Triterpenoids From Alisma Species: Phytochemistry, Structure Modification, and Bioactivities

Pengli Wang; Tongxin Song; Rui Shi; Mingshuai He; Rongrong Wang; Jialin Lv; Miaomiao Jiang

doi:10.3389/fchem.2020.00363

. 2020 Apr 30;8:363. doi: 10.3389/fchem.2020.00363

Triterpenoids From Alisma Species: Phytochemistry, Structure Modification, and Bioactivities

Pengli Wang ^1,^†, Tongxin Song ^1,^†, Rui Shi ¹, Mingshuai He ¹, Rongrong Wang ¹, Jialin Lv ¹, Miaomiao Jiang ^1,^*

PMCID: PMC7205456 PMID: 32426329

Abstract

Plants from Alisma species belong to the genus of Alisma Linn. in Alismataceae family. The tubers of A. orientale (Sam.) Juzep, also known as Ze Xie in Chinese and Takusha in Japanese, have been used in traditional medicine for a long history. Triterpenoids are the main secondary metabolites isolated from Alisma species, and reported with various bioactive properties, including anticancer, lipid-regulating, anti-inflammatory, antibacterial, antiviral and diuretic activities. In this brief review, we aimed to summarize the phytochemical and pharmacological characteristics of triterpenoids found in Alisma, and discuss their structure modification to enhance cytotoxicity as well.

Keywords: triterpenoids, Alisma, structure, anticancer, lipid-regulation

Introduction

Plants from the genus of Alisma Linn. (Alismataceae) are widely distributed in temperate regions and subtropics of the northern hemisphere, belonging to 11 species. Six species were found in China and Asia, including A. canaliculatum, A. gramineum, A. nanum, A. orientale, A. plantago-aquatica and A. lanceolatum (Flora of China Committee, 1992). The tubers of A. orientale, known as Ze Xie in Chinese or Takusha in Japanese, have been used as diuretic and detumescent medications for a long history (Chinese Pharmacopoeia Commission, 2015). It is also used to treat obesity, diabetes and hyperlipidemia nowadays.

Phytochemical studies have revealed that triterpenoids are dominant components in tubers of Alisma plants. A total of 118 triterpenoids have been isolated and identified from Alisma species so far. Most of them contain protostane tetracyclic aglycones, whereas glycosides are rarely found in other plants. These triterpenoids have been considered as chemotaxonomic markers of the genus (Zhao et al., 2007). A small amount of other kinds of compounds have also been isolated from A. orientale, including diterpenoids, sesquiterpenoids, polysaccharides, phytosterols, amino acids, flavonoids and fatty acids (Zhang et al., 2017). The presence of triterpenoids attributes to the bioactivities of A. orientales (Tian et al., 2014; Shu et al., 2016), such as alisol A 24-acatate (2), and alisol B 23-acetate (47) (Choi et al., 2019).

Alisols have shown a series of biological activities, such as anticancer (Law et al., 2010), lipid-regulating (Cang et al., 2017), anti-inflammatory (Kim et al., 2016), antibacterial (Jin et al., 2012), antiviral (Jiang et al., 2006), and diuretic activities (Zhang et al., 2017). Since alisol B 23-acetate (47) exhibits a significant anti-tumor activity, structure-based modification on alisol B 23-acetate (47) gives a profound change of activity.

This paper aims to systematically review triterpenoids from Alisma species, involving their phytochemical characteristics, biosynthesis, bioactivities and structure modification.

Triterpenoids

Starting from 1968, triterpenoids have been isolated from Alisma genus successively (Murata et al., 1968). All these compounds contain protostane tetracyclic skeleton with the structural characteristics of trans-fusions for A/B, B/C and C/D rings, α-methyl submitted at C-8, β-methyl at C-10, β-methyl at C-14 and side chain at C-17. At present there are 101 protostane triterpenoids, 12 nor-protostanes, and 5 seco-protostanes reported from Alisma. According to the changes of side chains submitted at C-17, protostane triterpenoids from Alisma are divided into four classes, including open aliphatic chains, epoxy aliphatic chains, spiro hydrocarbon at C-17, and epoxy at C-16, C-23 or C-16, C-24. The individual triterpenoids were detailed in Table 1.

Table 1.

A total of 118 triterpenoids isolated and identified from Alisma genus.

