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. 2023 Dec 11;16(1):70–81. doi: 10.1016/j.chmed.2023.06.003

Chemical composition and pharmacological activity of seco-prezizaane-type sesquiterpenes

Ye Jin a, Yanqing Xie a, Peng Zhang a, Afsar Khan b, Zhihong Zhou a, Lu Liu a,⁎
PMCID: PMC10874773  PMID: 38375047

Abstract

The seco-prezizaane-type sesquiterpenes (SPS), as a special class of sesquiterpenes with a highly oxidative five-ring cage structure and seven consecutive chiral centers, are isolated from the genus Illicium, which have a variety of biological activities, including neurotoxicity and neurotrophic effects, etc. This review summarizes the chemical constituents and pharmacological effects of SPS, and discusses the potential trend and scope of future research.

Keywords: anisatin, chemical composition, Illicium genus, majucin, pharmacological activity, seco-prezizaane-type sesquiterpenes

1. Introduction

Seco-prezizaane-type sesquiterpenes (SPS, Fig. 1A), as a class of sesquiterpenes, are known to be derived from bond cleavage in the backbone of prezizaanes (Li, Shen, & Zhang, 2016), which have a highly oxygenated fused tetra- or penta-cyclic structure with several continuous stereo centers (Kawamura et al., 2019), originated from tricyclo [6.2.1.01,5] undecane skeleton (Fig. 1B). Since, (-)-anisatin was first isolated from the fruits of Illicium anisatum by Lane et al. in 1952, many SPS had been successively isolated from various members of Illicium in the past 60 years (Li, Shen, & Zhang, 2016). SPS are found only in the genus Illicium and are considered to be characteristic chemical markers of the genus (Liu et al., 2014; (Liu et al., 2020). Among of these, the representative compounds are jiadifenin, neomajucin and jiadifenolide, which have a strong neurotoxic or physiological activity against nerve growth (Cheng & Micalizio, 2014; Li, Shen, & Zhang, 2016).

Fig. 1.

Fig. 1

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(A) Seco-prezizaane-type sesquiterpenes; (B) Tricyclo [6.2.1.01,5] undecane.

The structure of SPS has the following characteristics: (1) it has a highly oxidized five-ring cage structure, including continuous and bridged rings, etc., (2) it contains seven continuous chiral centers, where the core six-membered B ring contains five chiral carbons, and four of them are quaternary carbons, (3) it contains a variety of oxygen-containing functional groups, including α-hydroxy lactone, α-arsenate, etc. (Li, Shen, & Zhang, 2016). SPS belong to a distinct structural type with a distinctive caged structure consisting of lactones, acetals, or orthostatic ester groups (Liu et al., 2020).

SPS have neurotrophic, neurotoxic, anti-inflammatory, insecticidal, sedative, and analgesic activities. Nowadays, neurotrophic agents are being selected as candidates for therapeutic strategies to control cerebral nerve loss in patients with Alzheimer's disease. Therefore, compounds with significant physiological activity in promoting the growth of primary cultured rat cortical neurons, such as jiadifenolide, can be used as small molecule neurotrophic agents or lead compounds to develop drugs for the treatment of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and other neurodegenerative diseases (Li, Shen, & Zhang, 2016). Meanwhile, the discovery of new activities with selective effects on hepatitis B virus and coxsackie virus B3 infection has increased the interest of researchers in such compounds.

In the paper, the chemical constituents and pharmacological effects of SPS are reviewed, and the potential trend and scope of future research are discussed.

2. Seco-prezizaane-type sesquiterpenes

Since 1952, more than 140 SPS have been reported and classified into six subtypes based on their core carbon framework and functional groups: anisatin, majucin, minwanensin (floridanolide), pseudoanisatin, pseudomajucin, and cycloparvi-floralone (Liu et al., 2020, Yin et al., 2012, Zhu et al., 2009).

The classification of SPS is based on their different cyclization modes, which might be helpful for the subsequent structural studies (Fig. 2).

Fig. 2.

Fig. 2

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Seco-prezizaane-type sesquiterpenes classification.

