# Terpenoids and Their Biological Activities fromCinnamomum: A Review

Authors: Meiting Wu; Lin Ni; Haixiao Lu; Huiyou Xu; Shuangquan Zou; Xiaoxing Zou
Journal: Journal of Chemistry
 (2020)

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## Abstract

Cinnamomum is a genus of the family Lauraceae, which has been recognized worldwide as an important genus due to its beneficial uses. A great deal of research on its phytochemistry and pharmacological effects has been conducted. It is noteworthy that terpenoids are the characteristic of Cinnamomum due to the peculiar structures and significant biological effects. For a more in-depth study and the better use of Cinnamomum plants in the future, the chemical structures and biological effects of terpenoids obtained from Cinnamomum were summarized in the present study. To date, a total of 181 terpenoids with various skeletons have been isolated from Cinnamomum. These compounds have been demonstrated to play an important role in immunomodulatory, anti-inflammatory, antimicrobial, antioxidant, and anticancer activities. However, studies on the bioactive components from Cinnamomum plants have only focused on a dozen species. Hence, further studies on the potential pharmacological effects need to be conducted in the future.


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## Body

## 1. Introduction

Cinnamomum, which is a genus of the family Lauraceae, is represented by evergreen trees and shrubs [1]. Approximately 250 species of this genus have been found around the world and are mainly distributed in tropical and subtropical regions of Southeast Asia, Australia, and North, Central, and South America. There are approximately 46 species in China, and these are mainly in the southern religions. Yunnan province has the most species, followed by Guangdong and Sichuan [2, 3].Cinnamomum has been recognized worldwide as an important genus due to its beneficial uses. This has been traditionally used in flavoring food and in folk medicine for its sweating, antipyretic, and analgesic effects [4]. Some Cinnamomum species, including C. cassia, C. zeylanicum, C. tamala, and C. wilsonii, are famous herbs that have a long history of being used as medicine. In addition, the extracted essential oil from C. camphora, with the main ingredients of eucalyptol, linalool, and camphor, is an important raw material for the chemical industry and medicine. Furthermore, the Cinnamomi cortex, which is obtained from some Cinnamomum species, has been used for treating cardiovascular, chronic gastrointestinal, and inflammatory diseases [5, 6]. Cinnamaldehyde, which is the main constituent of the volatile oil of C. cassia bark, has been mainly used in medicine, foods, and cosmetics and has been proven to exert antifungal and antibacterial activities [7].To date, many studies on phytochemistry of the genusCinnamomum have been conducted. Over 500 compounds have been obtained from Cinnamomum plants, which cover lignans, terpenoids, flavonoids, phenylpropanoids, alkaloids, steroids, and butanolides. Among these compounds, approximately 300 compounds are from C. Cassia, which is the most thoroughly studied. This has been reported to show many special contents, particularly terpenoids. Other species also contain a number of unique terpenoids with rare structures, which can only be found from certain species. More importantly, terpenoids, which are the most abundant and diverse compounds in this genus, have also been proven to show great pharmacological activities, including immunomodulatory, anti-inflammatory, antimicrobial, antioxidant, and anticancer activities. Thus, the present review aimed at summarizing the phytochemistry and pharmacological effects of terpenoids from Cinnamomum species and providing a basis for the future in-depth study of the genus Cinnamomum.


## 2. Chemical Constituents and Biological Activities

A number of studies on the phytochemistry of the genusCinnamomum have been conducted, and focus has been given on approximately 14 species. From these studies, the genus has been shown to possess abundant and various terpenoids with unique structures. To date, a total of 181 terpenoids have been isolated from the genus Cinnamomum, including 43 monoterpenes, 83 sesquiterpenes, 53 diterpenes, and two triterpenes. Among these compounds, 119 terpenoids were obtained from C. cassia, 21 terpenoids were obtained from C. wilsonii, 19 terpenoids were obtained from C. camphora, 18 terpenoids were obtained from C. glanduliferum, 17 terpenoids were obtained from C. subavenium, eight terpenoids were obtained from C. zeylanicum, eight terpenoids were obtained from C. osmophloeum, three terpenoids were obtained from C. inunctum, three terpenoids were obtained from C. philippinense, two terpenoids were obtained from C. kotoense, one terpenoid was obtained from C. burmannii, one terpenoid was obtained from C. parthenoxylon, one terpenoid was obtained from C. reticulatum, and one terpenoid was obtained from C. tenuifolium, respectively.