No.	Name	Skeleton structure	R₁	R₂	R₃	R₄	R₅	R₆	Double bond position	Source	References
PROTOSTANES WITH OPEN ALIPHATIC CHAINS AT C-17
1	alisol A	A	βOH	H	βOH	βOH	OH	H	Δ¹³⁽¹⁷⁾	A. orientalis	Peng et al., 2002a
2	alisol A 24-acetate	A	βOH	H	βOH	βOAc	OH	H	Δ¹³⁽¹⁷⁾	A. orientalis	Peng et al., 2002a
3	alisol A 23-acetate	A	βOH	H	βOAc	βOH	OH	H	Δ¹³⁽¹⁷⁾	A. orientalis	Peng et al., 2002a
4	11-deoxyalisol A	A	H	H	βOH	βOH	OH	H	Δ¹³⁽¹⁷⁾	A. orientalis	Peng et al., 2002b
5	23-o-methyl alisol A	A	βOH	H	βOMe	βOH	OH	H	Δ¹³⁽¹⁷⁾	A. orientale	Nakajma et al., 1994
6	25-o-methoxy-alisol A	A	βOH	H	βOH	βOH	OMe	H	Δ¹³⁽¹⁷⁾	A. orientale	Nakajma et al., 1994
7	16-oxo-alisol A	A	βOH	O	βOH	βOH	OH	H	Δ¹³⁽¹⁷⁾	A. orientale	Mai et al., 2015
8	16-oxo-alisol A-23-acetate	A	βOH	O	βOAc	βOH	OH	H	Δ¹³⁽¹⁷⁾	A. orientale	Zhao et al., 2015
9	16-oxo-alisol A-24-acetate	A	βOH	O	βOH	βOAc	OH	H	Δ¹³⁽¹⁷⁾	A. orientale	Zhao et al., 2015
10	16-oxo-11-deoxy- alisol A	A	H	O	βOH	βOH	OH	H	Δ¹³⁽¹⁷⁾	A. orientale	Mai et al., 2015
11	5β,29-dihydroxy alisol A	A (5βOH)	βOH	H	βOH	βOH	OH	OH	Δ¹³⁽¹⁷⁾	A. plantago-aquatica	Wang et al., 2017b
12	25-o-butyl alisol A	A	βOH	H	βOH	βOH	OBu	H	Δ¹³⁽¹⁷⁾	A. orientalis	Zhang et al., 2017
13	alisol E	A	βOH	H	βOH	αOH	OH	H	Δ¹³⁽¹⁷⁾	A. orientale	Yoshikawa et al., 1993
14	alisol E-23-acetate	A	βOH	H	βOAc	αOH	OH	H	Δ¹³⁽¹⁷⁾	A. orientale	Yoshikawa et al., 1993
15	alisol E-24-acetate	A	βOH	H	βOH	αOAc	OH	H	Δ¹³⁽¹⁷⁾	A. orientale	Yoshikawa et al., 1993
16	25-o-ethylalisol A	A	βOH	H	βOH	βOH	OEt	H	Δ¹³⁽¹⁷⁾	A. orientale	Mai et al., 2015
17	alisol H	A	H	O	O	H	OH	H	Δ¹³⁽¹⁷⁾	A. orientale	Yoshikawa et al., 1999
18	16β-methoxyalisol E	A	βOH	βOMe	βOH	αOH	OH	H	Δ¹³⁽¹⁷⁾	A. orientale	Li et al., 2017
19	16β,25-dimethoxyalisol E	A	βOH	βOMe	βOH	αOH	OMe	H	Δ¹³⁽¹⁷⁾	A. orientale	Li et al., 2017
20	16β-hydroperoxyalisol E	A	βOH	βOOH	βOH	αOH	OH	H	Δ¹³⁽¹⁷⁾	A. orientale	Li et al., 2017
21	11,24-dihydroxy-alisol H	A	βOH	O	O	βOH	OH	H	Δ¹³⁽¹⁷⁾	A. orientale	Yoshikawa et al., 1999
22	alisol T	A	βOH	βOMe	OH	H	OH	H	Δ¹³⁽¹⁷⁾	A. orientale	Li et al., 2017
23	alismanin I	A	βOH	H	O	OH	H	H	Δ¹³⁽¹⁷⁾	A. orientale	Yi et al., 2019
24	15,16-dihydroalisol A.	A	βOH	H	βOH	βOH	OH	H	Δ^{13(17), 15(16)}	A. orientale	Mai et al., 2015
25	alismanol D	A	H	H	H	αOH	OH	H	Δ^{9(11), 12(13)}	A. orientale	Mai et al., 2015
26	24-epi-alismanol D	A	H	H	H	βOH	OH	H	Δ^{9(11), 12(13)}	A. orientalis	Xin et al., 2018
27	alismanol A	A	H	O	O	αOH	OH	H	Δ^{11(12), 13(17)}	A. orientale	Mai et al., 2015
28	alismanol C	A	H	O	βOAc	αOH	OH	H	Δ^{11(12), 13(17)}	A. orientale	Mai et al., 2015
29	16-oxo-11-anhydro alisol A	A	H	O	βOH	βOH	OH	H	Δ^{11(12), 13(17)}	A. orientale	Mai et al., 2015
30	16-oxo-11-anhydroalisol A 24-acetate	A	H	O	βOH	βOAc	OH	H	Δ^{11(12), 13(17)}	A. orientale	Ma et al., 2016
31	3-oxo-11β,23-dihydroxy-24,24-dimethyl−26,27-dinorprotost-13(17)-en-25-oic-acid	A	βOH	O	H	βOH	COOH	H	Δ¹³⁽¹⁷⁾	A. orientale	Zhao et al., 2013
32	alismanin B	A	βOH	O	H	βOH	H	H	Δ¹³⁽¹⁷⁾	A. orientale	Wang et al., 2017a
33	25-anhydroalisol A	B	βOH	H	βOH	βOH			Δ¹³⁽¹⁷⁾	A. orientalis	Peng et al., 2002a
34	11-acetate-25-anhydroalisol A	B	βOAc	H	βOH	βOH			Δ¹³⁽¹⁷⁾	A. orientalis	Peng et al., 2002a
35	24-acetate-25-anhydroalisol A	B	βOH	H	βOH	βOAc			Δ¹³⁽¹⁷⁾	A. orientalis	Peng et al., 2002a