2.1. C7-C11 esterification

The structural feature of this type of compounds is mainly the formation of a δ-lactone ring after the ring opening at the C7-C11 position (Fig. 3). They are mainly distributed in I. floridanum and I. minwanense, and some monomeric compounds have also been isolated from I. merrillianum, I. lanceolatum, and I. ternstroemioides. According to literature review, around 21 monomeric compounds of this type have been isolated so far.

Fig. 3.

Fig. 3

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C7-C11 esterification.

2.1.1. C13-C14 esterification

After the formation of a δ-lactone ring by ring opening at the C7-C11 position, this type of compounds further undergoes C13-C14 esterification to form a 13,14-β-lactone (Fig. 4). They are widely distributed, mainly in I. majus, and some monomeric compounds have also been isolated from I. verum, I. anisatum, and other plants. According to literature review, approximately 20 monomeric compounds of this type have been isolated so far.

Fig. 4.

Fig. 4

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C13-C14 esterification.

2.1.2. C12-C14 esterification

After the formation of a δ-lactone ring by ring opening at the C7-C11 position, this type of compounds further undergoes C12-C14 esterification to form a γ-lactone ring (Fig. 5). They are mainly distributed in I. majus and I. jiadifengpi. According to literature review, approximately 22 monomeric compounds of this type have been isolated so far.

Fig. 5.

Fig. 5

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C12-C14 esterification.

2.2. C11-C14 esterification

Some of these compounds also contain a 1,4-ether linkage and a 14,15-β-lactone, and some are found to coexist as ketones and acetals in equilibrium (Fig. 6). This type of compounds is mainly distributed in I. merrillianum, I. anisatum, and also found in other plants such as I. minwanense and I. parviflorum. According to literature review, approximately 29 monomeric compounds of this type have been isolated so far.

Fig. 6.

Fig. 6

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C11-C14 esterification.

Acetal-hemiacetal and/or ortholactone: This class of sesquiterpenes has been reported to be composed of unique acetal-hemiacetal and/or ortholactone structure, and it can be expected that they may be in equilibrium between acetal-hemiacetal and aldehydes or between normal esters and lactones (Fig. 7). This type of compounds is mainly distributed in I. merrillianum. According to literature review, around 17 monomeric compounds of this type have been isolated so far.

Fig. 7.

Fig. 7

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Acetal-hemiacetal and/or ortholactone.

2.3. C4-C11 esterification

This type of compounds from a γ-lactone ring between C4-C11, and some compounds also exhibit a keto-enol equilibrium between C7-C14 (Fig. 8). They are distributed in plants such as I. merrillianum and I. jiadifengpi. According to literature review, approximately 10 monomeric compounds of this type have been isolated so far.

Fig. 8.

Fig. 8

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C4-C11 esterification.

C6-C7 bond rupture: It should be noted that this class of compounds is formed by the esterification reaction between C4-C11, followed by the cleavage of C6-C7 bond and further esterification reaction (Fig. 9). Currently, there are limited reports on the isolation of these compounds from Illicium plants.

Fig. 9.

Fig. 9

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C6-C7 bond rupture.

2.4. C3-C11 esterification

This class of compounds is formed by the esterification reaction between C3-C11 (Fig. 10), and currently, there are limited reports on the isolation of these compounds from Illicium plants.

Fig. 10.

Fig. 10

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C3-C11 esterification.

2.5. C1-C11 esterification

This class of compounds is formed by the esterification reaction between C1-C11 (Fig. 11), and currently, there are limited reports on the isolation of these compounds from Illicium plants.

Fig. 11.

Fig. 11

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C1-C11 esterification.

The above information provides an overview of the structures of these compounds. Consequently, we have compiled their names, associated activities, and sources in Table 1.

Table 1.

Seco-prezizaane-type sesquiterpenes found in Illicium plants.

