Chemical and pharmacological research on the plants from genus Ajuga

Xia Qing; Hui-Min Yan; Zhi-Yu Ni; Christopher J. Vavricka; Man-Li Zhang; Qing-Wen Shi; Yu-Cheng Gu; Hiromasa Kiyota

doi:10.1515/hc-2017-0064

Article Open Access

Chemical and pharmacological research on the plants from genus Ajuga

Xia Qing , Hui-Min Yan , Zhi-Yu Ni , Christopher J. Vavricka , Man-Li Zhang , Qing-Wen Shi , Yu-Cheng Gu and Hiromasa Kiyota

Published/Copyright: July 22, 2017

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From the journal Heterocyclic Communications Volume 23 Issue 4

Abstract

Keywords: Ajuga; biological activity; chemical constituents; Lamiaceae; phytoecdysteroids; terpenoi

Introduction

The genus Ajuga, a member of the Lamiaceae family, is comprised of more than 300 species of annual and perennial herbaceous flowering plants mainly distributed throughout the temperate regions of Asia, Europe, Australia, North America and Africa. These species have been used as common house plants and are called bugle or bugleweed. They are mainly characterized by the color and shape of the flower. For example, the flower of Ajuga reptans is somewhat tall and blue, while that of Ajuga decumbens is short and purple. Many of these plants are of medicinal importance and are traditionally used as remedies for rheumatic fevers, dysentery, malaria, hypertension, diabetes and gastrointestinal disorders, as well as anthelmintic, astringent, febrifuge diuretic, antifungal and anti-inflammatory agents [1]. The genus Ajuga has attracted attention since the report in 1976 that Ajuga remota grown in Kenya is not attacked by African armyworms and contains three moderately strong antifeedants [2]. Since then, reports of the isolation of neoclerodanes and phytoecdysteroids, as the insect allelochemicals responsible for antifeedant activity from this genus, have appeared [3]. Several species of this genus have been chemically studied and a series of bioactive metabolites, including phytoecdysteroids, diterpenoids and iridoids have been isolated and characterized. Biological investigations demonstrate that some of these compounds display antibacterial [4], antifungal [5], antiplasmodial [6], cytotoxic, antitumor promoting [7], vasoconstricting [8], insect molting inhibitory, insect antifeeding [9] and enzyme-inhibitory [10] activities. This review summarizes phytochemical progress of the genus Ajuga covering the literature up to 2014. In addition, some biological activities of compounds obtained from this genus are also listed.

Chemical constituents

There have been many phytochemical investigations on the isolation of constituents from the Ajuga genus. This has resulted in the isolation and characterization of a series of secondary metabolites, including phytoecdysteroids, sesquiterpenoids, diterpenoids, triterpenoids, iridoids, withanolides and some other compounds. Phytoecdysteroids, the characteristic components of Ajuga plants, are discussed first.

Steroids

Phytoecdysteroids (Table 1, Figure 1)

Phytoecdysteroids are widespread in the genus Ajuga. These compounds display interesting physiological activities such as insect molting activity and other hormonal functions involving regeneration, metamorphosis, reproduction and differentiation in all arthropods. These compounds play important roles for defense against phytophagous insects. They also display antiulcer, antirheumatic, insulin regulation and diuretic or tonic activities in mammals [34]. Some of the successful applications of plants in folk medicine can be explained by the occurrence of phytoecdysteroids.

Table 1

Steroids 1: Phytoecdysteroids.

No.	Name	Source	Part	Ref.
1	Cyasterone	A. decumbens	whole plant	[11]
		A. turkestanica	leaf	[12]
		A. iva	aerial part	[13], [14], [15]
		A. chia	leaf, stem	[16]
		A. chamaepitys	whole plant	[17]
		A. multiflora	aerial part	[18]
		A. taiwanensis	whole plant	[19]
		A. nipponensis	aerial part	[20]
		A. macrosperma var. breviflora	root	[21]
2	Ecdysterone	A. decumbens	whole plant	[11]
		A. nipponensis	whole plant	[11], [22]
		A. turkestanica	leaf	[12]
		A. iva	aerial part	[13], [14], [15]
		A. chamaepitys	whole plant	[17]
		A. multiflora	aerial part	[18]
		A. macrosperma var. breviflora	root	[21]
		A. reptans	whole plant	[23], [24], [25]
		A. remota	leaf, root	[26]
3	Ajugalactone	A. reptans	whole plant	[25]
		A. turkestanica	root	[27]
4	22-Acetylcyasterone	A. turkestanica	root	[28]
5	Turkesterone	A. turkestanica	root	[29]
6	Ajugasterone A	A. nipponensis	whole plant	[22]
		A. reptans	whole plant	[23], [25]
7	Ajugasterone B	A. reptans	whole plant	[25]
		A. turkestanica	root	[29]
		A. iva	whole plant	[30]
8	Ajugasterone C	A. nipponensis	aerial part	[20]
		A. japonica	leaf	[31]
9	Ajugasterone D	A. nipponensis	whole plant	[22]
10	Stachysterone D	A. nipponensis	whole plant	[22]
11	Makisterone A	A. iva	whole plant	[14], [32]
		A. macrosperma var. breviflora	root	[21]
12	29-Norcyasterone	A. reptans	whole plant	[23], [24], [25]
13	29-Norsengosterone	A. reptans	whole plant	[23], [24], [25]
14	2-Acetyl-29-norcyasterone	A. reptans	whole plant	[33]
15	3-Acetyl-29-norcyasterone	A. reptans	whole plant	[33]
16	Sengosterone	A. reptans	whole plant	[25]
17	22-Dehydro-12-hydroxycyasterone	A. reptans var. atropurperea	aerial part	[34]
18	22-Dehydro-12-hydroxysengosterone	A. reptans var. atropurperea	aerial part	[34]
19	22-Dehydro-12-hydroxy-29-nor-cyasterone	A. reptans var. atropurperea	aerial part	[34]
20	22-Dehydro-12-hydroxy-29-nor-sengosterone	A. reptans var. atropurperea	aerial part	[34]
21	Reptansterone	A. reptans var. atropurperea	root	[35]
22	28-epi-Sengosterone	A. reptans var. atropurperea	root	[35]
23	5,29-Dihydroxycapitasterone	A. reptans var. atropurperea	root	[35]
24	2-Dehydroajugalactone	A. reptans var. atropurperea	root	[35]
25	3-Dehydroajugalactone	A. reptans var. atropurperea	root	[35]
26	Ponasterone A	A. remota	leaf, root	[26]
27	24,28-Dehydromakisterone A	A. iva	whole plant	[14]
28	22-Oxocyasterone	A. iva	whole plant aerial	[14]
	22-Dehydrocyasterone	A. nipponensis	part	[20]
29	24,25-Dehydroprecyasterone	A. iva	whole plant	[14]
		A. reptans var. reptans	whole plant	[36]
30	20-Hydroxyecdysone 22-acetate	A. nipponensis	aerial part	[20]
		A. reptans	whole plant	[37]
31	20-Hydroxyecdysone 25-acetate (Viticosterone E)	A. reptans	whole plant	[37]
32	Ajusterone	A. pseudoiva	leaf	[38]
33	Ajugalide-E	A. taiwanensis	whole plant	[19]
34	Isocyasterone	A. taiwanensis	whole plant	[19]
35	24-Hydroxycyasterone	A. iva	whole plant	[30]
36	22-Dehydrocyasterone 2-glucopyranoside	A. nipponensis	aerial part	[20]
37	Ajugacetalsterone A	A. nipponensis	aerial part	[20]
38	Ajugacetalsterone B	A. nipponensis	aerial part	[20]
39	Ajugacetalsterone C	A. macrosperma var. breviflora	root	[21]
40	Ajugacetalsterone D	A. macrosperma var. breviflora	root	[21]
41	Breviflorasterone	A. macrosperma var. breviflora	root	[21]
		A. reptans var. reptans	whole plant	[36]
42	20-Hydroxyecdysone 2-acetate	A. macrosperma var. breviflora	root	[21]
43	20-Hydroxyecdysone 3-acetate	A. macrosperma var. breviflora	root	[21]
44	Reptanslactone A	A. reptans var. reptans	whole plant	[36]
45	Reptanslactone B	A. reptans var. reptans	whole plant	[36]
46	Sendreisterone	A. reptans var. reptans	whole plant	[36]

Figure 1

Steroids 1: Phytoecdysteroids.

Compounds 1 and 2 are usually the most abundant phytoecdysones in the genus Ajuga, and they were reported in A. decumbens, Ajuga incisa, Ajuga turkestanica, Ajuga iva, Ajuga nipponensis, Ajuga chia, Ajuga chamaepitys and Ajuga multiflora [11], [12], [13], [16], [17], [18]. Compound 36 was reported as a 2-O-glucopyranoside [20]. Phytoecdysteroids bearing a γ-lactone ring at various positions, 41, 44 and 45, were also isolated [21], [36]. Derivatives with a δ-lactone ring, 3, 21, 23–25, 29, 37, and 46 were reported as well [14], [25], [27], [35], [36]. In addition, the reduced forms, 37 and 46 with a THP ring, and 38 and 40 with a THF ring, were isolated as acetals or hemiacetals [20], [21], [36]. Two other similar compounds with a THF ring 9 and 10, are biosynthesized from precursors via intramolecular hydration [22]. In addition, ajugacetalsterone C (39) has a rare 6,8-dioxabicyclo[3.2.1]oct-2-ene structure presumably formed by an intramolecular acetalization [21]. Fujimoto and co-workers summarized biosynthesis of ecdysteroids as well as sterols in Ajuga hairy root in detail [39].

Withanolides (Table 2, Figure 2)

Withanolides are characteristic of Solanaceous plants, though there are rare reports on their isolation from other families. In 1999, Khan and co-workers isolated a new withanolide 47 from Ajuga parvifora. This is the first report of naturally occurring withanolides in Lamiaceae [40]. In subsequent studies on the chemical constituents of A. parvifora, the same research group obtained a series of new withanolides 48–56, along with known 57 [41], [42], [43], [44], [45].

Table 2

Steroids 2: Withanolides.

No.	Name	Source	Part	Ref.
47	Ajugin	A. parviflora	whole plant	[40]
48	Ajugin A	A. parviflora	whole plant	[41]
49	Ajugin B	A. parviflora	whole plant	[41]
50	Ajugin C	A. parviflora	whole plant	[42]
51	Ajugin D	A. parviflora	whole plant	[42]
52	Ajugin E	A. parviflora	whole plant	[43]
53	Ajugin F	A. parviflora	whole plant	[43]
54	3,14,17,20,28-Pentahydroxy-1-oxo-(20R,22R)-witha-5,24-dienolide	A. parviflora	whole plant	[44]
55	3,17,20-Trihydroxy-1-oxo-(20S,22R)-witha-5,14,24-trienolide	A. parviflora	whole plant	[45]
56	28-Hydroxy-14,20-epoxy-1-oxo-(22R)-witha-2,5,24-trienolide	A. parviflora	whole plant	[45]
57	Coagulin-J	A. parviflora	whole plant	[44]
58	Bracteosin A	A. bracteosa	whole plant	[46]
59	Bracteosin B	A. bracteosa	whole plant	[46]
60	Bracteosin C	A. bracteosa	whole plant	[46]

Figure 2

Steroids 2: Withanolides.

Other steroids (Table 3, Figure 3)

Compounds 61 and 67, two C₂₉ monohydroxy sterols, were isolated from A. reptans and their structures were elucidated by spectral methods [47]. From the aerial parts of Ajuga salicifolia, Akbay and co-workers isolated one new stigmastane-type sterol 72 and eight new sterol glycosides 70, 71, 73–78 [53], [54]. The whole plant of Ajuga relicta afforded two new steroids 79, 80, as well as two known compounds 61, 68 [49]. A steroidal glucopyranoside 64 was isolated from A. chamaepitys ssp. laevigata [51].