36	11-deoxy-25-anhydro-alisol E.	B	H	H	βOH	αOH			Δ¹³⁽¹⁷⁾	A. orientale	Mai et al., 2015
37	alisol X	B	βOH	H	H	O			Δ¹³⁽¹⁷⁾	A. orientale	Xu et al., 2012
38	23-acetate-25-anhydroalisol E	B	H	H	βOAc	αOH			Δ¹³⁽¹⁷⁾	A. orientalis	Han et al., 2013
39	24-acetate-25-anhydroalisol E	B	H	H	βOH	αOAc			Δ¹³⁽¹⁷⁾	A. orientalis	Han et al., 2013
40	alismanol B	B	H	O	βOH	αOH			Δ^{11(12), 13(17)}	A. orientale	Mai et al., 2015
41	7-oxo-16-oxo-11-anhydro alisol A	C								A. orientale	Mai et al., 2015
42	alismanol M	D								A. orientale	Xin et al., 2016
43	13,17-epo-alisol A	E	βOH	αOH						A. orientalis	Peng et al., 2002b
44	13,17-epoalisol A 24-acetate	E	βOH	αOAc						A. orientalis	Peng et al., 2002b
45	11-deoxy-13,17-epoxy-alisol A	E	H	βOH						A. orientale	Nakajma et al., 1994
PROTOSTANES WITH EPOXY ALIPHATIC CHAINS AT C-17
46	alisol B	F	βOH	H	H	H	αMe	βOH	Δ¹³⁽¹⁷⁾	A. orientale	Nakajma et al., 1994
47	alisol B 23-acetate	F	βOH	H	H	H	αMe	βOAc	Δ¹³⁽¹⁷⁾	A. orientale	Nakajma et al., 1994
48	11-deoxy-alisol B-23-acetate	F	H	H	H	H	βMe	βOAc	Δ¹³⁽¹⁷⁾	A. orientale	Nakajma et al., 1994
49	11-deoxy-alisol B	F	H	H	H	H	βMe	βOH	Δ¹³⁽¹⁷⁾	A. orientale	Nakajma et al., 1994
50	16β-acetoxy alisol B	F	βOH	H	βOAc	H	αMe	βOH	Δ¹³⁽¹⁷⁾	A. orientalis	Cang et al., 2017
51	16α-acetoxy alisol B	F	βOH	H	αOAc	H	αMe	βOH	Δ¹³⁽¹⁷⁾	A. orientalis	Cang et al., 2017
52	16β-hydroxyalisol B-23-acetate	F	βOH	H	βOH	H	αMe	βOAc	Δ¹³⁽¹⁷⁾	A. orientalis	Peng and Lou, 2001
53	16β-methoxyalisol B-23- acetate	F	βOH	H	βOMe	H	αMe	βOAc	Δ¹³⁽¹⁷⁾	A. orientale	Jin et al., 2012
54	16β-ethoxy alisol B 23-acetate	F	βOH	H	βOEt	H	αMe	βOAc	Δ¹³⁽¹⁷⁾	A. orientalis	Zhang et al., 2017
55	alisol C	F	βOH	H	O	H	αMe	βOH	Δ¹³⁽¹⁷⁾	A. orientale	Nakajma et al., 1994
56	11-deoxy-alisol C-23-acetate	F	H	H	O	H	αMe	βOAc	Δ¹³⁽¹⁷⁾	A. orientale	Nakajma et al., 1994
57	11-deoxy-alisol C	F	H	H	O	H	αMe	βOH	Δ¹³⁽¹⁷⁾	A. plantago-aquatica	Fukuyama et al., 1988
58	20-hydroxyalisol C	F	βOH	H	O	OH	αMe	βOH	Δ¹³⁽¹⁷⁾	A. orientale	Mai et al., 2015
59	alisol C 23-acetate	F	βOH	H	O	H	αMe	βOAc	Δ¹³⁽¹⁷⁾	A. plantago-aquatica	Fukuyama et al., 1988
60	alisol M-23-acetate	F	βOH	βOH	O	H	αMe	βOAc	Δ¹³⁽¹⁷⁾	A. orientale	Li et al., 2017
61	alisol N-23-acetate	F	βOH	βOH	H	H	αMe	βOAc	Δ¹³⁽¹⁷⁾	A. orientale	Li et al., 2017
62	16β-hydroperoxyalisol B	F	βOH	H	βOOH	H	αMe	βOH	Δ¹³⁽¹⁷⁾	A. orientale	Li et al., 2017
63	16β-hydroperoxyalisol B 23-acetate	F	βOH	H	βOOH	H	αMe	βOAc	Δ¹³⁽¹⁷⁾	A. orientale	Li et al., 2017
64	alisol L	F	H	H	O	H	αMe	βOH	Δ^{11(12), 13(17)}	A. orientale	Zhao et al., 2015
65	alisol L-23-acetate	F	H	H	O	H	αMe	βOAc	Δ^{11(12), 13(17)}	A. orientale	Yoshikawa et al., 1999
66	13β,17β-epoxy-alisol B	G	βOH	βOH						A. orientale	Nakajma et al., 1994
67	13β,17β-epoxy-23- acetate-alisol B	G	βOH	βOAc						A. orientale	Jin et al., 2012
68	11-deoxy-13β,17β-epoxy-alisol B 23-acetate	G	H	βOAc						A. orientale	Nakajma et al., 1994
69	alisol D	G	βOH	αOAc						A. plantago-aquatica	Fukuyama et al., 1988
70	alisol D 11-acetate	G	βOAc	αOAc						A. plantago-aquatica	Fukuyama et al., 1988
71	11-deoxyalisol D	G	H	αOAc						A. orientale	Yoshikawa et al., 1999
72	alisol J−23 acetate	H								A. orientale	Yoshikawa et al., 1999
73	alisol K-23-acetate	I								A. orientale	Yoshikawa et al., 1999
74	alismanol O	J	H							A. orientale	Xin et al., 2016
