Introduction

Sesquiterpenes are a class of terpenes that consist of three isoprene units and often have the molecular formula C15H24. Like monoterpenes, sesquiterpenes may be acyclic or contains rings, with many unique combinations. Sesquiterpenes are the most distinct group in terms of the structure of the terpenoids, most of which exert biological activities (Hou et al. 2014). Guaiane-type sesquiterpenes belong to a special group of natural products with a wide range of pharmacological functions. Its basic skeletal structure contains a five-membered ring, a seven-membered ring, two methyl, and one isopropyl groups. Thapsigargin, a major ingredient in Thapsia garganica, could inhibit the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) to deplete the intracellular Ca2+ pool and induce apoptosis in human hepatoma cells. An X-ray structure of the thapsigargin-SERCA complex provided the foundation for understanding the structural conformation of the complex, as well as the surroundings of the binding site. This additionally provided detailed information for the design of a targeted prodrug with thapsigargin as the active component (Andersen et al. 2015), such as mipsagargin (G202). G202 has completed the phase II clinical trials in the treatment of glioblastoma multiforme and hepatocellular carcinoma, and is expected to enter the market in the near future. (Brennen et al. 2012; Denmeade et al. 2012; Jakobsen et al. 2001; Simonsen et al. 2013). But, to our knowledge, the related review of guaiane-type sesquiterpenes are insufficient since 1990s. Therefore, in this review, we summarize the current understanding of the chemical studies of guaiane-type sesquiterpenes in plants and the progress that has been made in uncovering their pharmacological activities from 1990 to 2018.

Biogenesis and sources

Plant species reported to contain guaiane-type sesquiterpenes are listed in Table 1 in alphabetical order. Guaiane-type sesquiterpenes are distributed in approximately 70 genera of 30 families, such as Asteraceae, Lamiaceae, Thymelaeaceae, Umbelliferae, and Zingiberaceae. Furthermore, they are the most widely present in ~26 genera of Asteraceae, especially in Saussurea, Artemisia, and Inula. As we all know, mevalonic acid (MVA) pathway is the main biosynthesis pathway of terpenoids, and farnesyl pyrophosphate (FPP) is the precursor of most sesquiterpenes. Through further literature research, it was found that guaiane-type sesquiterpenes were transformed from FPP by two possible mechanisms, the first was free radical mechanism, the second was ionic mechanism. The biosynthetic pathway of the two mechanisms is shown in Fig. 1 (Adekenov 2017; Zurich 1953). More than 50% of guaiane-type sesquiterpenes contains lactone fragments, and the previous studies showed that most of them possessed the better biological activities than guaiane-type sesquiterpenes without lactone ring. There were two possible pathways for the biotransformation of lactones: one is that guaiane-type sesquiterpenes might be oxidized directly to alcohols and acids, then dehydrated to form lactones. The other was germacranolides intermediates, through which guaianolides were mainly converted in Compositae and Umbelliferae, and their biosynthesis was related to cytochrome P450 enzymes (such as CYP71BL1 and CYP71BL2), adequate oxygen and nicotinamide adenine dinucleotide phosphate (NADPH). Their biosynthetic pathway is proposed in Fig. 2 (Adekenov 2017; Barquera-Lozada and Cuevas 2009; Fischer 1990; Simonsen et al. 2013).

Table 1 Plant species including guaiane-type sesquiterpenes in the references from 1990 to 2018
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Fig. 1
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On the left is the MVA pathway of FPP, and the right one are two mechanisms of transformation of guaiane-type sesquiterpenes. Pathway one (left): radical mechanisms in the biogenesis of sesquiterpenes, pathway two (right): ionic mechanisms in the biogenesis of sesquiterpenes

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Fig. 2
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The biosynthesis pathway of guaianolide. The left guaianolide is transformed by germacranolides intermediates, and the right guaianolide is formed directly by oxidation and dehydration