No. Compounds Activities Source References
1 Minwanensin I. minwanense Fukuyama & Huang, 2005
2 3-Acetoxy-14-n-butyryloxy-10-deoxyfloridanolide I. floridanum Fukuyama & Huang, 2005
3 14-Acetoxy-3-oxofloridanolide I. floridanum Fukuyama & Huang, 2005
4 13-Acetoxy-14-butyryloxyfloridanolide I. floridanum Huang, Yang, Takahashi, & Fukuyama, 2000
5 13-Acetoxy-14-(n-butyryloxy) floridanolide I. floridanum Schmidt, Schmidt, Müller, Peters, & Fischer, 1998
6 (1S)-Minwanenone Cytotoxicity I. minwanense Fukuyama & Huang, 2005
7 (1R)-Minwanenone I. minwanense Fukuyama & Huang, 2005
8 3,4-Dehydro-13,14-dihydroxyfloridanolide I. floridanum Fukuyama & Huang, 2005
9 3,4-Dehydrofloridanolide I. merrillianum Huang, Yang, Takahashi, & Fukuyama, 2000
10 3β,14-Dihydroxy-10-deoxyfloridanolide I. floridanum
 Schmidt, Okuyama, & Fronczek, 1999
11 14-O-Benzoylfloridanolide Cytotoxicity I. dunnianum Yadav, Mondal, & Ghosh, 2011
12 3β-Acetoxy-14-n-butyryloxy-10-deoxyfloridanolide I. floridanum Schmidt, Schmidt, Müller, Peters, & Fischer, 1998
13 1,6-Dihydroxy-3-deoxyminwanensin I. merrillianum Huang, Yang, Zhao, Takahashi, & Fukuyama, 2004
14 Dunnianolide A I. dunnianum Bai et al., 2012
15 Dunnianolide B I. dunnianum Bai et al., 2012
16 2-O-Benzoylfloridanolide I. dunnianum Bai et al., 2012
17 14-O-n-Butyrylfloridanolide I. merrillianum Huang, Yang, Takahashi, & Fukuyama, 2000
18 3,4-Anhydro-13,14-dihydroxyfloridanolide I. floridanum Schmidt, Müller, & Fronczek, 2001
19 (1R,5R,6S,7R,9R,10R)-3,4-Dehydro-12-hydroxy-floridanolide Neuroprotection I. lanceolatum Liu et al., 2020
20 3,4-Dehydrofloridanolide-13-oic-acid I. lanceolatum Liu et al., 2020
21 Burmanicumolide D I. ternstroemioides Zhang, Li, Yong, Yang, & Ma, 2021
22 Anisatin Neurotoxicity I. anisatum Huang et al., 2002b
23 1-Hydroxyneoanisatin Neuroprotection I. majus Fukuyama & Huang, 2005
24 6-Deoxy-1-hydroxyneoanisatin I. majus Fukuyama & Huang, 2005
25 2α-Hydroxyneoanisatin Neurotoxicity I. anisatum
 Fukuyama & Huang, 2005
26 2α-Hydroxyanisatin I. merrillianum Fukuyama & Huang, 2005
27 Neoanisatin I. dunnianum Huang et al., 2002b
28 Veranisatins A Neurotoxicity I. verum Fukuyama & Huang, 2005
29 Veranisatins B Neurotoxicity I. verum Fukuyama & Huang, 2005
30 Veranisatins C Neurotoxicity I. verum Fukuyama & Huang, 2005
31 3,4-Anhydro-2-oxo-1α-hydroxy-6-deoxyneoanisatin I. lanceolatum Nie et al., 2022
32 3,4-Dehydroxy-6-oxoneoanisatin I. majus Kouno et al., 1991
33 3,4-Dehydroxy-6-oxoneoanisatin I. majus Kouno et al., 1991
34 2-Oxo-6-dehydroxyneoanisatin Neurotoxicity I. majus Yang et al., 1990
35 10-O-(E)-Cinnamoyl-2-oxo-6-deoxyneoanisatin I. fargesi (Moriyama et al., 2008)
36 10-O-(Z)-Cinnamoyl-2-oxo-6-deoxyneoanisatin I. fargesi (Moriyama et al., 2008)
37 Veranisatin F I. simonsii Yin, Wang, Wang, & Kong, 2012
38 Veranisatin D I. oligandrum Zhu et al., 2009
39 Veranisatin E I. oligandrum Zhu et al., 2009
40 1,3-Dihydroxyneoanisatin Neuroprotection I. lanceolatum Liu et al., 2020
41 2β-Hydroxy-6-deoxyneoanisatin I. lanceolatum Nie et al., 2022
42 Majucin I. jiadifengpi Cheng & Micalizio, 2014
43 (2S)-Hydroxy-3,4-dehydroneomajucin I. jiadifengpi Cheng & Micalizio, 2014