75	alismanol P	J	αOH							A. orientale	Xin et al., 2016
76	alisolide H	K								A. plantago-aquatica	Jin et al., 2019
77	alisolide G	L	O	αOAc						A. plantago-aquatica	Jin et al., 2019
78	alisol Q 23-acetate	L	O	βOAc						A. orientale	Jin et al., 2012
79	alisol S 23-acetate	L	βOH	βOAc						A. orientale	Li et al., 2017
80	alisolide I	M								A. plantago-aquatica	Jin et al., 2019
81	alismaketone A-23-acetate	N								A. orientale	Yoshikawa et al., 1997
PROTOSTANES WITH SPIRO HYDROCARBON AT C-17
82	alismanol Q	O								A. orientale	Xin et al., 2016
83	alisol U	P								A. orientale	Li et al., 2017
84	alisol V	Q								A. orientale	Li et al., 2017
85	alisolide D	R								A. plantago-aquatica	Jin et al., 2019
86	alisolide E	S	βOH						Δ¹²⁽¹³⁾	A. plantago-aquatica	Jin et al., 2019
87	alisolide F	S	H						Δ^{9(11), 12(13)}	A. plantago-aquatica	Jin et al., 2019
88	neoalisol	T	βOH	βOH						A. orientalis	Peng et al., 2002a
89	neoalisol 11.24-diacetate	T	βOAc	βOAc						A. orientalis	Peng et al., 2002a
PROTOSTANES WITH FUSED RING AT C-16 AND C-17
90	16,23-oxidoalisol B	U	βOH						Δ¹³⁽¹⁷⁾	A. orientale	Nakajma et al., 1994
91	alisol I	U	βH						Δ¹³⁽¹⁷⁾	A. orientale	Yoshikawa et al., 1999
92	alisol F	V	βOH	βOH	OH				Δ¹³⁽¹⁷⁾	A. orientale	Yoshikawa et al., 1993
93	alisol F-24-acetate	V	βOH	βOAc	OH				Δ¹³⁽¹⁷⁾	A. orientalis	Peng and Lou, 2001
94	25-o-methylalisol F	V	βOH	βOH	OMe				Δ¹³⁽¹⁷⁾	A. orientalis	Chen et al., 2018
95	11-anhydroalisol F	V	H	βOH	OH				Δ^{11(12), 13(17)}	A. orientalis	Hu et al., 2008a
96	alisol O	V	H	βOAc	OH				Δ^{11(12), 13(17)}	A. plantago-aquatica	Jiang et al., 2006
97	25-anhydroalisol F	W	βOH						Δ¹³⁽¹⁷⁾	A. orientalis	Hu et al., 2008a
98	11,25-anhydro-alisol F	W	H						Δ^{11(12), 13(17)}	A. orientalis	Hu et al., 2008b
99	alismaketone B-23-acetate	X	βOH	αOAc					Δ¹³⁽¹⁷⁾	A. orientale	Matsuda et al., 1999
100	alismanol E	X	H	O					Δ^{11(12), 13(17)}	A. orientale	Mai et al., 2015
101	alismanol J	Y								A. orientalis	Zhang et al., 2017
NOR-PROTOSTANES
102	alismanol H	Z	H	Me						A. orientalis	Zhang et al., 2017
103	alismanin A	Z	C₆H₅	H						A. orientale	Wang et al., 2017a
104	alisolide A	a	O	βOH					C-17R	A. plantago-aquatica	Jin et al., 2019
105	alisolide B	a	O	βOOH					C-17S	A. plantago-aquatica	Jin et al., 2019
106	alisolide C	a	βOH	βOH					C-17S	A. plantago-aquatica	Jin et al., 2019
107	alisolide	b								A. orientalis	Xin et al., 2018
108	17-epi-alisolide	c								A. orientalis	Xin et al., 2018
109	alismanol F	d								A. orientale	Mai et al., 2015
110	alismanol G	e	H	O	Ac				Δ^{11(12), 13(17)}	A. orientale	Mai et al., 2015
111	alismanol I	e	βOH	O	OH				Δ¹³⁽¹⁷⁾	A. orientalis	Zhang et al., 2017
112	alisol R	e	βOH	H	O				Δ¹²⁽¹³⁾	A. orientale	Li et al., 2017
113	13β,17β-epoxy-24,25,26,27 -tetranor-alisol A 23-oic acid	f								A. orientale	Zhao et al., 2007
SECO-PROTOSTANES
114	alismanin C	g								A. orientale	Wang et al., 2017a
115	alismaketone C-23-acetate	h								A. orientale	Matsuda et al., 1999
116	alismalactone-23-acetate	i	H							A. orientale	Yoshikawa et al., 1997
117	3-methyl-alismalactone 23-acetate	i	Me							A. orientale	Yoshikawa et al., 1997
118	alisol P	j								A. orientale	Zhao et al., 2007

