A Brief Overview of the Classification and Research Progress of Sesquiterpenes

Terpenes are an important component of natural organic compounds, and there are currently more than 50,000 reported structures of terpenoid compounds.

Terpenes are an essential part of natural organic compounds, with over 50,000 reported structures of terpenoid compounds currently. Research has found that some natural terpenes possess strong anti-tumor, anti-inflammatory, and antibacterial activities. These biologically active natural terpenes include sesquiterpenes, diterpenes, monoterpenes, sesquiterpene dimers, and triterpenes. Among them, sesquiterpenes are the terpenes with the largest number and structural skeleton types. Their structures contain one or more double-bonded or triple-bonded carbon atoms. They can be classified into monocyclic, bicyclic, tricyclic, and tetracyclic types based on the number of carbon rings. They can also be divided into five-membered ring, six-membered ring, and seven-membered ring sesquiterpenes based on the number of carbon atoms in the ring. Furthermore, they can be grouped into sesquiterpene alcohols, sesquiterpene ketones, sesquiterpene lactones, and others based on different oxygen-containing groups.

Sesquiterpenes are widely found in plants, microorganisms, marine organisms, and some insects. Plants with the highest content of sesquiterpenes are birch trees and birch resin from the genus Betula in the Betulaceae family. Among traditional medicinal herbs, those with higher sesquiterpene content include Xanthium sibiricum from the Xanthium genus of the Asteraceae family, Atractylodes lancea from the Atractylodes genus of the Asteraceae family, Inula japonica from the Inula genus of the Asteraceae family; Mentha from the Mentha genus of the Lamiaceae family, Eupatorium from the Eupatorium genus of the Lamiaceae family; Verbena officinalis from the Verbena genus of the Verbenaceae family, and Gentiana scabra from the Gentiana genus of the Gentianaceae family. Modern research has found that sesquiterpenes possess a wide range of biological activities, including anti-tumor, antibacterial, anti-inflammatory, anti-neurotoxic, antiviral, immunosuppressive, liver-protecting, and cardiotonic properties.

1. Sesquiterpene Alcohols

Sesquiterpenes alcohols contain an alcohol hydroxyl group (-OH) as a common functional unit, and their structures are composed of 15 carbon atoms. Among them, the six most common sesquiterpene alcohols are farnesol, nerolidol, vetiverol, patchouli alcohol, sandalwood alcohol, and eucalyptol. Sesquiterpene alcohols exhibit various biological activities. Research has shown that sesquiterpene alcohols isolated from nerolidol possess insecticidal and anti-tumor activities. Some sesquiterpene alcohol monomers, such as baimuxiangchun (extracted from the resinous wood of Aquilaria sinensis, a member of the Aquilaria genus), have inhibitory effects on the release of nitric oxide (NO) induced by lipopolysaccharides (LPS) in RAW264.7 macrophages, indicating their good anti-inflammatory properties. Sesquiterpene alcohols extracted from Atractylodes chinensis, such as atractylol, β-eucalyptol, γ-eucalyptol, and elemol, have the ability to inhibit gastric acid secretion, suppress Helicobacter pylori activity, and promote the healing of peptic ulcers.

2. Sesquiterpene Ketones

The ketone group is the oxygen-containing group that constitutes the structure of sesquiterpene ketones. The functional group of ketones is the carbonyl group (C=O), where both ends of CO are attached to atomic groups, meaning that all ketone chemical structures share a common unit (C=O). Common sesquiterpene ketones include jasminone, damascenone, ionone, inulone, atlanticone, and valerianone. Research has shown that α,β-unsaturated ketones in the structure of sesquiterpene ketones have strong anti-tumor effects. Ezhu, a traditional Chinese medicine, refers to the rhizomes of Curcuma zedoaria, Curcuma kwangsiensis, and Curcuma wenyujin from the Curcuma genus. Studies have revealed that zedoarone, a sesquiterpene ketone extracted from Ezhu, exhibits a time- and dose-dependent inhibitory effect on liver cancer cells Hep G2. Besides anti-tumor effects, zedoarone extracted from Ezhu can also significantly reduce the degree of injury in mice with LPS-induced acute lung injury. Its mechanism of action is related to promoting the polarization of M1 macrophages to M2 and inhibiting the activation of NOD-like receptor protein 3 (NLRP3) inflammasomes, indicating that zedoarone has strong anti-inflammatory effects. Moreover, bisabolone, obtained from the roots of Angelica polymorpha Maxim. (Umbelliferae), has good inhibitory effects on H+, K+-ATP enzyme and anti-gastric ulcer activity. It also inhibits uterine smooth muscle contractions and has analgesic effects, with its mechanism of treating dysmenorrhea potentially related to calcium ion antagonism.