44 Neomajucin Anti-inflammation I. angustisepalum Fukuyama & Huang, 2005
45 (2S*)-Hydroxyneomajucin I. majus Fukuyama & Huang, 2005
46 6-Deoxy-neomajucin I. majus Fukuyama & Huang, 2005
47 Angustisepalin I. majus Sy & Brown, 1998
48 2-Oxoneomajucin Antiviral I. jiadifengpi Zhang et al., 2013
49 2,3-Dehydromajucin I. majus Fukuyama & Huang, 2005
50 1,2-Dehydroneomajucin I. jiadifengpi Fukuyama & Huang, 2005
51 (2R*)-Hydroxy-3,4-dehydroneomajucin I. majus Fukuyama & Huang, 2005
52 (1S*)-2-Oxo-3,4-dehydroneomajucin I. majus Fukuyama & Huang, 2005
53 (1R*)-2-Oxo-3,4-dehydroxyneomajucin I. majus Fukuyama & Huang, 2005
54 (1R*,10S*)-2-Oxo-3,4-dehydroneomajucin I. majus Fukuyama & Huang, 2005
55 Jiadifenoxolane A Neuroprotection I. jiadifengpi (Kubo et al., 2009)
56 Jiadifenoxolane B I. jiadifengpi (Kubo et al., 2009)
57 (2S)-Hydroxy-3,4-dehydroneomajucin Neuroprotection I. lanceolatum Mehta, Shinde, & Kumaran, 2012
58 Dehydro-neomajucin I. verum Hook.f. Mehta, Shinde, & Kumaran, 2012
59 (2R*)-Hydroxyneomajucin I. jiadifengpi (Kubo et al., 2012)
60 3,4-Dehydroneomajucin Anti-HBV I. jiadifengpi Liu et al., 2016
61 1,2,3,4-Tetradehydroneomajucin Anti-HBV I. jiadifengpi Liu et al., 2016
62 Jiadifenin I. jiadifengpi Gomes et al., 2016
63 Jiadifenolide Neuroprotection I. jiadifengpi Gomes et al., 2016
64 2α-Hydroxycycloparviflorolide I. merrillianum (Huang et al., 2002a)
65 Cycloparviflorolide Neuroprotection I. parviflorum Huang et al., 2002b
66 Cyclomerrillianolide I. merrillianum Huang et al., 2002b
67 10β-Hydroxy-cyclopseudoanisatin I. merrillianum Huang, Yang, Zhao, Takahashi, & Fukuyama, 2004
68 Pseudoanisatin I. anisatum Fukuyama & Huang, 2005
69 3-Deoxypseudoanisatin I. merrillianum Fukuyama & Huang, 2005
70 2β-Hydroxy-3,6-dedioxypseudoanisatin I. merrillianum Fukuyama & Huang, 2005
71 (2S)-Hydroxy-6-deoxypseudoanisatin I. minwanense Fukuyama & Huang, 2005
72 6-Deoxypseudoanisatin I. anisatum Fukuyama & Huang, 2005
73 3-Oxopseudoanisatin I. minwanense Fukuyama & Huang, 2005
74 1α-Hydroxypseudoanisatin I. anisatum Fukuyama & Huang, 2005
75 1α-Hydroxy-3-deoxypseudoanisatin I. merrillianum Fukuyama & Huang, 2005
76 1α-Hydroxy-6-deoxypseudoanisatin I. minwanense Fukuyama & Huang, 2005
77 3,6-Dideoxy-10-hydroxy-pseudoanisatin I. merrillianum Fukuyama & Huang, 2005
78 2,10-Epxoy-3-dehydroxypseudoanisatin I. merrillianum Fukuyama & Huang, 2005
79 1,4-Epoxy-6-deoxypseudoanisatin I. dunnianum Fukuyama & Huang, 2005
80 8α-Hydroxy-10-deoxycyclomerrillianolide I. merrillianum Huang, Yang, Zhao, Takahashi, & Fukuyama, 2004
81 10β-Hydroxypseudoanisatin I. merrillianum Huang, Yang, Zhao, Takahashi, & Fukuyama, 2004
82 Merrillianolide I. merrillianum Huang, Yang, Zhao, Takahashi, & Fukuyama, 2004
83 (3S*,6R*)-4,7-Epoxy-6-deoxypseudoanisatin I. minwanense Yokoyama et al., 2003
84 4,7-Hemiketal of pseudoanisatin I. parviflorum Schmidt, 1999
85 8-O-β-D-Glucopyranosyl-8α-hydroxy-6,10-dideoxy-cycloparviflorolide I. jiadifengpi Zhang et al., 2013
86 Illilanceolatin B I. lanceolatum Liu et al., 2020
87 Majusanol E Neuroprotection I. lanceolatum Liu et al., 2020
88 Parviflorohde I. parviflorum Fukuyama & Huang, 2005