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Protostanes With Open Aliphatic Chains at C-17

Forty-five protostanes with open aliphatic chains at C-17 (1–45) have been identified as shown in Figure 1. Alisol A (1) is a representative compound of this type. Hydroxyl groups may substitute at C-29 (11) (Wang et al., 2017b), disubstitute at C-23/C-24 (19) and C-23/C-25 (43-45) (Nakajma et al., 1994; Peng et al., 2002b), or trisubstitute at C-23, C-24, and C-25 (41, 42). The hydroxyl group at C-23 or C-24 is easily acetylated. Moreover, double bond may form at C-25 and C-26_(38, 39) (Han et al., 2013), or C-25 may be substituted by carboxyl group (31) (Zhao et al., 2013).

Carbonyl groups substitute at C-16 (8, 9) (Zhao et al., 2015), disubstitute at C-7/C-16 (41) (Mai et al., 2015) or C-16/C-23 (21) (Yoshikawa et al., 1999), or substitute at C-24 (37) (Xu et al., 2012) or C-23 (23) (Yi et al., 2019). Hydroxymethyl groups substitute at C-16 (18) (Li et al., 2017) or disubstitute at C-16/C-25 (19).

Protostanes With Epoxy Aliphatic Chains at C-17

Thirty-six protostanes with epoxy aliphatic chains at C-17 (46–81) have been found in the genus of Alisma and their structures are listed in Figure 2. Alisol B 23-acetate (47) is a representative compound of this type. Epoxy group usually forms at C-24 and C-25 (46–73, 77–79, 81) (Fukuyama et al., 1988), and C-23 may be substituted by hydroxyl (66) or acetoxyl group (67–71).

Except for epoxy ring, tetrahydrofuran ring from C-20 to C-24 (74, 75) and seven-membered peroxic ring from C-20 to C-25 (76) are also existed in the side chains at C-17.

