The Classification of Sesquiterpene Compounds and Their Research Progress

Terpenoids are an important part of natural organic compounds, and there are currently more than 50,000 reported terpenoid structures. Studies have found that some natural terpenoids have strong antitumor, anti-inflammatory and antibacterial activities, and these biologically active natural terpenoids include sesquiterpenes, diterpenoids, monoterpenoids, disesquiterpenoids and triterpenoids, among which sesquiterpenoids are the terpenoids with the largest number and structural skeleton types, and their structures contain one or more carbon atoms with double bonds or triple bonds carbon atoms, which can be divided into single-ring, double-ring, tripyclic and tetracyclic types according to the number of carbon rings. According to the number of carbon atoms constituting the ring, it can be divided into five-membered ring, six-membered ring and seven-membered ring sesquiterpene ring, and can also be divided into sesquiterpene alcohol, sesquiterpene ketone, sesquiterpene lactone, etc. according to different oxygen-containing groups.

Sesquiterpenes are widely found in plants, microorganisms, marine organisms and certain insects. The plants with the highest content of sesquiterpenes were birch and birch resin of the birch family, and the higher content of sesquiterpenes in traditional medicinal materials were Asteraceae in the genus Asteraceae, Atractylodes in the genus Asteraceae, and Mulchflower in the genus Asteraceae. mint in the genus Peppermint in the Lamiaceae family, Zeeland in the genus Shoots in the Lamiaceae family; Verbena in the genus Verbena in the Verbenaceae family and gentian in the gentian genus in the gentian family, etc. Modern studies have found that sesquiterpenoids have a wide range of biological activities such as antitumor, antibacterial, anti-inflammatory, antineurotoxic, antiviral, immunosuppressive activity, liver protection, and cardiotonic.

1. Sesquiterpene alcohol 

Sesquiterpene alcohol contains a structure composed of alcohol hydroxyl groups, all of which have a common group unit (-OH), and the functional group of sesquiterpene alcohol has a structure of 15 carbon atoms. Among the six most common sesquiterpene alcohols are farnesol, nerolidol, vetivol, patchouliol, sandalol, and eucalyptol. Sesquiterpene alcohol has a variety of biological activities, and studies have shown that sesquiterpene alcohol isolated from nerolidol has insecticidal activity and antitumor activity. Some sesquiterpene alcohol monomer compounds such as sesquiterpene alcohol extracted from resin-containing wood agarwood of the genus Agarwood inhibition inhibited the release of nitric oxide (NO) induced by lipopolysaccharide (LPS) in RAW264.7 macrophages, indicating that the compounds had good anti-inflammatory activity. The sesquiterpene alcohol and meadol, β-eucalyptol, γ-eucalyptol, elemenol and so on extracted from Atractylodes atractylodes have the effect of inhibiting gastric acid secretion, Helicobacter pylori and promoting the healing of peptic ulcer. 

2. Sesquiterpenone 

The ketone group is the oxygenated group that makes up the sesquiterpene ketone, the functional group of the ketone is the carbonyl group, and the two ends of the CO are connected with atomic clusters, that is, the chemical structure of all ketones has 1 common unit (C=O). Common sesquiterpenes include frangipani, damascenone, ionone, artemisinone, Atlantic ketone, and valenone, among others. Studies have shown that the α and β unsaturated ketones in the structure of sesquiterpenone have strong anti-tumor effects. The results of the study showed that the sesquiterpene ketone jimaketone in the extract of Curcuma had a time-dependent and dose-dependent inhibitory effect on hepatoma G2 cells. In addition to anti-tumor, the gemazone extracted from Curcuma can significantly reduce the degree of injury in mice with LPS-induced acute lung injury, and the mechanism of action is related to promoting M1 macrophage polarization to M2 and inhibiting the activation of  NOD-like receptor protein 3 (NLRP3) inflammasome, indicating that gemazone has a strong anti-inflammatory effect. The myrrh alkyl ketotimes obtained from the root of Angelica poly-morha Maxim., which belongs to the family Apiaceae, has good inhibition of H+, K+-ATPase, anti-gastric ulcer effect, and also has the effect of inhibiting uterine smooth muscle contraction and analgesia, and its mechanism of action in the treatment of dysmenorrhea may be related to calcium ion antagonism. 

