, Y.M.; Shin, J.S.; Park, S.J.; Choi, J.H.; Jung, H.J.; Park, H.J.; Lee, K.T. Fraxinellone Inhibits Lipopolysaccharide-Induced inducible nitric oxide synthase and cyclooxygenase-2 Expression by Negatively regulating nuclear factor-kappa B in RAW 264.7 macrophages cells. Biol. Pharm. Bull. 2009, 32, 1062–1068. [Google Scholar] [CrossRef]
Hiroaki, O.; Keiko, Y.; Keiji, M.; Tetsuo, L.; Munehiro, N. Synthesis and biological activities of degraded limonoids, (±)-fraxinellonone and its related compounds. Tetrahedron. Lett. 1997, 38, 263–266. [Google Scholar] [CrossRef]
Wu, Q.; Ye, C.; Han, W.; Song, P.L.; Zou, H.Y. Analysis of volatile oil in Gaultheria yunnanensis (Franch) Rehder. by SPME-GC-MS. J. Henan Univ. (Med. Sci.) 2007, 26, 32–33. [Google Scholar]
Wang, Y.F.; Li, X.F.; Yu, Z.X.; Zhang, Q.G.; Yang, X.H. The chemical constituents of the essential oil from the leaves of Gaultheria leucocarpa BL.var. crenulata (Kura.) T.Z. HSU. Acta Agric. Univ. Jiangxiensis 1992, 14, 250–255. [Google Scholar]
Ma, X.Y.; Wei, T.; Zhai, J.J.; Chen, Y.Z. Analysis of chemical compositions of volatile oil from root of Gaultheria yunnanensis in Guiyang province. J. Instrumental. Anal. 1992, 11, 63. [Google Scholar]
Yang, J.S.; Ma, J.J.; Yang, L.; Wu, J.L. Studies on solid adsorption and stability of essential oil from pericarp of Gaultheria yunnaensis (Franch.) Rehd. Chin. J. Chin. Mat. Med. 1998, 23, 29–32. [Google Scholar]
Tao, C.; Luo, Y.N.; Yang, X.S.; Wang, D.P. Analysis of chemical compositions of volatile oil from root of Gaultheria yunnanensis (Franch) Rehd. J. Anhui. Agric. Sci. 2011, 39, 114–117. [Google Scholar]
Zhang, J.W.; Guo, X.Y. Analysis of chemical compositions of volatile oil of Gaultheria yunnanensis (Franch) Rehd. J. Guiyang Coll. Tradit. Chin. Med. 1994, 4, 56–57. [Google Scholar]
Kim, J.; Seo, S.M.; Park , I.K. Nematicidal activity of plant essential oils and components from Gaultheria fragrantissima and Zanthoxylum alatum against the pine wood nematode, Bursaphelenchus xylophilus. Nematology 2011, 13, 87–93. [Google Scholar] [CrossRef]
Adhikary, S.R.; Bashyal, B.P. Aromatic plants of Nepal-part IV. essential oil from Gaultheria fragrantissima Wall. J. Nepal Pharm. 1985, 12, 9–19. [Google Scholar]
Nikolić, M.; Marković, T.; Mojović, M.; Pejin, B.; Savić, A.; Perić, T.; Marković, D.; Stević, T.; Soković, M. Chemical composition and biological activity of Gaultheria procumbens L. essential oil. Ind. Crop. Prod. 2013, 49, 561–567. [Google Scholar] [CrossRef]
Zhang, B.; He, X.L.; Ding, Y.; Du, G.H. Gaultherin, a natural salicylate derivative from Gaultheria yunnanensis. towards a better non-steroidal anti-inflammatory drug. Eur. J. Pharmacol. 2006, 530, 166–171. [Google Scholar] [CrossRef]
Zhang, D.; Liu, R.; Sun, L.; Huang, C.; Wang, C.; Zhang, D.M.; Zhang, T.T.; Du, G.H. Anti-inflammatory activity of methyl salicylate glycosides isolated from Gaultheria yunnanensis (Franch.) Rehder. Molecules 2011, 16, 3875–3884. [Google Scholar] [CrossRef]
Zhang, Z.Z.; Guo, D.A.; Li, C.L.; Zheng, J.H. Study on antibaeterial, anti-inflammatory and analgesic activities of Gaultheria yunnanensis. Northwest Pharm. J. 1999, 14, 60–61. [Google Scholar]
Li, D.C.; Guo, Z.Q.; Lv, H.N.; She, G.M. Antioxidant activity of extracts from G.aultheria leucocarpa var. yunnanensis. Acta Chin. Med. Pharm. 2010, 38, 62–66. [Google Scholar]
Karuppusamy, S.; Muthuraja, G.; Rajasekaran, K.M. Antioxidant activity of selected lesser known edible fruits from western ghats of India. Indian. J. Nat. Prod. Res. 2011, 2, 174–178. [Google Scholar]
Ulyana, M.A.; Daniel, E.A.; Ma, J.; Michael, H.N.; Edward, J.K. Antioxidant capacities of ten edible North American plants. Phytother. Res. 2002, 16, 63–65. [Google Scholar]
Ma, X.J.; Zhao, L.; Du, C.F. Screening of anti-bacteria activity of extracts of Gaultheria leucocarpa var. yunnanensis. Chin. J. Chin. Mat. Med. 2001, 26, 223–226. [Google Scholar]
Middleton, D.J. Infrageneric classification of the genus Gaultheria L. (Ericaceae). Botl. J. Linn. Soc 1991, 106, 229–258. [Google Scholar] [CrossRef]
Hsu, T.Z. Preliminary study of classification on Chinese Gaultheria. Acta. Bot. Yunnanica. 1981, 3, 417–434. [Google Scholar]

© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).

Share and Cite

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

APA Style

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

Article Menu

Gaultheria: Phytochemical and Pharmacological Characteristics

Abstract

1. Introduction

2. Chemical Constituents

2.1. Methyl Salicylate Derivatives

2.2. C₆-C₃ Constituents

2.2.1. Flavonoids

2.2.2. Lignans

2.2.3. Simple Phenylpropanoids

2.3. Terpenoids

2.4. Steroids

2.5. Other Compounds

3. Volatile Chemical Constituents

4. Biological Activities

4.1. Anti-Inﬂammatory Activities

4.2. Analgesic Activities

4.3. Anti-Oxidative Activities

4.4. Antibacterial Activities

4.5. Others

5. Conclusions

Acknowledgments

Conflicts of Interest

References

Share and Cite

Article Metrics

Article Access Statistics

Further Information

Guidelines

MDPI Initiatives

Follow MDPI

Article Menu

Gaultheria: Phytochemical and Pharmacological Characteristics

Abstract

1. Introduction

2. Chemical Constituents

2.1. Methyl Salicylate Derivatives

2.2. C6-C3 Constituents

2.2.1. Flavonoids

2.2.2. Lignans

2.2.3. Simple Phenylpropanoids

2.3. Terpenoids

2.4. Steroids

2.5. Other Compounds

3. Volatile Chemical Constituents

4. Biological Activities

4.1. Anti-Inﬂammatory Activities

4.2. Analgesic Activities

4.3. Anti-Oxidative Activities

4.4. Antibacterial Activities

4.5. Others

5. Conclusions

Acknowledgments

Conflicts of Interest

References

Share and Cite

Article Metrics

Article Access Statistics

Further Information

Guidelines

MDPI Initiatives

Follow MDPI

2.2. C₆-C₃ Constituents