### 2.1. Monoterpenes

A total of 43 monoterpenes have been reported fromCinnamomum (Table 1 and Figure 1), including 24 cyclic monoterpenes (1–17, 37–43) and 19 acyclic monoterpenes (18–36). Among these cyclic monoterpenes, compounds 1–13 are menthane monoterpenes, which are the most abundant types in the genus Cinnamomum. In addition, compounds 6–12 are the common constituents in the volatile oils of Cinnamomum plants. Compounds 14 and 15 are camphane monoterpenes and camphor (15), along with linalool (29) and eucalyptol (41), is one of the main components of volatile oil in C. camphora. Compounds 16 and 17 belong to the pinane-type monoterpenes, which are common in volatile oils. Monoterpenes 18–36 are laurane-type monoterpenes. Among these, compounds 18–24 have a geranylphenylacetate skeleton connected to glucose. Compounds 18–21, 23, and 24 were further cyclized to form a tetrahydrofuran ring. Interestingly, these compounds were only isolated from C. cassia and are the characteristic compounds for this species. Extracted from C. inunctum, compounds 25–27 were monoterpene lactones. Based on this structure, the original hydroxyl groups at the C-4 and C-7 positions of compound 27 were further cyclized to form a rare spironolactone structure. Obtained from C. camphora, compound 33 is an acyclic monoterpene with one carbon degraded and has shown strong anti-inflammatory activity. Compounds 37 and 38 are normonoterpenes from C. reticulatum, with one carbon degraded. Subamone (43), which was obtained from C. subavenium, has a cycloheptanone skeleton and has strong antitumor activity.Table 1
Monoterpenes from the genusCinnamomum.
No.TypeCompoundMolecular formulaMolecular weightOriginReferences1Menthane(3R,4R)-p-Menth-1-ene-3,4-diol 3-O-β-d-glucopyranosideC16H28O7332s[8]2(3R,4S,6R)-p-Menth-1-ene-3,6-diol 3-O-β-d -glucopyranosideC16H28O7332s[8]3(4R)-p-Menthane-1,2α,8-triolC10H20O3188s[8]4CarvacrolC10H14O150s[9]5ThymolC10H14O150s[9]6α-TerpineolC10H18O154c, d, g, o[10–12]7α-PhellandreneC10H16136d, g[10, 13]8α-TerpineneC10H16136d, g[10, 13]9p-CymeneC10H14134g[10]10TerpinoleneC10H16136d, g[10, 13]11Terpinen-4-olC10H18O154g[10]12LimoneneC10H16136g, z[10, 11]13(1R,2R,4S,6S)-4-(2-Hydroxypropan-2-yl)-1-methyl-7-oxabicy clo[4.1.0]heptan-2-olC10H18O3186c[14]14CamphaneBorneolC10H18O154c, g, z, o[10–12]15CamphorC10H16O152c, d, g[10, 13]16Pinaneα-PineneC10H16136d, g, z[10, 11]17β-PineneC10H16136c, d, g[10, 11]18LauraneCinnacasside AC25H36O11512c[15–17]19Cinnacasside BC25H36O11512c[15–17]20Cinnacasside CC25H36O11512c[15–17]21Cinnacasside DC25H36O11512c[15]22Cinnacasside EC25H38O11514c[15]23Cinnacasside FC26H40O12544c[17]24Cinnacasside GC26H40O12545c[17]255-(2,3-Dihydroxy-3-methylbutyl)-4-hydroxy-4-methyldihydrofuran-2(3H)-oneC10H18O5218i[18]265-(2,3-Dihydroxy-3-methylbutyl)-4-methylfuran-2(5H)-oneC10H16O4200i[18]278-Hydroxy-4,7,7-trimethyl-9-1,6-dioxaspiro[4.4]non-3-en-2-oneC10H14O4198i[18]28trans-Linalool-3,6-oxide-β-d-glucopyranosideC16H28O7332c[19]29LinaloolC10H18O154c, d[19, 20]303,7-Dimethyl-1-octene-3,6,7-triolC10H20O3188c[19]313,7-Dimethyl-oct-1-en-3,6,7-triol-6-O-β-d-glucopyranosideC16H30O8350c[19]32(6R)-Geraniol-6,7-diolC10H20O3188c[19]336-Hydroxy-6-methyl-4,7-octadien-2-oneC9H14O2154d[21]34β-OcimeneC10H16136d[13]35β-MyrceneC10H16136g[10]36Geranyl