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Classifications

This section summarizes the more than 300 guaiane-type sesquiterpenes reported since the 1990s. Their classification and structures are depicted in Figs. 3–10. Guaiane-type sesquiterpenes can be divided into five categories on the basis of their skeleton: guaianolides, tricycle guaiane-type sesquiterpenes, dimers or trimers containing guaiane-type sesquiterpenes mother nuclei, variant guaiane-type sesquiterpenes, other guaiane-type sesquiterpenes. Guaiane-type sesquiterpenes often occurs in oxygenated forms, such as guaiane alcohol, guaiane acid, guaiane ketone, and guaianolide. Of these, guaianolide is the most abundant guaiane-type sesquiterpene, and it can be further classified as 12,6-guaianolide, 12,8-guaianolide, and pseudoguaianolide. The only difference is that the linkage position of Me-15 on C-4 in 12,8-guaianolides whereas on C-5 in pseudoguaianolides. According to C-11 bonding sites, tricycle guaiane-type sesquiterpenes could be divided into 11,1, 11,6, and 11,10-guaiane. they can also be occasionally oxidized to alcohols, ketones, and acids. Several special structures, such as dimers or trimers containing guaiane-type sesquiterpenes mother nuclei and variant guaiane-type sesquiterpenes, have also been reported. These compounds are of interest because several of them possess biological or therapeutic activities, including antitumor, anti-inflammatory, and antibacterial effects.

Fig. 3
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The basic skeletal structure of guaiane-type sesquiterpenes from natural material

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Fig. 4
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The chemical structures of 12,6-guaianolides (1–144) from natural material (23 of them are 12,6-guaianolide glycosides.)

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Fig. 5
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The chemical structures of 12,8-guaianolides (145–192) from natural material

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Fig. 6
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The chemical structures of pseudoguaianolides (193–215) from natural material (the only difference is that the linkage position of Me-15 on C-4 in 12,8- guaianolides whereas on C-5 in pseudoguaianolides.)

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Fig. 7
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The chemical structures of tricycle guaiane-type sesquiterpenes (216–241) from natural material (according to their carbon skeleton links, compounds 216–229 were 11,1-guaianes, compounds 230 and 231 were 11,6 guaianes, and compounds 232–241 were 11,10 guaianes.)

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Fig. 8
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The chemical structures of dimers or trimers containing guaiane-type sesquiterpenes mother nuclei from natural material (Compounds 242–255 and 266–281 are guaiane dimers, 263 are guaiane trimers, and the rest are dimers with a guaiane mother-core structure.)

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Fig. 9
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The chemical structures of variant guaiane-type sesquiterpenes (282–302) from natural material

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Fig. 10
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The chemical structures of other guaiane-type sesquiterpenes (303–394) from natural material

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Biological activities

Experimental data have shown that guaiane-type sesquiterpenes possess a wide range of biological activities, including cytotoxic, antitumor, anti-inflammatory, antibacterial, and antiviral.

Cytotoxic and antitumor activities

Several recent studies have reported that guaiane-type sesquiterpenes possess potential anticancer activity through the inhibition of the proliferation of various cancer cells in vitro. Table 2 presents the plant origins of this bioactive guaiane-type sesquiterpenes and their cytotoxic activities. These in vitro data suggest that guaiane-type sesquiterpenes may not only have a broad spectrum but also strong cytotoxic activity, especially in breast cancer, liver cancer, lung cancer, and leukemia cells. Structures with antitumor activities are distributed in 11,10-guaiane, 12,6-guaianolide, 12,8-guaianolide, pseudoguaianolide, dimers or trimers containing guaiane-type sesquiterpenes mother nuclei, and other guaiane-type sesquiterpenes. Most compounds with antineoplastic activity belong to guaianolides, and the acyl diversity at C-8 is the only dissimilarity in compounds 10–14, which is a good opportunity to evaluate the effect of acyl groups on the antiproliferative activity of sesquiterpene derivatives because of the significant difference in their activity. Therefore, the lowest active compounds were isobutanol derivative 12 and acetyl derivative 14, while compounds 10, 11 and 13 are the most active guaianolides in this series. The above compounds either have oxygen functional groups, such as 13, or contain Michael receptors, such as 10. Compound 11 has both these two particular structures, so its biological activity is the supreme, at least on CCRF-CEM (Formisano et al. 2017).