89 7-Deoxy-7β-hydroxypseudoanisatin I. anisatum Fukuyama & Huang, 2005
90 Isodunnianin Neuroprotection I. merrillianum Fukuyama & Huang, 2005
91 6-Deoxydunnianin I. anisatum Fukuyama & Huang, 2005
92 Majusatone I. majus Fang, Zhang, & Liu, 2016
93 Cycloparvifloralone I. parviflorum Huang et al., 2002b
94 2α-Hydroxycycloparvifloralone I. merrillianum Huang et al., 2002a
95 3α-Hydroxycycloparvifloralone Neuroprotection I. merrillianum Fukuyama & Huang, 2005
96 Merrilliortholactone I. merrillianum Huang et al., 2002a
97 Merrillianone I. merrillianum Fukuyama & Huang, 2005
98 1,2-Dehydrocycloparvifloralone I. merrillianum Fukuyama & Huang, 2005
99 (11)7,14-Ortholactone-14-hydroxy-3-oxofloridanolide I. floridanum Fukuyama & Huang, 2005
100 (11)7,14-Ortholctone-3α-hydroxyfloridanolide Neuroprotection I. merrillianum Fukuyama & Huang, 2005
101 8-Deoxymerrilliortholactone I. merrillianum Huang, Yang, Zhao, Takahashi, & Fukuyama, 2004
102 7,14-Ortholactone-3α-hydroxy-floridanolide I. merrillianum Huang, Yang, Takahashi, & Fukuyama, 2000
103 Henrylactone C Neuroprotection I. lanceolatum Liu et al., 2019
104 Oligandriortholactone Anti-inflammation I. oligandrum Tang et al., 2009
105 (11)7,14-Ortholactone-1α-hydroxyfloridanolide I. jiadifengpi Zhang et al., 2013
106 Illilanceolatin A I. lanceolatum Liu et al., 2020
107 Majusanol A Neuroprotection I. lanceolatum Liu et al., 2019
108 11-O-Debenzoyl-11α-O-2-methylcyclopent-
1-Enecarboxyltashironin		 I. verum Wang, Hu, Huang, & Qin, 2011
109 Tashironin I. verum Wang, Hu, Huang, & Qin, 2011
110 Pseudomajucin I. majus Fukuyama & Huang, 2005
111 7-O-β-D-Glucoside pseudomajucin I. majus Fukuyama & Huang, 2005
112 7-O-Methylpseudomajucin I. minwanense Yokoyama et al., 2003
113 2-O-n-Butyrylpseudomajucin I. merrillianum Huang, Yang, Takahashi, & Fukuyama, 2000
114 14-O-β-D-Glucopyranosylpseudomajucinone Antiviral I. jiadifengpi Zhang et al., 2013
115 (6R)-Pseudomajucin I. merrillianum Fukuyama & Huang, 2005
116 (6R)-Pseudomajucinone I. merrillianum Fukuyama & Huang, 2005
117 Dunnianolide C I. dunnianum Bai et al., 2012
118 Dunnianolide D I. dunnianum Bai et al., 2012
119 2β-Benzoyloxy-6α-hydroxypseudomajucin I. jiadifengpi Zhang et al., 2013
120 Merrillianin I. merrillianum Huang et al., 2002b
121 7-Deoxy-7-oxodunnianin I. foridanum Schmidt, Okuyama, & Fronczek, 1999
122 Dunnianin I. dunnianum Schmidt, Gurrath, & Ozoe, 2004
123 Illilanceolide A I. lanceolatum Nie, Ding, Lei, Pan, & Zhao, 2021
124 Neodunnianin I. dunnianum Fukuyama & Huang, 2005
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SPS are complex polycyclic sesquiterpenes that are highly oxidized and formed via a series of structural transformations, including cleavage and rearrangement of the prezizaane scaffold between C7 and C11 positions, as well as additional modifications such as oxidation, esterification, condensation, and dehydration. By reviewing the SPS, we can establish the structural relationship between these compounds (Fig. 12), which may serve as a theoretical basis for future studies on the structure–activity relationship and synthetic applications of SPS.