Table 3

Steroids 3: other steroids.

No.	Name	Source	Part	Ref.
61	Clerosterol	A. reptans	whole plant	[47]
		A. pseudoiva	leaf	[48]
		A. relicta	whole plant	[49]
62	Clerosterol 3β-O-(β-D-glucopyranoside)	A. pseudoiva	leaf	[50]
63	Mighavide (3-O-Butanoylclerosterol)	A. pseudoiva	leaf	[48], [50]
64	3-O-β-D-Glucopyranosyl-stigmasta-5,25-diene	A. chamaepitys ssp. laevigata	whole plant	[51]
65	Stigmasterol	A. taiwanensis	whole plant	[19]
66	Stigmasterol 3-O-β-D-glucopyranoside	A. taiwanensis	whole plant	[19]
67	22,23-Didehydroclerosterol	A. reptans	whole plant	[47]
68	β-sitosterol	A. relicta	whole plant	[49]
		A. taiwanensis	whole plant	[19]
69	β-sitosterol 3-O-β-D-glucopyranoside	A. decumbens	whole plant	[52]
70	Ajugasalicioside A	A. salicifolia	aerial part	[53]
71	Ajugasalicioside B	A. salicifolia	aerial part	[53]
72	Ajugasalicigenin	A. salicifolia	aerial part	[54]
73	Ajugasalicioside C	A. salicifolia	aerial part	[53]
74	Ajugasalicioside D	A. salicifolia	aerial part	[53]
75	Ajugasalicioside E	A. salicifolia	aerial part	[53]
76	Ajugasalicioside F	A. salicifolia	aerial part	[54]
77	Ajugasalicioside G	A. salicifolia	aerial part	[54]
78	Ajugasalicioside H	A. salicifolia	aerial part	[54]
79	(24S)-24-Ethyl-11α-hydroxycholesta-5,25-dien-1-one	A. relicta	whole plant	[49]
80	(24S)-24-Ethyl-7α-hydroxycholesta-5,25-dien-3-one	A. relicta	whole plant	[49]
81	Ergosterol 5,8-endoperoxide	A. remota	aerial part	[55]

Figure 3

Steroids 3: other steroids.

Triterpenoids (Table 4, Figure 4)

In 1997, two lupan triterpenoids 82 and 83 were isolated from the aerial parts of Ajuga macrosperma [56]. Oleananes 84 and 85 were two known triterpenoids isolated from A. relicta [49]. From A. chamaepitys ssp. laevigata, two ursanes and one oleanane 86–88 were isolated [51].

Table 4

Triterpenoids.

No.	Name	Source	Part	Ref.
82	Betulinic acid	A. macrosperma	aerial part	[56]
83	3-epi-Betulinic acid	A. macrosperma	aerial part	[56]
84	Oleanolic acid	A. relicta	whole plant	[49]
85	3-O-Acetyloleanolic acid	A. relicta	whole plant	[49]
86	α-Amyrin	A. chamaepitys ssp. laevigata	whole plant	[51]
87	β-Amyrin	A. chamaepitys ssp. laevigata	whole plant	[51]
88	Ursolic acid	A. chamaepitys ssp. laevigata	whole plant	[51]

Figure 4

Triterpenoids.

Diterpenoids (Table 5, Figure 5)

Ajuga species are rich in diterpenoids. With respect to the carbocyclic skeleton, Ajuga diterpenoids roughly belong to two groups: neoclerodane and abietane types.

Table 5

Diterpenoids.

No.	Name	Source	Part	Ref.
89	Ajugarin I	A. remota	leaf	[2]
		A. nipponensis	aerial part	[57]
		A. parviflora	aerial part	[58]
		A. decumbens	whole plant	[59]
90	Ajugarin II	A. remota	leaf	[2]
		A. parviflora	aerial part	[58]
91	Ajugarin III	A. remota	leaf	[2]
92	Ajugarin IV	A. remota	leaf	[60]
		A. ciliata var. villosior	aerial part	[61]
93	Ajugarin V	A. remota	leaf	[62]
94	Clerodin	A. remota	leaf	[63]
		A. bracteosa	aerial part	[64]
95	Dihydroclerodin	A. parviflora	aerial part	[58]
		A. bracteosa	whole plant	[46], [64]
		A. remota	aerial part	[65]
96	Ajugareptansin	A. reptans	aerial part	[66], [67], [68]
97	Ajugareptansone A	A. reptans	whole plant	[69], [70]
98	Ajugareptansone B	A. reptans	whole plant	[69]
99	Ivain I	A. iva	whole plant	[71]
100	Ivain II	A. iva	whole plant	[71]
		A. bracteosa	aerial part	[64]
101	Ivain III	A. iva	whole plant	[71]
102	Ivain IV	A. iva	whole plant	[71]
103	Ajugapitin (Clerodendrin D)	A. chamaepitys	whole plant	[72], [73]
		A. australis	aerial part	[74]
		A. decumbens	leaf	[75]
		A. remota	aerial part	[65]
		A. turkestanica	aerial part	[76]
104	14,15-Dihydroajugapitin	A. chamaepitys	whole plant	[72], [73]
		A. pseudoiva	leaf	[77], [78]
		A. bracteosa	whole plant	[46], [64], [79]
		A. remota	aerial part	[65]
105	Chamaepitin	A. chamaepitys	whole plant	[80]
		A. turkestanica	aerial part	[76]
106	Ajugamarin	A. nipponensis	leaf	[81], [82], [83]
		A. decumbens	whole plant	[75], [84], [85], [86]
		A. ciliata	whole plant	[87]
107	Dihydroajugamarin	A. nipponensis	leaf	[81]
		A. decumbens	leaf	[75]
108	Ajugamarin chlorohydrin	A. nipponensis	leaf	[81]
		A. ciliata	whole plant	[87]
109	2-Acetylivain I	A. pseudoiva	whole plant	[77]
110	Ajugamarin A2	A. decumbens	whole plant	[88]
		A. nipponensis	aerial part	[83]
		A. ciliata	whole plant	[87]
111	Ajugamarin B1	A. ciliata	whole plant	[87]
112	Ajugamarin B2	A. nipponensis	aerial part	[57], [83]
		A. decumbens	whole plant	[88]
113	Ajugamarin B3	A. nipponensis	aerial part	[57]
114	Ajugamarin B4	A. ciliata var. villosior	aerial part	[61]
115	Ajugamarin B5	A. ciliata var. villosior	aerial part	[61]
116	Ajugamarin C1	A. nipponensis	aerial part	[57]
		A. taiwanensis	whole plant	[89]
		A. ciliata	whole plant	[90]
117	Ajugamarin D1	A. nipponensis	aerial part	[57]
118	Ajugamarin E1	A. ciliata var. villosior	aerial part	[61]
119	Ajugamarin E2	A. ciliata var. villosior	aerial part	[61]
120	Ajugamarin E3	A. ciliata var. villosior	aerial part	[61]
121	Ajugamarin F1	A. ciliata var. villosior	aerial part	[61]
122	Ajugamarin F2	A. ciliata var. villosior	aerial part	[61]
123	Ajugamarin F3	A. ciliata var. villosior	aerial part	[61]
124	Ajugamarin F4	A. decumbens	whole plant	[86], [88]
		A. parviflora	aerial part	[58]
		A. nipponensis	aerial part	[83]
125	Ajugamarin G1	A. decumbens	whole plant	[75], [88]
		A. ciliata	whole plant	[87]
126	Ajugamarin H1	A. decumbens	whole plant	[75], [88]
		A. ciliata	whole plant	[87]
127	Deacetylajugarin IV	A. ciliata var. villosior	aerial part	[61]
		A. remota	aerial part	[65]
		A. ciliata	whole plant	[91]
128	Ajugachin A	A. chamaepitys	aerial part	[73]
		A. reptans	aerial part	[68]
129	Ajugachin B	A. chamaepitys	aerial part	[73]
		A. turkestanica	aerial part	[76]
130	Ajugacumbin A	A. decumbens	whole plant	[59], [85], [92], [93]
		A. nipponensis	aerial part	[83]
		A. ciliata	whole plant	[87]
131	Ajugacumbin B	A. decumbens	whole plant	[59], [92], [93]
		A. nipponensis	aerial part	[83], [94]
		A. macrosperma	whole plant	[95]
		A. pantantha	whole plant	[95]
132	Ajugacumbin C	A. decumbens	whole plant	[85], [92]
133	Ajugacumbin D	A. decumbens	whole plant	[85], [92]
134	Ajugacumbin E	A. decumbens	whole plant	[84]
135	Ajugacumbin F	A. decumbens	whole plant	[84]
		A. ciliata	whole plant	[87]
136	Ajugacumbin G	A. decumbens	whole plant	[93]
137	Ajugacumbin H	A. decumbens	whole plant	[85]
138	Ajugacumbin J	A. decumbens	whole plant	[96]
139	Ajugavensin A	A. genevensis	aerial part	[97]
		A. reptans	aerial part	[70]
140	Ajugavensin B	A. genevensis	aerial part	[97]
141	Ajugavensin C	A. genevensis	aerial part	[97]
142	Ajugamacrin A	A. macrosperma	whole plant	[98]
143	Ajugamacrin B	A. macrosperma	whole plant	[98]
		A. taiwanensis	whole plant aerial part	[89]
		A. nipponensis	whole plant aerial part	[83]
144	Ajugamacrin C	A. macrosperma	whole plant	[95]
		A. pantantha	whole plant	[95]
145	Ajugamacrin D	A. macrosperma	whole plant	[95]
		A. pantantha	whole plant	[95]
146	Ajugamacrin E	A. macrosperma	whole plant	[95]
		A. pantantha	whole plant	[95]
147	Ajugapantin A	A. macrosperma	whole plant	[95]
		A. pantantha	whole plant	[95]
		A. taiwanensis	whole plant	[89]
		A. ciliata	whole plant	[87]
148	Deoxyajugarin-I	A. parviflora	aerial part	[58]
149	Ajugarin-I chlorohydrin	A. parviflora	aerial part	[58]
150	3β-Acetoxyclerodinin C	A. parviflora	aerial part	[58]
151	Clerodinin A	A. bracteosa	whole plant	[46]
152	Clerodinin C	A. parviflora	aerial part	[58]
153	Clerodinin D	A. parviflora	aerial part	[58]
154	15-α-Ethoxy-14-hydroajugapitin	A. parviflora	aerial part	[58]
155	15-β-Ethoxy-14-hydroajugapitin	A. parviflora	aerial part	[58]
156	Lupulin A	A. lupulina	whole plant	[99]
		A. bracteosa	whole plant	[46]
		A. turkestanica A. pseudoiva	aerial part leaf	[76] [78]
157	Lupulin B	A. lupulina	whole plant	[99]
158	Lupulin C	A. lupulina	whole plant	[99]
159	Lupulin D	A. lupulina	whole plant	[99]
160	Lupulin E	A. lupulina	whole plant	[4]
161	Lupulin F	A. lupulina	whole plant	[4]
162	2β-Hydroxy-2-methylbutanoyl-3α-lupulin	A. lupulina	whole plant	[100]
163	6-Deacetylajugarin IV	A. lupulina var. major	whole plant	[101]
164	Ajugorientin (3β-Hydroxyajugavensin B)	A. orientalis A. reptans	aerial part aerial part	[74] [67], [68]
165	14,15-Dihydro-15-hydroxyajugapitin	A. australis	aerial part	[74]
		A. bracteosa	whole plant	[64], [79]
		A. remota	aerial part	[65]
166	Ajugatakasin A	A. decumbens	leaf	[75]
		A. nipponensis	aerial part	[83]
		A. ciliata	whole plant	[87]
167	Ajugatakasin B	A. decumbens	leaf	[75]
		A. ciliata	whole plant	[87]
168	14,15-Dehydroajugareptansin	A. reptans	aerial part	[67]
169	3α-Hydroxyajugamarin F4	A. reptans	aerial part	[67]
170	Ajugapyrin A	A. pyramidalis	aerial part	[102]
171	Areptin A	A. reptans	aerial part	[68]
172	Areptin B	A. reptans	aerial part	[68]
173	(15R)-14,15-Dihydro-15-hydroxyajugachin A	A. laxmanii	aerial part	[103]
174	(15S)-14,15-Dihydro-15-hydroxyajugachin A	A. laxmanii	aerial part	[103]
175	Hativene A	A. pseudoiva	leaf	[78]
176	Hativene B	A. pseudoiva	leaf	[78]
177	Hativene C	A. pseudoiva	leaf	[78]
178	Hativene D	A. pseudoiva	leaf	[104]
179	Ajugatansin A1	A. reptans	aerial part	[70]
180	Ajugatansin B1	A. reptans	aerial part	[70]
181	Ajugatansin D1	A. reptans	aerial part	[70]
182	Bracteonin-A	A. bracteosa	whole plant	[79]
183	Ajugareptone	A. reptans	leaf	[105]
184	Ajugalaevigatic acid	A. chamaepitys ssp. laevigata	whole plant	[51]
185	(13S)-15-Hydroxylabd-8(17)-en-19-oic acid (Imbricatoloic acid)	A. chamaepitys ssp. laevigata	whole plant	[51]
186	Ajugalide A	A. taiwanensis	whole plant	[89]
187	Ajugalide B	A. taiwanensis	whole plant	[89]
		A. ciliata	whole plant	[87]
188	Ajugalide C	A. taiwanensis	whole plant	[89]
		A. ciliata	whole plant	[87]
189	Ajugalide D	A. taiwanensis	whole plant	[89]
		A. ciliata	whole plant	[91]
190	Ajuganipponin A	A. nipponensis	aerial part	[83]
		A. ciliata	whole plant	[90]
191	Ajuganipponin B	A. nipponensis	aerial part	[83]
		A. ciliata	whole plant	[87]
		A. decumbens	whole plant	[86]
192	14-Hydro-15-hydroxyclerodin	A. remota	aerial part	[65]
193	14,15-Hihydroajugachin B	A. turkestanica	aerial part	[76]
194	14-Hydro-15-methoxyajugachin B	A. turkestanica	aerial part	[76]
195	15-epi-Lupulin A	A. decumbens	whole plant	[106]
196	15-epi-Lupulin B	A. bracteosa	aerial part	[64]
197	6-O-Deacetylajugamarin	A. decumbens	whole plant	[106]
198	Ajugadecumbenins A	A. decumbens	whole plant	[106]
199	Ajugadecumbenins B	A. decumbens	whole plant	[106]
200	Ajubractin A	A. bracteosa	aerial part	[64]
201	Ajubractin B	A. bracteosa	aerial part	[64]
202	Ajubractin C	A. bracteosa	aerial part	[64]
203	Ajubractin D	A. bracteosa	aerial part	[64]
204	Ajubractin E	A. bracteosa	aerial part	[64]
205	3-epi-Caryoptin	A. bracteosa	aerial part	[64]
206	3-epi-14,15-Dihydrocaryoptin	A. bracteosa	aerial part	[64]
207	15-Hydroxyajubractin C	A. bracteosa	aerial part	[64]
208	14-Hydro-15-hydroxyajugachin A	A. bracteosa	aerial part	[64]
209	Ajugaciliatin A	A. ciliata	whole plant	[87]
210	Ajugaciliatin B	A. ciliata	whole plant	[87]
211	Ajugaciliatin C	A. ciliata	whole plant	[87]
212	Ajugaciliatin D	A. ciliata	whole plant	[87]
213	Ajugaciliatin E	A. ciliata	whole plant	[87]
214	Ajugaciliatin F	A. ciliata	whole plant	[87]
215	Ajugaciliatin G	A. ciliata	whole plant	[87]
216	Ajugaciliatin H	A. ciliata	whole plant	[87]
217	Ajugaciliatin I	A. ciliata	whole plant	[87]
218	Ajugaciliatin J	A. ciliata	whole plant	[87]
		A. decumbens	whole plant	[59]
219	(12S)-1β,6α,19-Triacetoxy-18-chloro-4α,12-dihydroxyneoclerod-13-en-15,16-olide	A. ciliata	whole plant	[91]
220	(12S,2′S)-12,19-Diacetoxy-18-chloro-4α,6α-dihydroxy-1β-(2-methylbutanoyloxy)neoclerod-13-en-15,16-olide	A. ciliata	whole plant	[91]
221	(12S)-6α,18,19-Triacetoxy-4α,12-dihydroxy-1β-tigloyloxyneoclerod-13-en-15,16-olide	A. ciliata	whole plant	[91]
222	(12S)-6α-Acetoxy-4α,18-epoxy-12-hydroxy-19-tigloyloxyneoclerod-13-en-15,16-olide	A. ciliata	whole plant	[90]
223	6α,18-Diacetoxy-4α-hydroxy-19-tigloyloxyneoclerod-13-en-15,16-olide	A. ciliata	whole plant	[90]
224	Ajugamarin A2 chlorohydrin	A. ciliata	whole plant	[87]
225	6α,19-Diacetoxy-4α-hydroxy-1β-tigloyloxyneoclerod-12-en-15-oic acid methyl ester-16-aldehyde	A. decumbens	whole plant	[59]
226	(12S)-18,19-Diacetoxy-4α,6α,12-trihydroxy-1β-tigloyloxyneoclerod-13-en-15,16-olide	A. decumbens	whole plant	[59]
227	4α,6α-Dihydroxy-18-(4′-methoxy-4′-oxobutyryloxy)-19-tigloyloxyneoclerod-13-en-15,16-olide	A. decumbens	whole plant	[59]
228	(12S)-1α,19-Epoxy-6α,18-diacetoxy-4α,12-dihydroxyneoclerod-13-en-15,16-olide	A. decumbens	whole plant	[86]
229	(12S)-6α,19-Diacetoxy-18-chloro-4α-hydroxy-12-tigloyloxyneoclerod-13-en-15,16-olide	A. decumbens	whole plant	[86]
230	(12S,2′′S)-6α,19-Diacetoxy-18-chloro-4α-hydroxy-12-(2-methylbutanoyloxy)neoclerod-13-en-15,16-olide	A. decumbens	whole plant	[86]
231	Ajugacumbin A chlorohydrin	A. ciliata	whole plant	[87]
		A. decumbens	whole plant	[59]
232	Ajuforrestin A	A. forrestii	whole plant	[107]
		A. decumbens	aerial part	[7]
233	Ajuforrestin B	A. forrestii	whole plant	[107]
		A. decumbens	aerial part	[7]
234	Ajugaside A	A. decumbens	whole plant	[108]
235	Ajudecumin A	A. decumbens	aerial part	[7]
236	Ajudecumin B	A. decumbens	aerial part	[7]
237	Ajudecumin C	A. decumbens	aerial part	[7]
238	Ajudecumin D	A. decumbens	aerial part	[7]
239	Carnosol	A. forrestii	whole plant	[109]
240	Epiisorosmanol	A. forrestii	whole plant	[109]
241	2,11,12-Trihydroxy-7,20-epoxy-8,11,13-abietatriene	A. forrestii	whole plant	[109]
242	Epirosmanol	A. forrestii	whole plant	[109]
243	7-Methoxyrosmanol	A. forrestii	whole plant	[109]
244	7-Ethoxyrosmanol	A. forrestii	whole plant	[109]
245	2α,3β,11,12-Tetrahydroxy-7β,20-epoxy-8,11,13-abietatriene	A. forrestii	whole plant	[109]