Table 2 Cytotoxic activities of guaiane-type sesquiterpenes from natural material
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Anti-inflammatory activity

Inflammation is a cell’s response to injury caused by noxious physical or chemical stimuli; it is a key component of multiple pathologies, such as arthritis, asthma, multiple sclerosis, inflammatory bowel disease, and atherosclerosis (Cho et al. 2009). Nitric oxide (NO) is a well-known proinflammatory mediator in the pathogenesis of inflammation. Numerous studies have reported the inhibitory effects of NO on guaiane sesquiterpenes. Compounds 311, 321, 327, 340, 7–9, 150, 164–173, 204–212, 393, 134, 366–368, 248, and 256–261 all had their NO production inhibited in lipopolysaccharide (LPS)-activated mouse macrophages; their IC50 data are listed in Table 3; compound 204 separated from Inula falconeri exhibited the highest potency (IC50 = 0.07 μM; Cheng et al. 2011). Likewise, compounds 186, 247–249, and 264 isolated from A. macrocephala, Ainsliaea fulvioides, Eupatorium perfoliatum, and Helenium microcephalum effectively regulated the expression of tumor necrosis factor (TNF) - α, interleukin (IL) −1β, IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) mRNAs in LPS-induced RAW264.7 cells (Qin et al. 2017).

Table 3 NO inhibitory activities of guaiane-type sesquiterpenes from natural material
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A structural activity analysis revealed that compounds with anti-inflammatory activity were mainly distributed in 12,8-guaianolides, pseudoguaianolides, and guaiane polymers, most of which contained 12,8-lactone rings. Therefore, we speculated that their lactone rings are key to their activity, further research is necessary to reach a definite conclusion. Among them, compounds 164, 165, 170, 204, 206, and 210 showed better NO inhibitory activity and their IC50 values were <1 μM. The compared chemical structure between 207 and 204, between 208 and 205, between 209 and 206, respectively, it was found that the deletion of an α,β-unsaturated carbonyl group reduced the inhibitory activities. Through comparing pseudoguaiacolide 204–205 and 207–208, it showed that the acetylation of the hydroxyl groups usually enhanced the lipophilicity of the compounds, which was conducive to better penetrating the cell membrane and enhancing the inhibition of NO production. On the contrary, the inhibitory activity of 205 was 5 times weaker than 206 lacking the hydroxyl in C-6, similarily 208 was two times weaker than 209. The above results demonstrated that the introduced hydroxyl might reduce the permeability of the cell membrane and its anti-inflammatory activity. Besides, the position of hydroxyl groups may play a more important role than the number of hydroxyl groups, because compounds 164 and 165 each contain two hydroxyl groups with IC50 values of 0.29 and 0.13 μM, respectively. Moreover, the cyclic olefinic bond between C-9 and C-10 might be an important group for inhibiting NO production activity, because the inhibitory effects between 164 and 165 were significantly different.(Cheng et al. 2011).

Antibacterial activity and antiviral activity

Antibacterial and antiviral activities are common in these compounds. Compound 7 isolated from Scorzonera divaricata exerted antibacterial activity against C. Perfringens and E. coli with minimal inhibitory concentrations (MICs) of 25 and 50 μM, respectively (Wu et al. 2018). Compounds 328, 329, and 284 isolated from Ulva fasciata exerted antibacterial activity against Vibrio parahaemolyticus American Type Culture Collection (ATCC) 17809, V. harveyi Microbial Type Culture Collection (MTCC) 3438, and V. vulnificus MTCC 1146, respectively. Of these, compound 284 exerted the most antibacterial activity, with MICs of 25, 30, and 25 μg/mL on these bacteria, respectively (Chakraborty et al. 2010). Compounds 104, 107, 109, and 110 separated from Ferula diversivittata similarly showed antimicrobial activity against E. coli (ATCC8739), Staphylococcus aureus (ATCC29737), and Aspergillus niger (ATCC1624), and compound 109 exhibited the strongest antibacterial activity about these bacteria (MIC: 80, 80, 80 μM; Iranshahi et al. 2008). In addition, compounds 325 and 297 separated from Syringa pinnatifolia exhibited antimicrobial activity (Ao et al. 2012). Observing the structure is of interest as these compounds are not as anti-inflammatory as they appear: 12,6-guaianolide had the strongest antimicrobial activity, whereas 12,8-type lactones had nearly no reported antimicrobial activity.