Fig. 12.

Fig. 12

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Possible biosynthetic pathways of seco-prezizaane-type sesquiterpenes.

3. Pharmacological characteristics

3.1. Neuroprotective activity

Neurotrophic factors are important regulatory substances in the nervous system and a subset of biologically active proteins, which are involved in the survival of developing neurons and in the maintenance of mature neurons throughout life. Taking nerve growth factor (NGF) promoting neurite outgrowth and maintaining cell viability as an example, the role of neurotrophic factors in the course of neuronal development has been well understood. Xia et al. showed that the addition of rat NGF in the treatment of Parkinson’s disease could significantly increase the level of neurotrophic factor, promote the repair of nerve injury and improve clinical symptoms (Xia, Yuan, & Zhang, 2021). These findings, therefore, offer a hope that NGF may be used as a drug therapy for neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease (Kubo et al., 2009; Wang, Hu, Huang, & Qin, 2011).

Fukuyama et al. found that isodunnianin (90) enhanced neurite sprouting during the development of neurons in a primary culture of fetal rat cerebral hemisphere at 10-5 mol/L and also increased choline acetyltransferase activity (243 ± 20 pmol/min/mg protein) at 10-5 mol/L in comparison with a control culture containing 0.5% ethanol (EtOH） (150 ± 8 pmol/min/mg protein) at 10 d after seeding (Fukuyama, Shida, & Kodama, 1993). Liu et al. evaluated the neuroprotective effect of 1,3-dihydroxyneoanisatin (40), and the study results showed a protective rate of 19.9% at 10 μmol/L (Liu et al., 2020). Kubo et al. found that jiadifenolide (63) strongly promoted neurite outgrowth in primary cultured rat cortical neurons at concentrations ranging from 0.01 to 10 μmol/L (Kubo et al., 2009).

Therefore, these SPS are expected to be the leading non-peptide neurotrophic agents for the treatment of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.

3.2. Anti-inflammatory activity

Some of the sesquiterpene lactones isolated from the genus Illicium are considered as responsible for the neurotoxicity of these plants. Such as anisatin (22) with a β-lactone structure acts as a picrotoxin-like, non-competitive γ-aminobutyric acid (GABA) antagonist. However, some sesquiterpenes were found not to be neurotoxic but to have neurotrophic activities. These properties can affect the effectiveness of the active sesquiterpene lactones as potential anti-inflammatory agents (Bai et al., 2012).

Tang et al. evaluated the anti-inflammatory activities of the compounds by measuring the inhibitory ratios of β-glucuronidase release in rat polymorphonuclear leukocytes (PMNs) induced by platelet-activating factor (PAF) in vitro. These suggested that the compounds oligandriortholactone (104) and neomajucin (44) showed weak inhibitory activities of β-glucuronidase release from rat PMNs induced by PAF (Tang et al., 2009). Bai et al. isolated and identified tashironin (109) from the roots of Illicium dunnianum and evaluated its anti-inflammatory activity. The results showed that tashironin exhibited significant anti-inflammatory activity with IC50 values of (2.10 ± 0.40) μmol/L and (1.93 ± 0.57) μmol/L (Bai et al., 2012). Therefore, SPS has the potential to be developed as an anti-inflammatory agent.