3. Sesquiterpene Lactones

Sesquiterpenes lactones are currently the most extensively studied among sesquiterpenes. The sesquiterpene ring is a cyclic structure composed of 15 carbon atoms, while the lactone ring is a cyclic structure composed of 5 carbon atoms and 1 oxygen atom. The uniqueness of this structure endows sesquiterpene lactones with diverse biological activities. Research has shown that α-methylene-γ-lactones in this class of compounds possess anti-tumor activity, while α,β-unsaturated γ-lactones exhibit strong anti-inflammatory activity. It has been found that nine sesquiterpene lactones in the leaves of yacon have anti-tumor activity, of which three sesquiterpene lactones, namely enhydrin, uvedalin, and sonchifolin, can inhibit the proliferation of human cervical cancer cell line (HeLa cells) by inducing apoptosis. Six sesquiterpene lactones, including uvedafolin, enhydrofolin, polymatin B, enhydrin, uvedalin, and sonchifolin, exhibit varying degrees of inhibitory effects on cell proliferation in three cell lines: HeLa, human acute promyelocytic leukemia cells (HL-60), and mouse melanoma cells (B16-F10). A new sesquiterpene lactone, Saussurea costus lactone A, isolated and identified from Saussurea costus of the Asteraceae family, has been shown to inhibit the release of NO from RAW264.7 cells induced by bacterial LPS. Four sesquiterpene lactones, including oxyelephantopin, isoelephantopin, isodeoxyelephantopin, and elephantopin, extracted from Elephantopus scaber of the Asteraceae family, can significantly inhibit the proliferative activity of human non-small cell lung cancer. Two sesquiterpene lactones, zaluzanin-C and estafiatone, isolated from Ainsliaea acerifolia of the Asteraceae family, can reduce the production of NO and inhibit the synthesis of PGE2 in RAW264.7 macrophages induced by LPS/IFN-γ. They can also inhibit the expression of iNOS, COX-2 proteins, and m-RNA in RAW264.7 macrophages induced by LPS/IFN-γ, as well as inhibit the activation of NF-κB and the phosphorylation of IκB, thus reducing the degradation of IκB. This indicates that zaluzanin-C and estafiatone can inhibit the expression of iNOS, COX-2, and the release of PGE2 by preventing the degradation of IκB and inhibiting the nuclear transcription of NF-κB, thus exerting anti-inflammatory effects. Costunolide exerts anti-inflammatory effects by inhibiting the activity of p38MAPK and ERK, thereby inhibiting the differentiation of CD4+ T cells. Parthenolide, a sesquiterpene lactone extracted from plants of the Asteraceae family, has its biological active site concentrated mainly on its α-methyl-γ-lactone ring. This special lactone ring structure can specifically bind to multifunctional proteins in cells, thereby regulating the expression of downstream proteins in signaling pathways. Research has shown that parthenolide has anti-tumor effects on cell lines such as colon cancer cells HCT116 and RKO, lung cancer cells NCI-H1299, and myeloblast HL604. Its mechanism of action mainly involves activating tumor suppressor proteins regulated by p53 and MDM2. Additionally, it can also promote cancer cell apoptosis by reducing the levels of p-AKT and pS166-Mdm2 and enhancing the expression of p53.

4. Other Types

In addition, there are other types of sesquiterpenes containing oxygen-bearing functional groups, such as sesquiterpene aldehydes and sesquiterpene carboxylic acids. Besides classification based on oxygen-bearing groups, there is also a class of sesquiterpenes known as sesquiterpenes, which can be further divided into guaiane-type, eudesmane-type sesquiterpenes, cadinane-type, and other types of sesquiterpenes. These sesquiterpenes are mainly found in medicinal plants, such as the families of Equisetaceae, Araliaceae, Fabaceae, and Asteraceae. Guaiane-type sesquiterpenes are a class of sesquiterpene compounds isolated from the leaves and stems of plants of the genus Guaiacum, with a five-membered and seven-membered ring coupling structure. Most of them contain 4,10-dimethyl-7-isopropenyl, and possess various biological activities such as antiviral, anti-tumor, and anti-inflammatory effects. Eudesmane-type sesquiterpenes are a class of bicyclic sesquiterpenes with a decahydronaphthalene skeleton, which is the most abundant monomer compound isolated from agarwood. Important biological activities have been identified, and 54 eudesmane-type sesquiterpenoid compounds have been isolated and identified from agarwood worldwide. Cadinane-type sesquiterpenes are similar to eudesmane-type in structure, but differ in the positions of the isopropyl substituent and the two methyl substituents. Currently, multiple cadinane-type sesquiterpenes have been isolated from plants of the genus Juniperus. Furthermore, sesquiterpenes can also be classified into furanoid, spirostane, eremophilane, prenylphorbolane, and humulane types.

In recent years, newly discovered monocyclic sesquiterpenoid compounds exhibit diverse structures and rich pharmacological activities. However, there are relatively few studies on their mechanisms of action and druggability. Based on the monocyclic sesquiterpenoid drugs that have been marketed and applied, monocyclic sesquiterpenes possess abundant pharmacological activities and good potential for drug development. It is believed that with further research, the mechanisms of biological activities of sesquiterpenoid compounds will become increasingly clear, and it is promising to discover new and efficient anti-tumor, anti-inflammatory, and other drugs from them.

References

[1] Yang Liyuan, Cheng Ju, Chen Jianjun, et al. Research Progress on the Biological Activities of Sesquiterpenoid Compounds [J]. Chinese Journal of Experimental Traditional Medical Formulae, 2024, 30(05): 289-298.

[2] Guo Limin, Lv Jieli, Zhang Laibin. Research Progress on the Anti-inflammatory Mechanism of Natural Sesquiterpenoid Compounds [J]. China Journal of Chinese Materia Medica, 2018, 43(20): 3989-3999.

[3] Fu Jia, Li Fenghua, Li Changkang, et al. Research Progress on the Structure and Pharmacological Activities of Monocyclic Sesquiterpenoid Compounds from Natural Sources [J]. China Journal of Chinese Materia Medica, 2019, 44(17): 3672-3683.

Author Introduction: Xiaomi Chong, a researcher in pharmaceutical quality, has long been committed to pharmaceutical quality research and validation of pharmaceutical analytical methods. Currently, she works for a large domestic pharmaceutical research and development company, engaging in drug inspection analysis and analytical method validation.

About the Author

 Xiaomi Chong, a researcher in pharmaceutical quality, has long been committed to pharmaceutical quality research and validation of pharmaceutical analytical methods. Currently, she works for a large domestic pharmaceutical research and development company, engaging in drug inspection analysis and analytical method validation.