Compound 317, a natural product from Curcuma aromatica, showed anti-influenza virus activities, with estimated IC50 values of 11.08 ± 1.74 μM (An et al. 2016; Chen et al. 2014b; Lu et al. 2012). Similarly, compounds 322, 187, 364, 365, 369, and 275 isolated from Curcuma wenyujin had anti-influenza virus activities (IC50: 9.18 ± 0.46, 6.80 ± 0.13, 22.21 ± 2.01, 13.27 ± 1.46, 15.95 ± 0.69, and 12.84 ± 0.73 μM; Dong et al. 2013; Xia et al. 2015; Zhou et al. 2017). Compounds 216–226 isolated from Cyperus rotundus had anti- hepatitis B virus (HBV) activities, and compound 217 had the strongest activity, with IC50 values as follows: hepatitis B surface antigen (HBsAg): 77.2 ± 13.0 μM, hepatitis B e antigen (HBeAg): 1210.2 ± 101.1 μM, HBV DNA: 74.7 ± 7.2 μM (Xu et al. 2015). The 11,1-guaiane exert some anti-HBV activities, but some modifications are necessary to enhance its activity.

Other biological activities

Per several reports, compounds 220, 238, 239, and 361 produced from Pogostemon cablin have reduced the damage induced by d-galactosamine (D-GalN) on human liver (HL) −7702 cells by 33.0% ± 0.026, 40.5% ± 0.043, 32.4% ± 0.036, 32.3% ± 0.016 at 10 μM (Li et al. 2013a; Zhu et al. 2017). Compound 314 isolated from Chloranthus japonicus had inhibitory effects on memory impairment (Amoah et al. 2015; Mu et al. 2016). At 50 μg/mL, compounds 146–149 separated from Gyrinops salicifolia exhibited acetylcholinesterase (AChE) inhibitory activity and the inhibition rates were 35.3 ± 1.2, 21.1 ± 1.9, 46.2 ± 0.9, and 54.2 ± 1.4%, respectively (Shao et al. 2016). Likewise, compounds 318, 319, and 328–331 isolated from Aquilaria sinensis also had AChE inhibitory activity (Hashim et al. 2016; Yang et al. 2016a; Yang et al. 2016b). Zidorn observed that 125 isolated from Lactuca tatarica had free radical-scavenging activity and that its IC50 was 5.52 μg/mL (Wang et al. 2010b). Compound 363 produced from Daucus carota had hepatoprotective activity (Fu et al. 2010a). In addition, compound 375 isolated from Commiphora myrrha had neuroprotective effects (Xu et al. 2012a). Moreover, compounds 287–288 isolated from Daphne aurantiaca had anti-insect activity (Huang et al. 2017).

Conclusion

Sesquiterpenes are a focus of current research given their unique structural characteristics and various biological activities in natural products. This review summarized the extant literature on the distribution, chemical classification, and pharmacological effects of guaiane-type sesquiterpenes. Guaiane-type sesquiterpenes mainly exist in the form of inner esters, with the 12,6- guaianolide being the most common. They are distributed in approximately 70 genera of 30 families, and most belong to the Asteraceae, Lamiaceae, Thymelaeaceae, and Zingiberaceae families. These families have attracted considerable attention in the research field due to a large number of sesquiterpenes with major bioactive antitumor, antibacterial, and anti-inflammatory effects. However, the bioactivity of these compounds is largely limited to in vitro studies. Guaianolides and guaiane polymers exerted various biological activities. Compounds with the 12,8-lactone ring structure (including 12,8-guaianolide, pseudoguaianolides and guaiane polymers which have anti-inflammation activities) have stronger biological activity than do those without this ring. Acetylation of hydroxyl groups tended to be more lipophilic, which leads to better penetration of cell membranes and enhanced inhibition of NO production, such as IC50 of 204 reaching 0.07 μM for this reason. Compounds containing a peculiar structural trait of an oxygenated functionality exhibited more prominent effects, and their inhibitory effects were all less than 5 μM, just like 10, 11, and 13. An extended discussion on the structure–activity relationship would require additional contributions to the literature.