Protostanes With Spiro Hydrocarbon at C-17

Eight protostanes with spiro hydrocarbon at C-17 (82–89) have been isolated from the genus of Alisma as shown in Figure 3. Oxaspiro-nonane moiety is generated between D ring and its side chain with C-17 as spiro hydrocarbon. Methyl group substituted at C-20 with α- (82) (Xin et al., 2016) or β- (85) (Jin et al., 2019) conformation. Alisol U (83) differs from alisol V (84) by forming an epoxy at C-24 and C-25.

Protostanes With Fused Ring at C-16 and C-17

Twelve protostanes with fused-ring at C-16 and C-17 (90–101) have been isolated from Alisma as shown in Figure 4. Tetrahydropyrane ring is fused at C-16 and C-17 (90–98) (Yoshikawa et al., 1993; Peng and Lou, 2001; Hu et al., 2008a,b; Chen et al., 2018). Oxacycloheptane ring is fused at C-16 and C-17 (99–101). Alismanol J (101) differs from alismaketone B-23-acetate (99) by forming an oxygen bridge between C-16 and C-23.

Nor- and seco-protostanes

Twelve nor-protostanes (102–113) have been found in Alisma, including two demethyl-protostanes (102, 103) and ten tetranorprotostanes (104–113). Among C-2 may be submitted by carbanyl group (109) (Mai et al., 2015). The configuration of C-17 is determined (107, 108) (Xin et al., 2018).

Only five seco-protostanes (114–118) have been known in Alisma, including two 13, 17-seco-protostanes (114, 115) (Matsuda et al., 1999; Wang et al., 2017a) and three 2, 3-seco-protostanes (116–118) (Yoshikawa et al., 1997). Their structures were detailed in Figure 5.

Chemical structures of the nor- and seco-protostanes.

Biosynthesis

Alisma triterpenoids is commonly biosynthesized through mevalonic aid (MVA) pathway (Zhang et al., 2018) as shown in Figure 6. Three molecules of acetyl-CoA are catalyzed by enzymes to form mevalonate acid (MVA) (Vinokur et al., 2014). It is catalyzed by mevalonate pyrophosphate decarboxylase to produce isopentyl pyrophosphate (IPP), which reacts with dimethylallyl pyrophosphate (DMAPP) to generate geranyl pyrophosphate (GPP) by farnesyl pyrophosphate synthase of A. orientale (AOFPPS) (Peng et al., 2018). Squalene is synthesized by squalene synyase of A. orientale (AOSS) (Shen et al., 2013), which is then catalyzed by squalene epoxidase of A. orientale (AOSE) to produce 2,3-oxidosqualeneand further to form protostane tetracyclic skeleton (Zhang et al., 2018). AOFPPS and AOSS are rate-limiting enzymes in Alisma triterpenoids biosynthesis pathway (Zhou et al., 2018).

Fresh materials of A. orientalis are naturally rich in alisol B 23-acetate (47) (Zhu and Peng, 2006), which can convert into alisol A 24-acetate (2), alisol A (1), and alisol B (46) after processing at high temperature (Zheng et al., 2006). Other triterpenoids, such as alisol A (1) (Peng et al., 2002a) and their derivatives, were formed during the drying process (Yoshikawa et al., 1994).

Bioactivities

Alisma orientale is traditionally used to treat oliguria, edema, gonorrhea with turbid urine, leukorrhea, diarrhea, dizziness and hyperlipidemia (Chinese Pharmacopoeia Commission, 2015). Modern pharmacological studies have demonstrated its diuretic and lipid-lowering efficiency, together with anticancer, lipid-regulating, anti-inflammatory, antibacterial, antiviral activities.

Anticancer Activities

Recently, the experiments in vitro highlight that alisols induce apoptosis and autophagy in human tumor cells, such as lung cancer (Wang et al., 2018), ovarian cancer (Zhang et al., 2016), and prostate cancer (Huang et al., 2006) cell lines. The cytotoxicities of alisol B 23-acetate (47), cancer cell lines, including L1210 and K562 leukemia alisol C 23-acetate (59), alisol B (46) and alisol A 24-acetate (2) are examined on several cells, B16-F10 melnoma cells, A549 lung adenocarcinoma cells, SK-OV3 ovarian cells, HT 1080 fibrosarcoma cells. The results show that alisol B 23-acetate (47), alisol C 23-acetate (59) and alisol A 24-acetate (2) have weaker inhibitory activities against all the tested cancer cells with ED₅₀ values in the range of 10~20 μg/ml, while alisol B (46) exhibits significant effect on SK-OV3, B16-F10, and HT1080 with ED₅₀ values of 7.5, 7.5, and 4.9 μg/ml, respectively (Lee et al., 2001). Moreover, alisol F 24-acetate (93) and alisol B 23-acetate (47) are found inducing cell apoptosis via inhibiting P-glycoprotein mediation and reversing the multidrug resistance in cancer cell lines (Wang et al., 2004; Hyuga et al., 2012; Pan et al., 2016).