Figure 5

Diterpenoids.

Neoclerodanes

Most of the neoclerodane diterpenoids produced by species of the genus Ajuga contain a substituted decalin with a 4α,18-oxirane ring and two oxygenated substituents bound to C(6) and C(19) [110]. The side chain features several moieties with the most common being: (i) a butenolide function (α-substituted α,β-unsaturated γ-lactone, or 13-en-15,16-olide) as in 89–93 isolated from A. remota [2], [60], [62]; (ii) a tetrahydrofurofuran as in 94 reported as a constituent of A. remota [63]; and (iii) a hexahydrofurofuran as in 95 reported as a component of Ajuga parviflora [58]. In 1983, three new bitter principles, 106–108, were isolated from the leaves of A. nipponensis. The β-hydrin structure of 108 was confirmed by treatment of 106 with methanolic HCl [81], [82]. In addition, by reinvestigation of the aerial parts of A. nipponensis, four new bitter neoclerodanes 112, 113, 116, 117 and a known diterpenoid 89 were isolated [57]. The configuration of methoxy group at C(15) (R⁵) of lupulin A (156) [99] was revised to be α by Huang and co-workers [106]. Consequently, hativene D (178) [104] is not 15-epi-lupulin (195) but lupulin (156). The structure of 15-epi-lupulin B (196) [64] with a 2β-OH group coincides with lupulin A 156.

Abietanes

A new abietane diglucopyranoside 234 was isolated from the whole plants of A. decumbens [108]. In the course of the search for bioactive metabolites with anticancer effects, Wang et al. isolated four new rearranged abietane hydroquinones 235–238, together with two known abietanes 232 and 233 from the aerial parts of A. decumbens collected in China [7].

Sesquiterpenoids (Table 6, Figure 6)

Only a few other sesquiterpenoids, bisabolene, eudesmanolides and seco-sesquiterpenoids, were reported. Compound 246, a bisabolene sesquiterpenoid, was isolated from the aerial parts of A. decumbens [7]. Research on Ajuga forrestii resulted in the isolation of four eudesmane sesquiterpene lactones 247–250. Among them, compounds 247–249 are new. Compound 249 exhibits weak cytotoxic activity against HepG2 and MCF-7 human cell lines [109]. Four megastigmane derivatives 251–254 and 257 were isolated in 2012 [7], [112]. A new ionone glycoside 255 was also isolated from this plant. This is the first report of the occurrence of ionone glycosides in Ajuga species [111].

Table 6

Sesquiterpenoids.

No.	Name	Source	Part	Ref.
246	Glecholone	A. decumbens	aerial part	[7]
247	3α-Acetoxy-1α,8β-dihydroxyeudesm-7(11)-en-8,12-olide	A. forrestii	whole plant	[109]
248	3α-Acetoxy-1α-hydroxyeudesm-8,7(11)-dien-8,12-olide	A. forrestii	whole plant	[109]
249	1α-Acetoxy-8α-oxyethyl-2-oxoeudesman-3,7(11)-dien-8,12-olide	A. forrestii	whole plant	[109]
250	1α-Acetoxy-8α-hydroxy-2-oxoeudesman-3,7(11)-dien-8,12-olide	A. forrestii	whole plant	[109]
251	(6R,7E,9R)-9-Hydroxy-4,7-megastigmadien-3-one	A. decumbens	aerial part	[7]
252	(3S,5R,6S,7E)-5,6-Epoxy-3-hydroxy-7-megastigmen-9-one	A. decumbens	aerial part	[7]
253	(6E,9S)-9-Hydroxy-4,6-megastigmadien-3-one	A. decumbens	aerial part	[7]
254	6-Hydroxy-4,7-megastigmadiene-3,9-dione	A. decumbens	aerial part	[7]
255	4β-Hydroxy-7,8-dihydro-3-oxo-β-ionol 9-O-β-D-glucopyranoside	A. salicifolia	aerial part	[111]
256	Corchoionoside C	A. salicifolia	aerial part	[111]
257	Loliolide	A. decumbens	whole plant	[112]

Figure 6

Sesquiterpenoids.