3.3. Calm, analgesic and convulsive activities

Nakamura et al. reported that veranisatins (A-C) (28–30) exhibited convulsive and lethal toxicity in mice at a dose of 3 mg/kg (p.o.), and at lower doses, they induced hypothermia. Veranisatin A (28) and its related compound, anisatin (22), were also evaluated for other pharmacological activities, including locomotor activity and analgesic effects. Both compounds reduced locomotion enhanced by methamphetamine at oral doses of 0.1 and 0.03 mg/kg, respectively. Additionally, they demonstrated analgesic effects on acetic acid-induced writhing and tail pressure pain at doses that were almost identical (Nakamura, Okuyama, & Yamazaki, 1996).

Okuyama et al. showed that veranisatin A and B (28, 29) exhibited convulsive effects and lethal toxicity at a dose of 3 mg/kg, (p.o.), while at 1 mg/kg, both compounds induced hypothermia (ΔTmax 4.5 ℃, P < 0.001) but no convulsions (Okuyama, Nakamura, & Yamazaki, 1993). Therefore, these compounds may be used as analgesic and sedative drugs.

3.4. Antiviral activity

Zhang et al. evaluated the antiviral activity of 14-O-β-D-glucopyranosylpseudomajucinone (114) by measuring the in vitro activity against Coxsackie virus B3 (Li et al., 2010). They found that the compound had certain inhibitory activity against Coxsackie virus B3, with IC50 value of 40.50 μmol/mL (the positive control, ribavirin, IC50 = 1.25 μmol/mL) (Zhang et al., 2013).

3.5. Other activities

Liu et al. evaluated the anti-HBV activity of 3,4-dehydroneomajucin (60) and 1,2,3,4-tetradehydroneomajucin (61) in HBV-transfected HepG 2.2.15 cell line at non-cytotoxic concentration with amivudine (3TC) as a positive control. They found that the inhibitory rates of compounds 3,4-dehydrooneomajucin and 1,2,3,4-tetradehydrooneomajucin on the Hepatitis B e antigen (HBeAg) and Hepatitis B surface antigen (HBsAg) expression were (30.08 ± 3.09)% and (11.43 ± 1.92)% at a concentration of 68.00 μmol/L, and (7.88 ± 1.21)% and (16.96 ± 4.24)% at a concentration of 68.50 μmol/L, respectively. The results revealed that the anti-HBV activities of the tested compounds were weak in the measured concentration range (Liu et al., 2016).

Fang et al. used MTT method to study the cytotoxicity of majusatone (92). The results showed that the IC50 values of majusatone on human colon cancer cell HCT-8, human liver cancer cell BEL-7402, human gastric cancer cell BGC-823, and human lung cancer cell A549 were 42.3, 48.5, 51.1, and 39.9 μmol/L, respectively. It means that they have no obvious cytotoxicity (Fang, Zhang, & Liu, 2016).

4. Toxicity

4.1. Neurotoxicity

Fukuyama et al. reported that anisatin (22) and neoanisatin (27) were convulsive toxic components of I. anisatum and regarded as picrotoxin-like potent phytotoxins (Fukuyama & Huang, 2005). Neuropharmacological study demonstrates that the convulsive toxicity of anisatin may be due to its function as a picrotoxin-like, non-competititve GABA-antagonist (Kudo, Oka, & Yamada, 1981). But at the present, which structural part of anisatin is of significance to cause convulsive activity is equivocal. Among anisatin related compounds, veranisatins A, B and C (28–30) isolated from non-toxic chinese star anise (I. vernum) caused convulsions and death at 3 mg/kg (p.o.) in mice, whereas 2α-hydroxyneoanisatin (25), a positional isomer of the potent neurotoxic anisatin, induced no anisatin/picrotoxin-like convulsions and dramatically decreased the neurotoxicity in mice in comparison with anisatin and neoanisatin (Fukuyama & Huang, 2005). Therefore, it is speculated that the presence of β-lactone may be the cause of neurotoxicity, but it is not the absolute cause.