Alisol B (46) targets on Ca²⁺-ATP enzymes in the sarcoplasmic reticulum or endoplasmic reticulum to induce autophagy of cancer cells (Law et al., 2010). This compound can also induce cell apoptosis by inhibiting the invasion and metastasis of SGC7901 cells (Xu et al., 2009).

Alisol B 23-acetate (47) can inhibit the proliferation of PC-3 prostate cancer (Huang et al., 2006), and induce the apoptosis of lung cancer A549 and NCI-H292 cells through the mitochondrial caspase pathway (Wang et al., 2018). Alisol B 23-acetate (47) obviously inhibits the proliferation, migration and invasion of ovarian cancer cell lines and induces accumulation of the G1 phase in a concentration-dependent manner. The protein levels of cleaved poly ADP-ribose polymerase (PARP) and the ratio of Bax/Bcl-2 are up-regulated, while the levels of CDK4, CDK6 and cyclin D1 are down-regulated after alisol B 23-acetate (47) treatment. Moreover, it can up-regulate the expression levels of IRE1α and Bip, and down regulate MMP-2 and MMP-9 in a dose- and time- dependent manner (Zhang et al., 2016). However, current studies of Alisma triterpenoids are limited into drug screening in vitro, and their anticancer activities need to be validated in vivo.

Lipid-Lowering Effects

One of A. orientale traditional effects is to treat hyperlipidemia. Studies have shown that the extracts of A. orientale tubers have potential effects on hyperlipidemia diseases (Park et al., 2014; Jang et al., 2015; Li et al., 2016; Miao et al., 2017). Alisol B 23-acetate (47) and alisol A 24-acetate (2) reduce the levels of TC and LDL-C in hyperlipidemia mice via inhibiting the activity of HMG-CoA reductase (Murata et al., 1970; Xu et al., 2016). According to the evaluations of alisols on inhibiting pancreatic lipase, the IC50 of alisol F 24-acetate (93) on pancreatic lipase was 45.5 μM (Cang et al., 2017). Studies results show that alisol B 23-acetate (47) can bound plasma protein (Xu et al., 2014).

Alisol A (1), alisol A 24-acetate (2) and alisol B (46) can decrease TG level in plasma by improving lipoprotein lipase (LPL) activity (Xu et al., 2018). The effects of alisols with epoxy aliphatic chain at C-17 on LPL are stronger than those with an open aliohatic chain at C-17. Hydroxyl groups submitted at C-14, C-22, C-28, C-30, and an acetyl group at C-29 are necessary for lipid-regulation action of alisols.

Anti-inflammatory

Alisol B 23-acetate (47) prevents the production of NO in RAW264.7 cells by inhibiting iNOS mRNA expression (Kim et al., 1999). Alisol A 24-acetate (2) effectively alleviates liver steatosis by down-regulating SREBP-1c, ACC, FAS genes and up-regulating CPT1 and ACOX1 genes to activate AMPK signaling pathway and inhibit inflammatory cytokines TNF-α, IL-6 levels (Zeng et al., 2016). In addition, alisol B (46) and alisol B 23-acetate (47) significantly inhibit the production of leukotriene and the release of β-hexosaminidase in the concentrations of 1–10 mM (Lee et al., 2012).

Antibacterial

Alisol B (46), alisol B 23-acetate (47), alisol C 23-acetate (59), and alisol A 24-acetate (2) have significant bacteriostatic actions on four gram positive and four gram negative antibiotic resistant strains with the MICs ranged from 5 to 10 μg/ml (Jin et al., 2012). In addition, alisol A (1), 25-o-ethylalisol A (16), 11-deoxyalisol A (4), alisol E 24-acetate (15) and 25-anhydroalisol F (97) fight off gram-positive strains of bacillus subtilis and staphylococcus aureus with MICs ranged from 12.5 to 100 mg/ml (Ma et al., 2016).

Antiviral

Studies have shown that alisols from A. orientale exhibit obvious anti-hepatitis b virus effect (Jiang et al., 2006). Alisol F (92) and alisol F 24-acetate (93) significantly inhibit the secretion of HBV surface antigen with an IC₅₀ value of 7.7 and 0.6 μM, and HBVe antigen secretion with an IC₅₀ value of 5.1 and 8.5 μM, respectively. A series of derivatives of alisol A (1) obtained after structural modification also showed potential effect (Zhang et al., 2008, 2009).