Monoterpenoids (Table 7, Figure 7)

Major monoquiterpenoids isolated from the genus Ajuga belong to iridoids. In 1974, Guiso and co-workers isolated three iridoid glucopyranosides 258–260 from A. reptans. Compound 259 is an 8-O-acetyl derivative of 260 and a 6-epimer of 8-O-acetylmioporoside 271 [113], [117]. Four new iridoid glucopyranoside cis- and trans-p-coumaroyl esters 263–266 were isolated from methanol extract of the dried plant of A. decumbens, together with the known compounds 258 and 262 [116]. Compound 270, isolated from the leaves of Ajuga pseudoiva, possesses an unusual 13-membered macrocyclic structure [121].

Table 7

Iridoids.

No.	Name	Source	Part	Ref.
258	Reposide	A. reptans	whole plant	[113], [114], [115]
		A. decumbens	whole plant	[116]
259	Ajugoside	A. reptans	whole plant	[117]
260	Ajugol	A. reptans	whole plant	[117]
261	Jaranidoside	A. spectabilis	whole plant	[118]
262	8-O-Acetylharpagide	A. multiflora	whole plant	[119]
		A. remota	aerial part	[6]
		A. decumbens	whole plant	[116]
		A. iva	aerial part	[120]
		A. reptans	whole plant	[114], [115]
263	Decumbeside A	A. decumbens	whole plant	[116]
264	Decumbeside B	A. decumbens	whole plant	[116]
265	Decumbeside C	A. decumbens	whole plant	[116]
266	Decumbeside D	A. decumbens	whole plant	[116]
267	Harpagide	A. iva	aerial part	[120]
		A. reptans	whole plant	[114], [115]
268	6-Deoxyharpagide	A. iva	aerial part	[120]
269	Ajureptoside	A. reptans	whole plant	[114]
270	7-O-6′-O-Malonylcachinesidic acid	A. pseudoiva	leaf	[121]
271	8-O-Acetylmioporoside	A. salicifolia	aerial part	[111]
272	Galiridoside	A. taiwanensis	whole plant	[19]
273	Teuhircoside	A. taiwanensis	whole plant	[19]
274	6-Keto-8-acetylharpagide	A. remota	aerial part	[122]
275	6,7-Dehydro-8-acetylharpagide	A. remota	aerial part	[122]
276	7,8-Dehydroharpagide	A. remota	aerial part	[122]
277	8-Acetylharpagide 6-O-β-glucopyranoside	A. remota	aerial part	[122]
278	Harpagide 6-O-β-glucopyranoside	A. remota	aerial part	[122]
279	2′,3′-Diacetylharpagide	A. remota	underground part	[123]
280	6′-O-Rhamnosylharpagide	A. remota	underground part	[123]
281	6′-O-Galloyl-7,8-dehydroharpagide	A. remota	underground part	[123]
282	6-O-Xylosylharpagoside-B	A. remota	underground part	[123]
283	Ajureptaside A	A. reptans	whole plant	[115]
284	Ajureptaside B	A. reptans	whole plant	[115]
285	Ajureptaside C	A. reptans	whole plant	[115]
286	Ajureptaside D	A. reptans	whole plant	[115]
287	6-epi-8-O-Acetylharpagide	A. reptans	whole plant	[115]

Figure 7

Iridoids.

Flavonoids (Table 8, Figure 8)

Flavonoids 288–305 including flavones and flavonols isolated from the genus Ajuga are outlined in Table 8.

Table 8

Flavonoids.

No.	Name	Source	Part	Ref.
288	Luteolin	A. chia	aerial part	[124]
		A. lupulin	whole plant	[101], [125]
289	Luteolin 7-O-glucopyranoside	A. chia	aerial part	[124]
		A. lupulina	whole plant	[101], [125]
290	Apigenin	A. chia	aerial part	[124]
		A. multiflora	aerial part	[126]
		A. forrestii	whole plant	[107]
291	Naringin	A. iva	aerial part	[15]
292	Apigenin 7-O-neohesperidoside	A. iva	aerial part	[15]
293	Chrysoriol	A. lupulina	whole plant	[125]
294	Diosmetin	A. lupulina	whole plant	[125]
295	Kaempferide	A. lupulina	whole plant	[125]
296	Quercetin	A. lupulina	whole plant	[125]
297	Acacetin	A. forrestii	whole plant	[107]
298	Gnetifolin B	A. forrestii	whole plant	[107]
299	Apigenin 7-glucuronide	A. multiflora	aerial part	[18]
300	Kaempferol	A. taiwanensis	whole plant	[19]
301	Myricetin 3-O-rutinoside 4′-O-rutinoside	A. remota	aerial part	[122]
302	Myricetin 3-O-rutinoside 3′-O-rutinoside	A. remota	aerial part	[122]
303	Isorhamnetin 3-O-rutinoside 7-O-rutinoside 4′-O-β-glucopyranoside	A. remota	aerial part	[122]
304	3,4′-Dihydroxy-3,6,7-trimethoxyflavone	A. bracteosa	whole plant	[127]
305	7-Hydroxy-3,6,3′,4′-tetramethoxyflavone	A. bracteosa	whole plant	[127]

Figure 8

Flavonoids.

Polyketides and alkaloids (Table 9, Figure 9)

From the leaves of A. iva, three new homologous 1,3-diglycerides 331–333 and compound 339 were obtained. In 1986, Takasaki and co-workers isolated three phenethyl alcohol glycosides 323–325, including a new derivative 323 [108]. A phenylalanine derivative 346 was isolated from this plant recently [96]. In addition, Yu and co-workers isolated a phthalic ester 321 from the aerial parts of A. multiflora [18].

Table 9

Polyketides and alkaloids.

No.	Name	Source	Part	Ref.
306	Ethyl (1-acetoxy-4-oxo-2,5-cyclohexadien-1-yl)acetate	A. parviflora	whole plant	[128]
307	Methyl (1-acetoxy-4-oxo-2,5-cyclohexadien-1-yl)acetate	A. parviflora	whole plant	[128]
308	Ethyl (1-hydroxy-4-oxo-2,5-cyclohexadien-1-yl)acetate	A. parviflora	whole plant	[128]
309	Methyl (1-hydroxy-4-oxo-2,5-cyclohexadien-1-yl)acetate	A. parviflora	whole plant	[128]
310	(1-Hydroxy-4-oxo-2,5-cyclohexadien-1-yl)acetic acid	A. parviflora	whole plant	[129]
311	2-Hydroxy-4β-methyl-4α-(β-D-glucopyranoside)-2,5-cyclohexadien-1-one	A. parviflora	whole plant	[129]
312	Methyl 2-(2,2-dimethyl-6-oxo-7-dihydro-1,3-benzodioxol-3(6H)-yl)acetate	A. parviflora	whole plant	[129]
313	6,7-Dihydroxycoumarin (Esculetin)	A. decumbens	whole plant	[52]
314	Coumarin	A. laxmanii	aerial part	[103]
315	Vanillic acid	A. decumbens	whole plant	[112]
		A. taiwanensis	whole plant	[19]
316	Melilotic acid methyl ester	A. laxmanii	aerial part	[103]
317	Methyl caffeate	A. decumbens	whole plant	[112]
318	Methyl (E)-4-acetoxy-3-methoxycinnamate	A. pseudoiva	leaf	[38]
319	Methyl (E)-4-acetoxycinnamate	A. pseudoiva	leaf	[38]
320	Ajuganane	A. bracteosa	whole plant	[127]
321	Bis(2-ethylhexyl) phthalate	A. multiflora	aerial part	[18]
322	Bis(2S-methylheptyl) phthalate	A. bracteosa	whole plant	[130]
323	Galactosylmartynoside	A. decumbens	whole plant	[108]
324	Martynoside	A. decumbens	whole plant	[108]
325	Darendoside B	A. decumbens	whole plant	[108]
326	Lavandulifolioside	A. salicifolia	aerial part	[111]
327	Leonoside A	A. salicifolia	aerial part	[111]
328	Leonoside B	A. salicifolia	aerial part	[111]
329	1-Ethenylhexyl 6-O-β-L-arabinopyranosyl-2-O-β-D–glucopyranosyl-β-D-glucopyranoside	A. decumbens	whole plant	[52]
330	Butyl β-D-fructopyranoside	A. decumbens	whole plant	[52]
331	Ivade A	A. iva	leaf	[131]
		A. pseudoiva	leaf	[48]
332	Ivade B	A. iva	leaf	[131]
		A. pseudoiva	leaf	[48]
333	Ivade C	A. iva	leaf	[131]
		A. pseudoiva	leaf	[48]
334	Hizivaide A	A. pseudoiva	leaf	[132]
335	Hizivaide B	A. pseudoiva	leaf	[132]
336	Hizivaide C	A. pseudoiva	leaf	[132]
337	Hizivaide D	A. pseudoiva	leaf	[132]
338	Hizivaide E	A. pseudoiva	leaf	[132]
339	Methyl 3-hydroxyhexadecanoate	A. iva	leaf	[133]
340	(10E,15Z)-9,12,13-Trihydroxyoctadeca-10,15-dienoic acid	A. decumbens	whole plant	[112]
341	Heptacos-3-en-25-one	A. bracteosa	aerial part	[134]
342	Bractic acid	A. bracteosa	whole plant	[10]
343	Ligularinine	A. parviflora	whole plant	[44]
344	Senecionine	A. parviflora	whole plant	[45]
345	Integerrimine	A. parviflora	whole plant	[45]
346	Aurantiamide acetate	A. decumbens	whole plant	[96]
347	Pheophytin-a	A. taiwanensis	whole plant	[19]
348	Pheophytin-b	A. taiwanensis	whole plant	[19]
349	13²-Hydroxy(13²-S)pheophytin-a	A. taiwanensis	whole plant	[19]
351	Nicotinic acid	A. taiwanensis	whole plant	[19]
352	Bractin A	A. bracteosa	whole plant	[10]
353	Bractin B	A. bracteosa	whole plant	[10]

During the search for bioactive metabolites from A. pseudoiva leaves, Ben and co-workers isolated five novel monoglycerides 334–338, two novel cinnamic acids 318, 319 and one new steroid 63, along with five known compounds 61, 62, 331–333. Three compounds 331–333 show significant antifeedant activity, which might be associated with the presence of two β-hydroxyalkanoic moieties in each compound [38], [48], [50], [132]. A phytochemical investigation on A. parviflora resulted in the isolation of quinols 306–312 and pyrrolizidine alkaloids 343–345. Derivatives 306–308 are new compounds. Compound 309, isolated previously from the leaves and branches of Jacaranda species, display cytotoxic and antitumor activities. Three pyrrolizidine alkaloids 343–345 were reported for the first time from this plant [44], [45], [128], [129].

The plant of Ajuga bracteosa afforded several new compounds including unsaturated ketone 341, phthalic ester 322, phenolic compound 320, two sphingolipids 352, 353 and a long-chain polyhydroxy acid 342 [10], [130], [134].

Figure 9

Polyketides and alkaloids.