3. Sesquiterpene lactone

Sesquiterpene lactones are the most studied sesquiterpenoids, sesquiterpene rings are cyclic structures composed of 15 carbon atoms, and lactone rings are cyclic structures composed of 5 carbon atoms and 1 oxygen atom, the uniqueness of this structure makes sesquiterpene lactones have a variety of biological activities. Studies have shown that α-methylene-γ-lactones have anti-tumor activity, while α, β unsaturated γ-lactones have strong anti-inflammatory activities. It was found that 9 sesquiterpene lactones in yacon leaves had antitumor activity, and three sesquiterpene lactones enhydrin, uvedalin and sonchifolin could inhibit the proliferation of human cervical cancer cell lines (HeLa cells) by inducing apoptosis. 6 sesquiterpene lactones uvedafolin, enhydrofolin, polymatin B, enhydrin, uvedalin, sonchifolin inhibits cell proliferation to varying degrees on three cell lines, including HeLa, human promyelomyelotic acute leukemia cells (HL-60) and mouse melanoma cells (B16-F10).   A new sesquiterpene lactone, marivolin A, was isolated and identified from Asteraceae genus Asteraceae, and the results showed that this compound showed an inhibitory effect on the release of NO from RAW264.7 cells induced by bacterial LPS. Four sesquiterpene lactones oxydicholicin, isodeoxydicholicin, ectocholides and dicholides extracted from the genus Asteraceae could 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 reduced LPS/IFN-γ, induced NO production in RAW264.7 macrophages, inhibited PGE2 synthesis, and inhibited LPS/IFN-γ  It induces iNOS, COX-2 protein and m-RNA expression in RAW264.7 macrophages, and can also inhibit the activation of NF-κB  and the phosphorylation of IκB, thereby reducing  IκB It was suggested that zaluzanin-C and estafiatone could exert  anti-inflammatory effects by preventing the degradation of IκB, inhibiting NF-κB nuclear transcription, and then inhibiting the expression of iNOS, COX-2 and the release of PGE2. Costuno-lide can exert anti-inflammatory effects by inhibiting the activity of p38MAPK and ERK, thereby inhibiting the differentiation of CD4+ T cells. Feverolide is a sesquiterpene lactone extracted from Asteraceae plants, and its bioactive sites are mainly concentrated on its α-methyl-γ-lactone ring, which can specifically bind to multifunctional proteins in cells, thereby regulating the expression of downstream proteins in the signaling pathway. Studies have shown that feverolide has anti-tumor effects on colon cancer cells HCT116 and RKO, lung cancer cells NCI-H1299, meeloblastoma HL604 and other cell lines, and its mechanism of action is mainly to activate p53 and MDM2-regulated tumor suppressor proteins, in addition, it can also enhance p53 by reducing the levels of p-AKT and pS166-Mdm2 to promote apoptosis in cancer cells. 

4. Other types 

 In addition, there are other oxygen-containing functional groups of sesquiterpene classifications, such as sesquiterpene aldehydes, sesquiterpene carboxylic acids, etc. In addition to the classification according to the oxygen-containing group, there is also a class of sesquiterpenes called sesquiterpenes, which can be divided into guaiacyane, eucalyptane, juniper and other types of sesquiterpenes according to their structure. This type of semiterpene is mainly found in medicinal plants, such as equisetae, eleutheroaceae, legumes, and Asteraceae. Guaiacane-type sesquiterpenes are a class of sesquiterpene compounds isolated from the leaves and stems of guaiac, with five- and seven-membered ring-coupled structures, most of which contain 4,10-dimethyl-7-Isopropylene-based, with antiviral, antitumor and anti-inflammatory activities. Eucalyptane-type sesquiterpenoids are a class of bicyclic sesquiterpenoids with decahydronaphthalene backbone, which is the most abundant monomer compound isolated in agarwood, and has important biological activity, and 54 eucalyptane-type sesquiterpenoids have been isolated and identified from agarwood at home and abroad. Juniper sesquiterpenes are similar in structure to eucalyptane, with the difference that isopropyl substituents and 2 methyl substituents are in different positions. In addition, sesquiterpenes are also divided into furan, spiralane, erimophenol, provanillane, and hops. 

In recent years, the newly discovered monocyclic sesquiterpenoids have diverse structures and rich pharmacological activities, but there are few studies on their mechanism of action and druggability. It is believed that with the deepening of research, the mechanism of action of the biological activity of sesquiterpenoids will become more and more clear, and it is expected that new and efficient anti-tumor and anti-inflammatory drugs will be discovered from them.

Resources

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About the Author:

Xiaomichong

Xiaomichong is a researcher in drug quality, who has long been committed to the research of drug quality and the validation of drug analysis methods. Currently, Xiaomichong is employed by a large Chinese pharmaceutical research and development company, engaging in drug inspection and analysis as well as validation of analytical methods.