Structure Modification

Alisol B 23-acetate can induce apoptosis and autophagy in cancer cell lines (Xu et al., 2015), and structure modification on alisol B 23-acetate (47) allows to obtain a diverse of derivatives (Lee et al., 2002). Alisol B 23-acetate (47) reacts with m-chloroperoxybenzoic acid (mCPBA) in CH₂Cl₂ at room temperature to gain 13β, 17β-epoxy-23-acetate-alisol B (67), and reacts with NH₂OH.HCl in pyridine and MeOH to achieve amination at C-3. Deacetylation of alisol B 23-acetate (47) by NaOH yields alisol B (46). Although there is no significant difference of inhibition effect on B16-F10 and HT1080 cell lines between 13β, 17β-epoxy-23-acetate-alisol B (67) (ED50 values of 17 and 18 μg/ml) and alisol B 23-acetate (47) (ED50 values of 20 μg/ml, respectively), alisol B (46) (B16-F10 and HT1080 with ED50 values of 5.2 and 3.1 ug/ml), amination at C-3 of alisol B 23-acetate (47) (with ED50 values of 7.5 and 5.1 ug/ml) show exhibited greater activation against B16-F10 and HT1080 cancer cells. It indicates that deacetylation of C-23 and amination at C-3 significantly enhance the inhibition effect on B16-F10 and HT1080 cell lines.

Four hydroxyl groups of alisol A (1) are usually the target sites for modification by reacting with acetic anhydride in N, N′- dicyclohexylcarbodiimide and 4-dimethylamnopyridine. Alisol A (1) can also dehydrate by SOCl₂ in the presence of anhydrous pyridine. The assessments of anti-hepatitis B virus (HBV) activities suggest alisol A (1) analogs with acetoxyl groups at C-11, C-23, C-24 or the epoxy ring at C-13 and C-17 increase the effects on HBV. Dehydration at C-25/C-26 enhances its sensitivity on HBV (Zhang et al., 2008, 2009).

Biotransformation of alisol A (1) also derives a series of active compound by several bacteria strains, such as C. elegans AS 3.2028 and P. janthinellum AS 3.510. Alisol A (1) can inhibit the proliferation of HCE-2 cells on the IC₅₀ of 99.65 ± 2.81 μM (Zhang et al., 2017). The activity screening results reveal hydroxylation at C-7 and C-12 increases the inhibiting effects of alisol A (1) on human carboxylesterase 2 (IC₅₀ values of 7.39 ± 1.21 and 3.73 ± 0.76 μM) and the acetyl group at C-23 or C-24 also increases its inhibition effect on HCE-2 cells (IC₅₀ values of 3.78 ± 0.21 and 6.11 ± 0.46 μM).

Taken together, epoxidation at C-13 and C-17, hydroxylation at C-23, C-7/C-12, amination at C-3, and dehydration at C-25/C-26 contribute to the activities of protostane tetracyclic skeleton of A. orientale, including anticancer activity, anti-hepatitis B virtus, and the inhibiting activity on human carboxylesterase 2.

Conclusion

The present work systematically summarized the information concerning the phytochemistry, bioactivities and structure modification of triterpenoids in Alisma species. To date, more than 100 protostane-type terterpenoids have been isolated and identified. Alisols are reported with anticancer, lipid-regulating, anti-inflammatory, antibacterial, and antiviral activities. Structure modification might contribute to the investigation of the therapeutic potential of alisols.

Author Contributions

MJ designed the review and was responsible for the study conception. PW and MJ wrote the paper. PW, TS, and RS contributed to summarizing the phytochemistry and structure modification studies on triterpenoids. MH, RW, and JL contributed to summarizing the bioactivity studies on triterpenoids.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Footnotes

Funding. This work was supported by the National major new drug creation science and technology major special support project (Nos. 2018ZX09735-002 and 2018YFC1707904) and the Natural Science Foundation of Tianjin (No. 18JCZDJC97700).

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PERMALINK

Triterpenoids From Alisma Species: Phytochemistry, Structure Modification, and Bioactivities

Pengli Wang

Tongxin Song

Rui Shi

Mingshuai He

Rongrong Wang

Jialin Lv

Miaomiao Jiang

Abstract

Introduction

Triterpenoids

Table 1.

Protostanes With Open Aliphatic Chains at C-17

Figure 1.

Protostanes With Epoxy Aliphatic Chains at C-17

Figure 2.

Protostanes With Spiro Hydrocarbon at C-17

Figure 3.

Protostanes With Fused Ring at C-16 and C-17

Figure 4.

Nor- and seco-protostanes

Figure 5.

Biosynthesis

Figure 6.

Bioactivities

Anticancer Activities

Lipid-Lowering Effects

Anti-inflammatory

Antibacterial

Antiviral

Structure Modification

Conclusion

Author Contributions

Conflict of Interest

Footnotes

References

ACTIONS

PERMALINK

RESOURCES

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