4.2. Insecticidal activity

Insects possess GABA receptors that are similar but exhibit pharmacological differences, not only in their central nervous system but also in their peripheral nervous system (Anthony, Unruh, Ganser, & Ffrench-Constant, 1998). Some SPS, such as anisatin, have been identified as non-competitive antagonists (NCAs) of GABA receptors (Kuriyama, Schmidt, Okuyama, & Ozoe, 2002). NCAs can block the chloride channel of nerve cells by interacting with the amino acid residues of GABA-gated chloride channel (GABA-Cl), causing changes in receptor conformation, thereby interfering with the normal function of the central nervous system. This causes excessive excitation of nerves and muscles, eventually leading to the death of insects (Liu et al., 2022). Kuriyama et al. studied the insecticidal activity of anisatin and pseudoanisatin (68) by injecting them into German cockroaches (Blattella germanica L.), which was topically pretreated with cytochrome P450 or piperonyl butoxide to depress the oxidative metabolism of the compounds. They found that pseudoanisatin and anisatin exhibited a similar level of insecticidal activity, with LD50 of 26 and 70 mg/g, respectively (Kuriyama, Schmidt, Okuyama, & Ozoe, 2002). The insecticidal activity of anisatin and pseudoanisatin on German cockroaches was moderate (Wang, Hu, Huang, & Qin, 2011). Therefore, these compounds may be used as probes for GABA receptors or lead compounds with insecticidal activity.

4.3. Cytotoxicity

Yin et al. evaluated anisatin and (1S)-minwanenone (6) for cytotoxic activity by the MTT method in 96-well microplates, using two human cancer cell lines NCI-H460 (human large cell lung cancer cell line) and SMMC-7721 (human hepato-cellular carcinoma cell line), with 5-fluorouracil (5-FU) as a positive control. They found that the potent inhibitory effects of anisatin and (1S)-minwanenone (6) on NCI-H460 and SMMC-7721 cells were comparable to that of 5-FU (Yin, Wang, Wang, & Kong, 2012).

5. Conclusion

Changes in the structure of the lactone rings in SPS, such as the formation of 11,14-ε-lactone or 11,3-δ-lactone or mutation of 13,14-β-lactone to 13-methyl-14-hydroxy or -O-acyl substituents, lead to a complete loss of the activity (Schmidt, Okuyama, & Fronczek, 1999). When anisatin undergoes hydroxy transfer, it forms 2α-hydroxyneoanisatin, which is still active, but its potency is 53 times lower than that of anisatin. The substitution of the β-lactone ring and the bulk group at the C5 position are somewhat admissible, while the acetylation of the C3 hydroxy group is deleterious. Similarly, the analogues in different cyclysis modes (lack of a closed lactone ring between C11 and C7) have little activity (Kuriyama, Schmidt, Okuyama, & Ozoe, 2002).

From the above summary, it is not difficult to find that the C ring is more easily to cleaved and combined with other sites. The activity of a compound can differ if its method of binding to other sites is different, and there will also be a lower probability of ring opening of the AB ring. Although a few of these compounds were isolated, it is impossible to judge whether the ring opening of the AB-ring will affect the activity of the compounds. When there is present a 13,14-β-lactone, most of the neurotoxic compounds show no toxicity and neurotrophic activity after β-lactone ring opening. When there is 11,14-lactone, the compounds have nerve protective effect, while in the presence of γ-lactone some compounds showed anti-inflammatory and antiviral activity. At the same time, when there is no hydroxy at the C10 position, the compounds have almost no activity. Sesquiterpenes belong to a complex class of compounds, so it is difficult to separate them. However, we may modify the structures of sesquiterpenes by a series of reactions such as esterification and oxidation, so as to obtain the compounds with a higher activity.

CRediT authorship contribution statement

Ye Jin: Data curation, Formal analysis, Visualization, Writing – original draft. Yanqing Xie: Writing – review & editing. Peng Zhang: . Afsar Khan: Supervision, Writing – review & editing. Zhihong Zhou: Supervision, Writing – review & editing. Lu Liu: Conceptualization, Data curation, Project administration, Validation, Writing – original draft, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was financially supported by Yunnan Provincial Science and Technology Department-Applied Basic Research Joint Special Funds of Chinese Medicine (No. 202101AZ070001-004); Major Science and Technology Special Project from Yunnan Provincial Science and Technology Department (No. 202202AA100009, 202302AA310006); Universities Engineering Research Center of Yunnan Province (No. 2020YGG01), and Open and Shared Public Science and Technology Service Platform of Traditional Chinese Medicine Science and Technology Resources in Yunnan.

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