Biological activity

Antifeedant and larvicidal activity

A neoclerodane 103 was isolated from the leaves of A. decumbens as a feeding stimulant for Athalia rosae ruficornis [75]. Three new neoclerodanes 164, 168, 169 were isolated from the aerial parts of A. reptans cv. catlins giant. Insect antifeedant testing revealed that 168 has significant activity against sixth stadium larvae of Spodoptera littoralis [67]. A series of active clerodanes 104, 156, 175–177 were isolated from the acetone extract of A. pseudoiva leaves by bioassay-guided chromatography. The behavioral responses of Spodoptera littoralis larvae to all clerodanes showed strong antifeedant activity at 100 to 1 mg/L. In addition, this study also indicated that a methoxy group at C(15), either in the α- or β-position, might decrease antifeedant activity [9]. Manguro and co-workers tested larvicidal activity of the extracts of A. remota using second instar Aedes aegypti larvae [123]. The ethyl acetate extract is toxic with LC₅₀ value of 5.30 μg/L, while the methanol extract displays weak toxicity with an LC₅₀ of 65.94 μg/L. Compound 81, obtained from the ethyl acetate extract, is the active component with an LC₅₀ value of 4.40 μg/L.

Antimicrobial activity

Compounds 156–161 are six new neoclerodanes isolated from Ajuga lupulina. The diterpenoids 156 and 160 show strong activity against Pseudomonas aeruginosa and Escherichia coli (inhibitory zones are 3–5 mm and 3.5–4.5 mm, respectively, at a concentration of 0.02 mg/mL). In addition, 156 displays weak activity against Staphylococcus aureus (1.5 mm). The antibacterial activity of 161 against P. aeruginosa (2.1 mm) and E. coli (2.0 mm) is poor compared to 156 and 160. Compound 157 exhibits weak antibacterial activity against S. aureus and E. coli (1.2 mm) [4], [99]. In 2001, Kariba tested the extracts of A. remota for in vitro antifungal activity. The petroleum ether and methanol extracts exhibit antifungal activity against the dermatophytic fungi Trichophyton mentagrophytes and Microsporum gypseum [5]. Ergosterol 5,8-endoperoxide 81, isolated from the methanol extract of A. remota, shows activity against Mycobacterium tuberculosis [55].

Antimalarial activity

Ajuga remota is commonly used as medicinal herb for malaria treatment in Kenya. Three isolates, 81, 89 and 262, were tested for their in vitro antiplasmodial activity. Compound 89 is moderately active against a chloroquine-sensitive (FCA 20/GHA) strain of Plasmodium falciparum, with an IC₅₀ of 23.0 μm, compared to a 0.041 μm IC₅₀ for chloroquine. Compared to 89, compound 262 is approximately 3 times as potent. Compound 262 is also equally potent towards chloroquine-sensitive (FCA 20/GHA) and chloroquine-resistant (W2) strains [6]. An excellent review article summarizes antimalarial activity of compounds contained in A. remota and A. bracteosa [135].

Anti-inflammatory activity

Gautam et al. tested a 70% ethanol extract of A. bracteosa whole plants in a mice acute inflammation model based on topical application of TPA. The result showed that the extract exhibits a remarkable and dose-dependent anti-inflammatory activity at 0.5 and 1.0 mg/ear. In addition, it showed a significant in vitro COX-1 and COX-2 inhibitory activity at 25 and 50 μg/mL. Among the isolates from the bioactive extract, compound 156 exhibited the highest inhibition of COX-1, and compound 268 displayed the highest inhibition of COX-2 [136]. The compounds 342, 352, 353 exhibited remarkable inhibition of lipoxygenase. Compound 342 was more active than baicalein (IC₅₀=22.4 μm) with an IC₅₀ of 10.0 μm [10].

Hypoglycemic activity

Ajuga iva has been used as traditional medicine to control diabetes mellitus for many centuries. In 2002, a study to examine the hypoglycemic effect of A. iva was carried out, and the results demonstrated that A. iva aqueous extract exhibits strong hypoglycemic activity. Lyophilized aqueous extract of A. iva whole plant was found to decrease plasma glucopyranose levels of streptozotocin-induced diabetic rats from 337 to 102.2 mg/dL after 6 h of oral administration. Furthermore, repeated oral administration significantly reduced plasma glucopyranose levels after 1 week of treatment (112 mg/dL at 1 week vs. 337 mg/dL at the baseline values) [137].

Cytotoxic activity

Compounds 70–75 are five new sterol glycosides isolated from a methanol extract of the aerial parts of A. salicifolia. Their cytotoxicity against HeLa cells (KB), human T cell leukemia (Jurkat), and peripheral mononuclear blood cells (PMBC) have been evaluated. Compounds 70–74 significantly inhibit the viability and growth of Jurkat T cells at concentrations below 10 μm. Compound 73 is the most active substance with an IC₅₀ values of 3 μm, followed by 70 (IC₅₀=6 μm). An additional glucopyranose substituent leads to weaker cytotoxicity against Jurkat T cells, as observed for 71 (IC₅₀=10 μm) and 74 (IC₅₀=8 μm). Compound 70 induces cell-cell contacts in a Jurkat T cell population, and remarkably up-regulated mRNA levels of the cell-cycle regulator cyclin D1, which might be an indication for cell differentiation [53]. In 2003, Akbay and co-workers investigated the cytotoxicity of sterols obtained from A. salicifolia against KB (HeLa) and Jurkat T cancer cells. This study demonstrated that compound 72 is active against KB cells with an IC₅₀ of 1 μg/mL, while the corresponding 3-O-β-glucopyranoside, compound 76, is less potent (IC₅₀=13 μg/mL) [54]. Four new A. decumbens abietane diterpenoids, 235–238, were evaluated for in vitro inhibition of cell proliferation. The diterpenoids 235 and 237 exhibit moderate cytotoxic activities against MCF-7 cells (human breast cancer), with IC₅₀ values of 19.4 and 12.5 μm, respectively [7].

Cholinesterase inhibitory activity

Compounds 95, 104, 151, 156, 342, 352 and 353 were obtained from A. bracteosa, and their enzyme-inhibitory potential was evaluated. The diterpenoids 95, 104, 151 and 156 display inhibitory activity against cholinesterase (AChE and BChE) with IC₅₀ values in the range of 14.0–35.2 μm for AChE and 10.0–19.0 μm for BChE, respectively. Compound 104 is the most active against cholinesterase while 156 is comparatively less active, indicating that the presence of a MeO group at C(15) increases the cholinesterase inhibitory activity [10].

Antioxidative activity

Bouderbala and co-workers studied the effect of A. iva aqueous extract on lipid peroxidation and antioxidant enzyme activity in hypercholesterolemic rats. The results showed that A. iva extract is more effective at improving RBC antioxidant capacity relative to that of tissues. In addition, A. iva aqueous extract can reduce oxidative stress, which may prevent lipid peroxidation in hypercholesterolemic models by increasing antioxidant enzyme activity [138].

Vasorelaxant activity

El-Hilaly and co-workers investigated vascular activity of A. iva aqueous extract in normotensive Wistar rats. The aqueous extract displayed NO-mediated and NO-independent vasorelaxing properties in vitro. The A. iva extract contains more than one active compound. One of these compounds is responsible for inhibition of noradrenaline evoked contraction. Another compound was identified in vitro as a transient NO-dependent relaxation [8].

Conclusions

The plants of the genus Ajuga are widely distributed globally and many of these plants are used as traditional herbal medicines. The compounds isolated from this genus exert a broad spectrum of biological and pharmacological activities, however, our review indicates that phytochemical investigation has mainly focused on a few species. Further studies on the remaining species, their constituents and biological activities, should be carried out.

Funding source: National Natural Science Foundation of China

Award Identifier / Grant number: 81302664

Award Identifier / Grant number: 81241101

Funding statement: We are grateful for the financial supports from the National Natural Science Foundation of China (81302664, 81241101), and the Scientific Research Foundation of Hebei Province (C2010000489). We also wish to extend our sincere thanks for financial support from Syngenta Ltd. (20013-Hebei Medical University-Syngenta-04) and JSPS KAKENHI (Grant Numbers 19580120, 22560112, 25450144, 17K07772, 26•04392).

References

[1] Israili, Z. H.; Lyoussi, B. Ethnopharmacology of the plants of genus Ajuga. Pak. J. Pharm. Sci.2009, 22, 425–462.Search in Google Scholar

[2] Kubo, I.; Lee, Y.-W.; Balogh-Nair, V.; Nakanishi, K.; Chapya, A. Structure of ajugarins. J. Chem. Soc., Chem. Commun.1976, 949–950.10.1039/c39760000949Search in Google Scholar

[3] Camps, F.; Coll, J. Insect allelochemicals from Ajuga plants. Phytochemistry1993, 32, 1361–1370.10.1016/0031-9422(93)85139-ISearch in Google Scholar

[4] Chen, H.; Liu, D. Q.; Li, X. Z.; Xia, Z. H.; Li, Y.; Liu, Z. L.; Tan, R. X. Two new clerodane diterpenes with antibacterial activity from Ajuga lupulina. Indian J. Chem. B1999, 38, 743–745.Search in Google Scholar

[5] Kariba, R. M. Antifungal activity of Ajuga remota. Fitoterapia2001, 72, 177–178.10.1016/S0367-326X(00)00280-XSearch in Google Scholar

[6] Kuria, K. A. M.; Chepkwony, H.; Govaerts, C.; Roets, E.; Busson, R.; Witte, P. D.; Zupko, I.; Hoornaert, G.; Quirynen, L.; Maes, L.; et al. The antiplasmodial activity of isolates from Ajuga remota. J. Nat. Prod.2002, 65, 789–793.10.1021/np0104626Search in Google Scholar

[7] Wang, B.; Wang, X. N.; Shen, T.; Wang, S. Q.; Guo, D. X.; Lou, H. X. Rearranged abietane diterpenoid hydroquinones from aerial parts of Ajuga decumbens Thunb. Phytochem. Lett.2012, 5, 271–275.10.1016/j.phytol.2012.01.010Search in Google Scholar

[8] El-Hilaly, J.; Lyoussi, B.; Wibo, M.; Morel, N. Vasorelaxant effect of the aqueous extract of Ajuga iva in rat aorta. J. Ethnopharmacol.2004, 93, 69–74.10.1016/j.jep.2004.03.020Search in Google Scholar

[9] Jannet, H. B.; Harzallah-Skhiri, F.; Mighri, Z.; Simmonds, M. S. J.; Blaney, W. M. Responses of Spodoptera littoralis larvae to Tunisian plant extracts and to neo-clerodane diterpenoids isolated from Ajuga pseudoiva leaves. Fitoterapia2000, 71, 105–112.10.1016/S0367-326X(99)00146-XSearch in Google Scholar

[10] Riaz, N.; Nawaz, S. A.; Mukhtar, N.; Malik, A.; Afza, N.; Ali, S.; Ullah, S.; Muhammad, P.; Choudhary, M. I. Isolation and enzyme-inhibition studies of the chemical constituents from Ajuga bracteosa. Chem. Biodivers.2007, 4, 72–83.10.1002/cbdv.200790008Search in Google Scholar PubMed

[11] Imai, S.; Toyosato, T.; Sakai, M.; Sato, Y.; Fujioka, S.; Murata, E.; Goto, M. Isolation of cyasterone and ecdysterone from plant materials. Chem. Pharm. Bull.1969, 17, 340–342.10.1248/cpb.17.340Search in Google Scholar

[12] Usmanov, B. Z.; Gorovits, M. B.; Abubakirov, N. K. Phytoecdysones from Ajuga turkestanica. Khim. Prir. Soedin.1971, 7, 535–536.10.1007/BF00564772Search in Google Scholar

[13] Ikan, R.; Ravid, U. The isolation and identification of ecdysterone from Ajuga iva. Planta Med.1971, 20, 33–35.10.1055/s-0028-1099661Search in Google Scholar PubMed

[14] Wessner, M.; Champion, B.; Girault, J. P.; Kaouadji, N.; Saidi, B.; LaFont, R. Ecdysteroids from Ajuga iva. Phytochemistry1992, 31, 3785–3788.10.1016/S0031-9422(00)97527-7Search in Google Scholar

[15] Ghedira, K.; Chemli, R.; Richard, B.; Zeches, M.; Men-Olivier, L. L. Contribution to the study of the traditional Tunisian pharmacopoeia: study of aerial parts of Ajuga iva (L.) Schreb. Plant. Med. Phytother.1991, 25, 100–111.Search in Google Scholar

[16] Ikan, R.; Ravid, U. The isolation and identification of cyasterone from Ajuga chia (labiatae). Phytochemistry1971, 10, 1659–1661.10.1016/0031-9422(71)85043-4Search in Google Scholar

[17] Camps, F.; Coll, J.; Dargallo, O. Phytoecdysteroids from Ajuga chamaepitys. An. Quim., Ser. C.1985, 81, 74–75.Search in Google Scholar

[18] Yu, Y. J.; Do, J. C.; Kwon, S. Y.; Son, K. H. Studies on the constituents from the herbs of Ajuga multiflora (II). Saengyak Hakhoechi1998, 29, 318–322.Search in Google Scholar

[19] Chan, Y.-Y.; Wu, T.-S.; Kuoh, C. S.; Damu, A. G. A new phytoecdysteroid from Ajuga taiwanensis. Chem. Pharm. Bull.2005, 53, 836–838.10.1248/cpb.53.836Search in Google Scholar PubMed

[20] Coll, J.; Tandron, Y. A.; Zeng, X. New phytoecdysteroids from cultured plants of Ajuga nipponensis Makino. Steroids2007, 72, 270–277.10.1016/j.steroids.2006.11.017Search in Google Scholar PubMed

[21] Castro, A.; Coll, J.; Tandron, Y. A.; Pant, A. K.; Mathela, C. S. Phytoecdysteroids from Ajuga macrosperma var. breviflora Roots. J. Nat. Prod.2008, 71, 1294–1296.10.1021/np800131fSearch in Google Scholar PubMed

[22] Sinica, I. H. Isolation and identification of phytoecdysones from Ajuga nipponensis Makino. Huaxue Xuebao1981, 39, 466–470.Search in Google Scholar

[23] Camps, F.; Coll, J.; Cortel, A. Allelochemicals on insects isolated from Ajuga reptans (Labiatae). Rev. Latinoam. Quim.1981, 12, 81–88.Search in Google Scholar

[24] Camps, F.; Coll, J.; Cortel, A. 29-Norsengosterone and 29-norcyasterone, new C-28 phytoecdysteroids from Ajuga reptans (Labiatae). Chem. Lett.1982, 1313–1316.10.1246/cl.1982.1313Search in Google Scholar

[25] Alekseeva, L. I.; Lafont, R.; Volodin, V. V.; Luksha, V. G. Ecdysteroids from Ajuga reptans. Russ. J. Plant Physiol.1998, 45, 316–321.Search in Google Scholar

[26] Kubo, I.; Klocke, J. A. Plant resistance to insects. ACS Symp. Ser.1983, 208, 329–346.10.1021/bk-1983-0208.ch019Search in Google Scholar

[27] Saatov, Z.; Usmanov, B. Z.; Abubakirov, N. K. Phytoecdysones of Ajuga turkestanica. IV. Khim. Prir. Soedin.1977, 422.10.1007/BF00573570Search in Google Scholar

[28] Usmanov, B. Z.; Rashkes, Y. V.; Abubakirov, N. K. Phytoecdysones of Ajuga turkestanica. VI. 22-Acetylcyasterone. Khim. Prir. Soedin.1978, 215–219.10.1007/BF01134622Search in Google Scholar

[29] Usmanov, B. Z.; Saatov, Z.; Abubakirov, N. K. Phytoecdysones of Ajuga turkestanica. V. Khim. Prir. Soedin.1977, 710.10.1007/BF00569612Search in Google Scholar

[30] Coll, J. New minor ecdysteroids from Ajuga iva (Labiatae) and complete 1H-NMR assignment of cyasterone. Afinidad2007, 64, 242–250.Search in Google Scholar

[31] Imai, S.; Murata, E.; Fujioka, S.; Koreeda, M.; Nakanishi, K. Structure of ajugasterone C, a phytoecdysone with an 11-hydroxy-group. J. Chem. Soc. D.1969, 546–547.10.1039/c29690000546Search in Google Scholar

[32] Khafagy, S. M.; Sabri, N. N.; El-Sebakhy, N.; Blessington, B.; Asaad, A. A C-28 ecdysone-like substance from Ajuga iva. Planta Med.1979, 35, 184–185.10.1055/s-0028-1097201Search in Google Scholar

[33] Camps, F.; Coll, J.; Cortel, A.; Molins, E.; Miravitlles, C. 2-Acetyl- and 3-acetyl-29-norcyasterone, new minor phytoecdysteroids from Ajuga reptans (Labiatae). J. Chem. Res (S).1985, 14–15.Search in Google Scholar

[34] Calcagno, M. P.; Camps, F.; Coll, J.; Mele, E.; Sanchez-Baeza, F. A new family of phytoecdysteroids isolated from aerial part of Ajuga reptans var. atropurpurea. Tetrahedron1995, 51, 12119–12126.10.1016/0040-4020(95)00767-3Search in Google Scholar

[35] Calcagno, M. P.; Camps, F.; Coll, J.; Mele, E.; Sanchez-Baeza, F. New phytoecdysteroids from roots of Ajuga reptans varieties. Tetrahedron1996, 52, 10137–10146.10.1016/0040-4020(96)00536-4Search in Google Scholar

[36] Vanyolos, A.; Simon, A.; Toth, G.; Polgar, L.; Kele, Z.; Ilku, A.; Matyus, P.; Bathori, M. C-29 Ecdysteroids from Ajuga reptans var. reptans. J. Nat. Prod.2009, 72, 929–932.10.1021/np800708gSearch in Google Scholar

[37] Alekseeva, L. I.; Volodin, V. V.; Luksha, V. G.; Lafont, R. Ecdysteroid acetates from Ajuga reptans. Chem. Nat. Compd.1999, 35, 532–534.10.1007/BF02323288Search in Google Scholar

[38] Chaari, A.; Jannet, H. B.; Mighri, Z. Isolement et élucidation structurale d’un nouveau phytoecdystéroïde antibactérien et de deux dérivés de l’acide cinnamique des feuilles de la plante Ajuga pseudo-iva. J. Soc. Chim. Tunis.2000, 4, 789–799.Search in Google Scholar

[39] Fujimoto, Y.; Ohyama, K.; Nomura, K.; Hyodo, R.; Takahashi, K.; Yamada, J.; Morisaki, M. Biosynthesis of sterols and ecdysteroids in Ajuga hairy roots. Lipids2000, 35, 279–288.10.1007/s11745-000-0524-zSearch in Google Scholar

[40] Khan, P. M.; Ahmad, S.; Rubnawaz, H.; Malik, A. The first report of a withanolide from the family Labiatae. Phytochemistry1999, 51, 669–671.10.1016/S0031-9422(99)00045-XSearch in Google Scholar

[41] Khan, P. M.; Malik, A.; Ahmad, S.; Nawaz, H. R. Withanolides from Ajuga parviflora. J. Nat. Prod.1999, 62, 1290–1292.10.1021/np990029kSearch in Google Scholar

[42] Khan, P. M.; Nawaz, H. R.; Ahmad, S.; Malik, A. Ajugins C and D, new withanolides from Ajuga parviflora. Helv. Chim. Acta1999, 82, 1423–1426.10.1002/(SICI)1522-2675(19990908)82:9<1423::AID-HLCA1423>3.0.CO;2-FSearch in Google Scholar

[43] Nawaz, H. R.; Malik, A.; Khan, P. M.; Ahmed, S. Ajugin E and F: two withanolides from Ajuga parviflora. Phytochemistry1999, 52, 1357–1360.10.1016/S0031-9422(99)00345-3Search in Google Scholar

[44] Nawaz, H. R.; Riaz, M.; Malik, A.; Khan, P. M.; Ullah, N. Withanolides and alkaloid from Ajuga parviflora. J. Chem. Soc. Pak.2000, 22, 138–141.Search in Google Scholar

[45] Nawaz, H. R.; Malik, A.; Muhammad, P.; Ahmed, S.; Riaz, M. Chemical constituents of Ajuga parviflora. Z. Naturforsch. B.2000, 55, 100–103.10.1515/znb-2000-0116Search in Google Scholar

[46] Riaz, N.; Malik, A.; Aziz ur, R.; Nawaz, S. A.; Muhammad, P.; Choudhary, M. I. Cholinesterase-inhibiting withanolides from Ajuga bracteosa. Chem. Biodivers.2004, 1, 1289–1295.10.1002/cbdv.200490091Search in Google Scholar

[47] Camps, F.; Coll, J.; Cortel, A. Sterols from Ajuga reptans (Labiatae). An. Quim., Ser. C.1983, 79, 228–229.Search in Google Scholar

[48] Jannet, H. B.; H-Skhiri, F.; Mighri, Z.; Simmonds, M. S. J.; Blaney, W. M. Antifeedant activity of plant extracts and of new natural diglyceride compounds isolated from Ajuga pseudoiva leaves against Spodoptera littoralis larvae. Ind. Crops Prod.2001, 14, 213–222.10.1016/S0926-6690(01)00086-3Search in Google Scholar

[49] Kokdil, G.; Topcu, G.; Goren, A. C.; Voelter, W. Steroids and terpenoids from Ajuga relicta. Z. Naturforsch. B.2002, 57, 957–960.10.1515/znb-2002-0817Search in Google Scholar

[50] Chaari, A.; Jannet, H. B.; Martin, M. T.; Mighri, Z. Identification of a new steroid and a biological active heteroside in Ajuga pseudoiva leaves. J. Soc. Chim. Tunis.1998, 4, 257–266.Search in Google Scholar

[51] Topcu, G.; Kokdil, G.; Turkmen, Z.; Voelter, W.; Adou, E.; Kingston, D. G. I. A new clerodane diterpene and other constituents from Ajuga chamaepitys ssp. laevigata. Z. Naturforsch. B.2004, 59, 584–588.10.1002/chin.200437183Search in Google Scholar

[52] Guo, X.; Huang, Z.; Bao, Y.; An, L.; Ma, L.; Gu, L. Isolation and structure identification of chemical constituents in Ajuga decumbens. Zhongcaoyao2005, 36, 646–648.Search in Google Scholar

[53] Akbay, P.; Gertsch, J.; Cahs, I.; Heilmann, J.; Zerbe, O.; Sticher, O. Novel antileukemic sterol glycosides from Ajuga salicifolia. Helv. Chim. Acta2002, 85, 1930–1942.10.1002/1522-2675(200207)85:7<1930::AID-HLCA1930>3.0.CO;2-CSearch in Google Scholar

[54] Akbay, P.; Calis, I.; Heilmann, J.; Sticher, O. New stigmastane sterols from Ajuga salicifolia. J. Nat. Prod.2003, 66, 461–465.10.1021/np020427eSearch in Google Scholar

[55] Cantrell, C. L.; Rajab, M. S.; Franzblau, S. G.; Fronczek, F. R.; Fischer, N. H. Antimycobacterial ergosterol-5, 8-endoperoxide from Ajuga remota. Planta Med.1999, 65, 732–734.10.1055/s-1999-14053Search in Google Scholar

[56] Dinda, B.; Banerjee, J.; Guha, S. Triterpenes from Ajuga macrosperma Wall. J. Indian Chem. Soc.1997, 74, 424.Search in Google Scholar

[57] Shimomura, H.; Sashida, Y.; Ogawa, K. Neo-clerodane diterpenes from Ajuga nipponensis. Chem. Pharm. Bull.1989, 37, 354–357.10.1248/cpb.37.354Search in Google Scholar

[58] Beauchamp, P. S.; Botini, A. T.; Caselles, M. C.; Dev, V.; Hope, H.; Larter, M.; Lee, G.; Mathela, C. S.; Melkani, A. B.; Millar, P. D.; et al. Neo-clerodane diterpenoids from Ajuga parviflora. Phytochemistry1996, 43, 827–834.10.1016/0031-9422(96)00207-5Search in Google Scholar

[59] Sun, Z.; Li, Y.; Jin, D.-Q.; Guo, P.; Xu, J.; Guo, Y.; Zhang, L. Structure elucidation and Inhibitory effects on NO production of clerodane diterpenes from Ajuga decumbens. Planta Med.2012, 78, 1579–1593.10.1055/s-0032-1315215Search in Google Scholar

[60] Kubo, I.; Klocke, J. A.; Miura, I.; Fukuyama, Y. Structure of ajugarin-IV. J. Chem. Soc., Chem. Commun.1982, 618–619.10.1039/c39820000618Search in Google Scholar

[61] Shimomura, H.; Sashida, Y.; Ogawa, K. Neo-clerodane diterpenes from Ajuga ciliata var. villosior. Chem. Pharm. Bull.1989, 37, 988–992.10.1248/cpb.37.988Search in Google Scholar

[62] Kubo, I.; Fukuyama, Y.; Chapya, A. Structure of ajugarin W. Chem. Lett.1983, 223–234.10.1246/cl.1983.223Search in Google Scholar

[63] Kubo, I.; Kido, M.; Fukuyama, Y. X-Ray crystal structure of 12-bromoajugarin-I and conclusion on the absolute configuration of ajugarins. J. Chem. Soc., Chem. Commun.1980, 897–898.10.1039/c39800000897Search in Google Scholar

[64] Castro, A.; Coll, J.; Arfan, M. Neo-Clerodane diterpenoids from Ajuga bracteosa. J. Nat. Prod.2011, 74, 1036–1041.10.1021/np100929uSearch in Google Scholar

[65] Coll, J.; Tandron, Y. Isolation and identification of neo-clerodane diterpenes from Ajuga remota by high-performance liquid chromatography. Phytochem. Anal.2005, 16, 61–67.10.1002/pca.812Search in Google Scholar

[66] Camps, F.; Coll, J.; Cortel, A.; Messeguer, A. Ajugareptansin, a new diterpenoid from Ajuga reptans (L.). Tetrahedron Lett.1979, 20, 1709–1712.10.1016/S0040-4039(01)93631-7Search in Google Scholar

[67] Bremner, P. D.; Simmonds, M. S. J.; Blaney, W. M.; Veitch, N. C. Neo-clerodane diterpenoid insect antifeedants from Ajuga reptans cv Catlins Giant. Phytochemistry1998, 47, 1227–1232.10.1016/S0031-9422(97)00706-1Search in Google Scholar

[68] Malakov, P. Y.; Papanov, G. Y. Areptins A and B two new neo-clerodane diterpenoids from Ajuga reptans. Phytochemistry1998, 49, 2443–2447.10.1016/S0031-9422(98)00445-2Search in Google Scholar

[69] Camps, F.; Coll, J.; Cortel, A. Two new clerodane diterpenids from Ajuga reptans (Labiatae). Chem. Lett.1981, 1093–1096.10.1246/cl.1981.1093Search in Google Scholar

[70] Carbonell, P.; Coll, J. Ajugatansins, neo-clerodane diterpenes from Ajuga reptans. Phytochem. Anal.2001, 12, 73–78.10.1002/1099-1565(200101/02)12:1<73::AID-PCA561>3.0.CO;2-8Search in Google Scholar

[71] Camps, F.; Coll, J.; Cortel, A. New clerodane diterpenoids from Ajuga iva. Chem. Lett.1982, 1053–1056.10.1246/cl.1982.1053Search in Google Scholar

[72] Hernandez, A.; Pascual, C.; Sanz, J.; Rodriguez, B. Diterpenoids from Ajuga chamaepitys: Two neo-clerodane derivatives. Phytochemistry1982, 21, 2909–2911.10.1016/0031-9422(80)85066-7Search in Google Scholar

[73] Boneva, I.; Mikhova, B.; Malakov, P.; Papanov, G.; Duddeck, H.; Spasov, S. Neo-clerodane diterpenoids from Ajuga chamaepitys. Phytochemistry1990, 29, 2931–2933.10.1016/0031-9422(90)87108-7Search in Google Scholar

[74] Torre, M. C. D. L.; Rodriguez, B.; Bruno, M.; Piozzi, F.; Vassallo, N.; Bondi, M. L.; Servettaz, O. Neo-clerodane diterpenoids from Ajuga australis and A. orientalis. Phytochemistry1997, 45, 121–123.10.1016/S0031-9422(96)00850-3Search in Google Scholar

[75] Amano, T.; Nishida, R.; Kuwahara, Y. Ajugatakasins A and B, new diterpenoids from Ajuga decumbens, and feeding stimulative activity of related neoclerodane analogs toward the turnip sawfly. Biosci. Biotechnol. Biochem.1997, 61, 1518–1522.10.1271/bbb.61.1518Search in Google Scholar

[76] Grace, M. H.; Cheng, D. M.; Raskin, I.; Lila, M. A. Neo-clerodane diterpenes from Ajuga turkestanica. Phytochem. Lett.2008, 1, 81–84.10.1016/j.phytol.2008.03.004Search in Google Scholar

[77] Camps, F.; Coll, J.; Dargallo, O. Neo-clerodane diterpenoids from Ajuga pseudoiva. Phytochemistry1984, 23, 387–389.10.1016/S0031-9422(00)80337-4Search in Google Scholar

[78] Jannet, H. B.; Chaari, A.; Mighri, Z.; Martin, M. T.; Loukaci, A. Neo-clerodane diterpenoids from Ajuga pseudoiva leaves. Phytochemistry1999, 52, 1541–1545.10.1016/S0031-9422(99)00337-4Search in Google Scholar

[79] Verma, V. H. K.; Mahmood, U.; Singh, B. Clerodane diterpenoids from Ajuga bracteosa Wall. Nat. Prod. Lett.2002, 16, 255–259.10.1080/10575630290020578Search in Google Scholar

[80] Camps, F.; Coll, J.; Dargallo, O.; Rius, J.; Miravitlles, C. Clerodane diterpenoids from Teucrium and Ajuga plants. Phytochemistry1987, 26, 1475–1479.10.1016/S0031-9422(00)81838-5Search in Google Scholar

[81] Shimomura, H.; Sashida, Y.; Ogawa, K.; Iitaka, Y. The chemical constituents of Ajuga plants. I. neo-Clerodanes from the leaves of Ajuga nipponensis MAKINO. Chem. Pharm. Bull.1983, 31, 2192–2199.10.1248/cpb.31.2192Search in Google Scholar

[82] Shimomura, H.; Sashida, Y.; Ogawa, K.; Iitaka, Y. Ajugamarin, a new bitter diterpene from Ajuga nipponensis Makino. Tetrahedron Lett.1981, 22, 1367–1368.10.1016/S0040-4039(01)90321-1Search in Google Scholar

[83] Coll, J.; Tandron, Y. A. Isolation and identification of neo-clerodane diterpenes from Ajuga nipponensis Makino. Nat. Prod. Commun.2006, 1, 183–189.10.1177/1934578X0600100302Search in Google Scholar

[84] Min, Z.; Mizuno, M.; Wang, S.; Iinuma, M.; Tanaka, T. Two new neo-clerodane diterpenes in Ajuga decumbens. Chem. Pharm. Bull.1990, 38, 3167–3168.10.1248/cpb.38.3167Search in Google Scholar

[85] Sang, Y.-S.; Huang, Z.-H.; Min, Z.-D. A new neoclerodane diterpene isolated from Ajuga decumbens. Zhongguo Tianran Yaowu2005, 3, 284–286.Search in Google Scholar

[86] Sun, Z.; Li, Y.; Jin, D.-Q.; Guo, P.; Song, H.; Xu, J.; Guo, Y.; Zhang, L. neo-Clerodane diterpenes from Ajuga decumbens and their inhibitory activities on LPS-induced NO production. Fitoterapia2012, 83, 1409–1414.10.1016/j.fitote.2012.08.003Search in Google Scholar PubMed

[87] Guo, P.; Li, Y.; Xu, J.; Liu, C.; Ma, Y.; Guo, Y. Bioactive neo-clerodane diterpenoids from the whole plants of Ajuga ciliata Bunge. J. Nat. Prod.2011, 74, 1575–1583.10.1021/np2001557Search in Google Scholar PubMed

[88] Shimomura, H.; Sashida, Y.; Ogawa, K. Neo-clerodane diterpenes from Ajuga decumbens. Chem. Pharm. Bull.1989, 37, 996–998.10.1248/cpb.37.996Search in Google Scholar

[89] Chan, Y.-Y. Neoclerodane diterpenoids from Ajuga taiwanensis. Chem. Pharm. Bull.2005, 53, 164–167.10.1248/cpb.53.164Search in Google Scholar PubMed

[90] Guo, P.; Li, Y.; Jin, D.-Q.; Xu, J.; He, Y.; Zhang, L.; Guo, Y. Neo-Clerodane diterpenes from Ajuga ciliata and their inhibitory activities on LPS-induced NO production. Phytochem. Lett.2012, 5, 563–566.10.1016/j.phytol.2012.05.014Search in Google Scholar

[91] Guo, P.; Li, Y.; Xu, J.; Guo, Y.; Jin, D.-Q.; Gao, J.; Hou, W.; Zhang, T. Neo-Clerodane diterpenes from Ajuga ciliata Bunge and their neuroprotective activities. Fitoterapia2011, 82, 1123–1127.10.1016/j.fitote.2011.07.010Search in Google Scholar

[92] Min, Z.-D.; Wang, S.-Q.; Zheng, Q.-T.; Wu, B.; Mizuno, M.; Tanaka, T.; Inuma, M. Four new insect antifeedant neo-clerodane diterpenoids, ajugacumbins A, B, C and D, from Ajuga decumbens. Chem. Pharm. Bull.1989, 37, 2505–2508.10.1248/cpb.37.2505Search in Google Scholar

[93] Chen, H.-M.; Min, Z.-D.; Iinuma, M.; Tanaka, T. Clerodane diterpenoids from Ajuga decumbens. Chem. Pharm. Bull.1995, 43, 2253–2255.10.1248/cpb.43.2253Search in Google Scholar

[94] Liu, Z.; Li, Z. Q.; Zhang, C. X.; Chen, R. Y.; Zhang, Y. G.; Qiu, Y. T.; Zhao, S. H. A new neo-clerodane diterpene from Ajuga nipponensis. Chin. Chem. Lett.1995, 6, 581–582.Search in Google Scholar

[95] Shen, X.; Isogai, A.; Furihata, K.; Sun, H.; Suzuki, A. Neo-clerodane diterpenoids from Ajuga macrosperma and Ajuga pantantha. Phytochemistry1993, 34, 1091–1094.10.1016/S0031-9422(00)90721-0Search in Google Scholar

[96] Lv, H.; Luo, J.; Kong, L. A new neo-clerodane diterpene from Ajuga decumbens. Nat. Prod. Res.2014, 28, 196–200.10.1080/14786419.2013.866114Search in Google Scholar

[97] Malakov, P. Y.; Papanov, G. Y.; Torre, M. C. D. l.; Rodriguez, B. Neo-clerodane diterpenoids from Ajuga genevensis. Phytochemistry1991, 30, 4083–4085.10.1016/0031-9422(91)83472-WSearch in Google Scholar

[98] Shen, X.; Isogai, A.; Furihata, K.; Sun, H.; Suzuki, A. Two neo-clerodane diterpenoids from Ajuga macrosperma. Phytochemistry1993, 33, 887–889.10.1016/0031-9422(93)85297-5Search in Google Scholar

[99] Chen, H.; Tan, R.-X.; Liu, Z.-L.; Zhang, Y.; Yang, L. Antibacterial neoclerodane diterpenoids from Ajuga lupulina. J. Nat. Prod.1996, 59, 668–670.10.1021/np960385sSearch in Google Scholar PubMed

[100] Chen, H.; Tan, R.-X.; Liu, Z.-L.; Zhao, C.-Y.; Sun, J. A clerodane diterpene with antibacterial activity from Ajuga lupulina. Acta Crystallogr., Sect. C: Cryst. Struct. Commun.1997, 53, 814–816.10.1107/S0108270196013637Search in Google Scholar

[101] Li, B.; Zheng, C.; Lin, Z.; Sun, H. Chemical constituents of Ajuga lupulina var. Major. Tianran Chanwu Yanjiu Yu Kaifa2000, 12, 45.Search in Google Scholar

[102] Boneva, I. M.; Malakov, P. Y.; Papanov, G. Y. Ajugapyrin A, a neo-clerodane diterpene from Ajuga pyramidalis. Phytochemistry1997, 47, 303–305.10.1016/S0031-9422(97)00558-XSearch in Google Scholar

[103] Malakov, P. Y.; Papanov, G. Y.; Torre, M. C. D. L.; Rodriguez, B. Constituents of Ajuga laxmanii. Fitoterapia1998, 69, 552–555.Search in Google Scholar

[104] Jannet, H. B.; Oueslati, M. H.; Chaari, A.; Martin, M. T.; Loukaci, A.; Simmonds, M. J.; Mighri, Z. Structure of a new neo-clerodane diterpenoid from Ajuga pseudoiva leaves and its insect antifeedant and antibacterial activities. J. Soc. Chim. Tunis.2002, 4, 1545–1549.Search in Google Scholar

[105] Nishida, R.; Kawai, K.; Amano, T.; Kuwahara, Y. Pharmacophagous feeding stimulant activity of neo-clerodane diterpenoids for the turnip sawfly, Athalia rosae ruficornis. Biochem. System. Ecol.2004, 32, 15–25.10.1016/S0305-1978(03)00160-1Search in Google Scholar

[106] Huang, X.-C.; Qin, S.; Guo, Y.-W.; Krohn, K. Four new neoclerodane diterpenoids from Ajuga decumbens. Helv. Chim. Acta2008, 91, 628–634.10.1002/hlca.200890066Search in Google Scholar

[107] Wang, A. G.; Lu, Y.; Feng, X. Z. Chemical constituents of Ajuga forrestii Diels. Yaoxue Xuebao1994, 29, 899–904.Search in Google Scholar

[108] Takasaki, M.; Yamauchi, I.; Haruna, M.; Konoshima, T. New glycosides from Ajuga decumbens. J. Nat. Prod.1998, 61, 1105–1109.10.1021/np980148kSearch in Google Scholar

[109] Xiong, Y.; Qu, W.; Sun, J.-B.; Wang, M.-T.; Liang, J.-Y. Eudesmane sesquiterpenoid lactones and abietane diterpenoids from Ajuga forrestii Diels. Phytochem. Lett.2013, 6, 457–460.10.1016/j.phytol.2013.05.017Search in Google Scholar

[110] Coll, J. NMR shift data of neo-clerodane diterpenes from the genus Ajuga. Phytochem. Anal.2002, 13, 372–380.10.1002/pca.671Search in Google Scholar

[111] Akbay, P.; Calis, I.; Heilmann, J.; Sticher, O. Ionone, iridoid and phenylethanoid glycosides from Ajuga salicifolia. Z. Naturforsch. C.2003, 58, 177–180.10.1515/znc-2003-3-406Search in Google Scholar

[112] Sun, Z.-P.; Gui, L.-P.; Guo, Y.-Q.; Xu, J.; Li, Y.-S. Isolation and identification of chemical constituents from whole plants of Ajuga decumbens. Shenyang Yaoke Daxue Xuebao2012, 29, 758–764.Search in Google Scholar

[113] Guiso, M.; Agosini, A.; Marini-Bettolo, R. Reptoside: structure and configuration. Gazz. Chim. Ital.1974, 104, 403–407.Search in Google Scholar

[114] Shoji, N.; Umeyama, A.; Sunahara, N.; Arihara, S. Ajureptoside, a novel C9 iridoid glucoside from Ajuga reptans. J. Nat. Prod.1992, 55, 1004–1006.10.1021/np50085a030Search in Google Scholar

[115] Ono, M.; Furusawa, C.; Ozono, T.; Oda, K.; Yasuda, S.; Okawa, M.; Kinjo, J.; Ikeda, T.; Miyashita, H.; Yoshimitsu, H.; et al. Four new iridoid glucosides from Ajuga reptans. Chem. Pharm. Bull.2011, 59, 1065–1068.10.1248/cpb.59.1065Search in Google Scholar

[116] Takeda, Y.; Tsuchida, S.; Fujita, T. Four new iridoid glucoside p-coumaroyl esters from Ajuga decumbens. Phytochemistry1987, 26, 2303–2306.10.1016/S0031-9422(00)84707-XSearch in Google Scholar

[117] Guiso, M.; Marini-Bettolo, R.; Agostini, A. Ajugoside and ajugol: structure and configuration. Gazz. Chim. Ital.1974, 104, 25–33.Search in Google Scholar

[118] Chung, B.-S.; Lee, H.-K.; Kim, J.-W. Iridoid glycoside. I. Studies on the iridoid glycoside of Ajuga spectabilis Nakai. Saengyak Hakhoechi1980, 11, 15–23.Search in Google Scholar

[119] Chung, B. S.; Yoo, W. K. Iridoid glycoside (VI). Studies on the iridoid glycoside of Ajuga multiflora Bunge. Saengyak Hakhoechi1985, 16, 160–164.Search in Google Scholar

[120] Assaad, A. M.; Lahloub, M. F. Irdoid glycosides of Ajuga iva (L.) Schreb. (Lamiaceae). Alex. J. Pharm. Sci.1988, 2, 132–135.Search in Google Scholar

[121] Chaari, A.; Jannet, H. B.; Mighri, Z.; Lallemand, M.-C.; Kunesch, N. 7-O-6′-O-Malonylcachinesidic acid, a new macrocyclic iridoid ester of malonic acid from the Tunisian plant Ajuga pseudoiva. J. Nat. Prod.2002, 65, 618–620.10.1021/np010453xSearch in Google Scholar

[122] Manguro, L. O. A.; Ogur, J. A.; Okora, D. M.; Wagai, S. O.; Lemmen, P. Further flavonol and iridoid glycosides from Ajuga remota aerial parts. J. Asian Nat. Prod. Res.2007, 9, 617–629.10.1080/10286020600979480Search in Google Scholar

[123] Manguro, L. O. A.; Lemmen, P.; Hao, P. Iridoid glycosides from underground parts of Ajuga remota. Rec. Nat. Prod.2011, 5, 147–157.Search in Google Scholar

[124] Prokopenko, S. A. Chemical composition of the forb Ajuga chia. Khim. Prir. Soedin.1986, 514.10.1007/BF00579839Search in Google Scholar

[125] Wang, M.; Zhang, H.; Chen, Y. Studies on the chemical constituents of Ajuga lupulina Maxim. Lanzhou Daxue Xuebao, Ziran Kexueban1991, 27, 93–96.Search in Google Scholar

[126] Yu, Y. J.; Do, J. C.; Jung, K. Y.; Kwon, S. Y.; Son, K. H. Studies on the constituents of the herb Ajuga multiflora (I). Saengyak Hakhoechi1998, 29, 75–78.Search in Google Scholar

[127] Hussain, J.; Begum, N.; Hussain, H.; Khan, F. U.; Rehman, N. U.; Al-Harrasi, A.; Ali, L. Ajuganane: a new phenolic compound from Ajuga bracteosa. Nat. Prod. Commun.2012, 7, 615–616.10.1177/1934578X1200700518Search in Google Scholar

[128] Muhammad, P.; Ahmad, S.; Nawaz, H. R.; Ullah, N.; Malik, A. New acetylated quinols from Ajuga parviflora. Fitoterapia1999, 70, 229–232.10.1016/S0367-326X(99)00019-2Search in Google Scholar

[129] Akbar, E.; Nawaz, H. R.; Malik, A. Dihydroquinol and quinol derivatives from Ajuga parviflora. Z. Naturforsch. B.2001, 56, 842–846.10.1515/znb-2001-0819Search in Google Scholar

[130] Singh, N.; Mahmood, U.; Kaul, V. K.; Jirovetz, L. A new phthalic acid ester from Ajuga bracteosa. Nat. Prod. Res.2006, 20, 593–597.10.1080/14786410500185550Search in Google Scholar PubMed

[131] Jannet, H. B.; Mighri, Z.; Serani, L.; Laprevote, O.; Jullian, J. C.; Roblot, F. Isolation and structure elucidation of three new diglyceride compounds from Ajuga iva leaves. Nat. Prod. Lett.1997, 10, 157–164.10.1080/10575639708043732Search in Google Scholar

[132] Jannet, H. B.; Chaari, A.; Martin, M. T.; Mighri, Z. Structure of five new monoglyceride compounds isolated from Ajuga pseudoiva. J. Soc. Chim. Tunis.1999, 4, 483–488.Search in Google Scholar

[133] Jannet, H. B.; Chaari, A.; Martin, M. T.; Mighri, Z. Clerosterol and 3-hydroxyhexadecanoic acid methyl ester from Ajuga iva leaves. J. Soc. Chim. Tunis.1998, 4, 179–187.Search in Google Scholar

[134] Bhakuni, R. S.; Shukla, Y. N.; Thakur, R. S. Heptacos-3-en-25-one. A new unsaturated ketone from Ajuga bracteosa. J. Indian Chem. Soc.1990, 67, 355.Search in Google Scholar

[135] Cocquyt, L.; Cos, P.; Herdewijn, P.; Maes, L.; Van den Steen, P. E. Laekeman, Ajuga remota Benth.: From ethnopharmacology to phytomedical perspective in the treatment of malaria. Phytomedicine2011, 18, 1229–1237.10.1016/j.phymed.2011.08.063Search in Google Scholar PubMed

[136] Gautam, R.; Jachak, S. M.; Saklani, A. Anti-inflammatory effect of Ajuga bracteosa Wall Ex Benth. mediated through cyclooxygenase (COX) inhibition. J. Ethnopharmacol.2011, 133, 928–930.10.1016/j.jep.2010.11.003Search in Google Scholar PubMed

[137] El, H. J.; Lyoussi, B. Hypoglycaemic effect of the lyophilised aqueous extract of Ajuga iva in normal and streptozotocin diabetic rats. J. Ethnopharmacol.2002, 80, 109–113.10.1016/S0378-8741(01)00407-XSearch in Google Scholar

[138] Bouderbala, S.; Lamri-Senhadji, M.; Prost, J.; Lacaille-Dubois, M. A.; Bouchenak, M. Changes in antioxydant defense status in hypercholesterolemic rats treated with Ajuga iva. Phytomedicine2008, 15, 453–461.10.1016/j.phymed.2007.10.001Search in Google Scholar PubMed

Received: 2017-3-24

Accepted: 2017-6-15

Published Online: 2017-7-22

Published in Print: 2017-8-28

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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https://doi.org/10.1515/hc-2017-0064

Keywords for this article

Ajuga; biological activity; chemical constituents; Lamiaceae; phytoecdysteroids; terpenoi

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