acetateC12H20O2196c[20]37NormonoterpenesReticuoneC9H14O3170r[22]38(3,3-Dimethylcyclohex-1-ene-1,4-diyl) dimethanolC15H26O7318c[14]39Othersα-ThujeneC10H16136d, g[10]40SabineneC10H16136d, g[10]41EucalyptolC10H18O154d, g[10, 13]42CampheneC10H16136c, d, g[13, 20]43SubamoneC10H16O2168s[23, 24]Note: b:C. burmannii; c: C. cassia; d: C. camphora; g: C. glanduliferum; i: C. inunctum; k: C. kotoense; o: C. osmophloeum; p: C. parthenoxylon; q: C. philippinense; r: C. reticulatum; s: C. subavenium; t: C. tenuifolium; w: C. wilsonii; z: C. zeylanicum. The same is given in Figure 1.Figure 1
The structures of monoterpenes fromCinnamomum.Some monoterpenes fromCinnamomum plants have shown potent antimicrobial activities. Carvacrol (4) showed a broad spectrum of antibacterial activity against both Gram-positive and Gram-negative bacteria [25]. The antimicrobial activity of compound 4 against numerous bacteria was studied and it showed a high inhibitory effect against all these strains, including Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumonia, Escherichia coli, Klebsiella pneumonia, Enterobacter spp., Serratia spp., and Proteus mirabilis [26]. Furthermore, 4 is also effective against various fungi, such as Aspergillus niger, Aspergillus flavus, Alternaria alternata, Penicillium rubrum, Trichoderma viride, Candida spp., and dermatophytes [27]. The antibacterial activity of compounds 4 and 9 (a precursor of 4) was studied against the foodborne microorganism V. cholerae. Compound 4 exerted a good inhibitory effect against V. cholerae, while 9 exhibited a weak activity. However, it was interesting to find that the inhibitory effects were enhanced when the two compounds were used together, showing a synergistic effect [28]. According to the findings both 16 and 29 exerted antibacterial activity against E. faecalis and S. aureus, and 16 showed antifungal activity against C. albicans. Similarly, compound 7 was effective against Ae. aegypti and Ae. albopictus [29], as well as Culex pipiens molestus [30].The antioxidant activities of some monoterpenes were evaluated. The assessment on antioxidant capacity of carvacrol (4) showed that 4 at the doses of 25 (49.79 IU/mg) and 50 mg/kg (52.43 IU/mg) enhanced the level of hippocampal SOD activity in ischemic rats, when compared with the ischemic group (42.9 IU/mg). In the DPPH assay, the percentage of oxidant inhibition was significantly increased in the ischemic group treated with 4 at doses of 25 (41.5%) and 50 mg/kg (36.83%), when compared to the untreated ischemic group (11.29%) [31]. Hakimi et al. confirmed that three doses of compound 4 (25, 50, and 100 mg/kg) could significantly increase the thiol content and improve the activities of both CAT and SOD compared with LPS groups in the hippocampus of rats [32]. In the trolox equivalent antioxidant capacity assay, the antioxidant effects of compounds 4 and 5 were evaluated and compared to that of the synthetic antioxidant trolox. Both compounds have exerted significant antioxidant activity similar to trolox, and the capacity of 4 has been proven to be higher than that of its isomer thymol at the same concentration [25]. Moreover, the antioxidant potential of p-cymene (9) was evaluated in the hippocampus of adult mice. The treatment with 9 at a concentration of 50 mg/kg (0.42 ± 0.03) has produced a significant decrease in lipid peroxidation 65.54%, when compared with the control group. Furthermore, compound 9 at all tested doses (50, 100, and 150 mg/kg) could significantly decrease the nitrite content and produce an increase in SOD and catalase activities [33].Some monoterpenes were reported to show significant anti-inflammatory effects. Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme in prostaglandin biosynthesis, which plays a key role in inflammation. In human macrophage-like U937 cells, compound4 was shown to suppress the LPS-induced expression of COX-2 and activate the peroxisome proliferator-activated receptors (PPAR) α and γ [34]. Furthermore, 4 could also inhibit the production and actions of NO [25]. Moreover, NF-κB has been reported to play an important role in the inflammatory response and LPS/GalN-induced liver injury [35]. The effects of linalool (29) on NF-κB expression were assessed, and it was found that 29 could significantly inhibit LPS-induced p65 NF-κB translocation into the nucleus and IκBα degradation. In addition to the NF-κB inhibition, compound 29 could also induce antioxidant defense via Nrf2 activating and consequently protect against LPS/GalN-induced liver injury [36]. Other than this, another study demonstrated that 29 protected against CS-induced lung inflammation through inhibiting CS-induced NF-κB activation [37].The anticancer activity of linalool (29) against human prostate cancer (DU145) cells was evaluated by the MTT assay and it was observed that 4.36%, 11.54%, 21.88%, and 15.54% of the cells underwent early apoptosis after treatment with 0, 20, 40, and 80 μM of 29, respectively [38]. In addition, Okumura et al. confirmed that terpinolene (10) could markedly reduce the expression of protein kinase AKT, which can mediate cell proliferation and survival signals, and contribute to cancer progression [39].In an immunosuppression assay, Zeng et al. found that monoterpenes18, 19, and 23 exhibited potent immunosuppressive activities against murine lymphocytes. Compound 23 inhibited the proliferation of T cells and B cells with an inhibitory ratio of 36.1% and 20.3%, respectively, at a concentration of 400 μM [17]. In another assay, the effect of α-terpineol (6) on the generation of nitric oxide in macrophages induced by LPS was evaluated. The nitrite production induced by LPS in these cells was reduced at all concentrations of compound 4 tested (1, 10, and 100 μg/mL) [40]. Rufino et al. reported that α-pinene (16) could decrease NO production in a dose-dependent manner in primary human chondrocytes, showing the highest inhibition of NO production at a dose of 200 μg/mL, with a decrease to 31.5% relative to cells treated with IL-1β alone [41].


### 2.2. Sesquiterpenes

A total of 83 sesquiterpenoids (44–126) were isolated from Cinnamomum plants, which contain multiple structural types (Table 2 and Figure 2).Table 2
Sesquiterpenes from the genusCinnamomum.
No.TypeCompoundMolecular formulaMolecular weightOriginReferences44InoneWilsonol AC13H24O4244w[42]45Wilsonol BC13H24O4244w[42]46Wilsonol CC13H22O4242w[42]47Wilsonol DC13H24O3228w[42]48(3S,4S,5S,6S,9S)-Wilsonol EC13H26O3230w[42]49(3S,4S,5S,6S,9R)-Wilsonol EC13H26O3230w[42]50Wilsonol FC13H26O3230w[42]51Wilsonol GC13H24O4244s, w[8, 42]52(3S,4S,5S,6S,9S)-3,4-Dihydroxy-5,6-dihydro-β-ionolC13H24O3228w[42]53Lasianthionoside AC19H32O9404w[42]54BoscialinC13H22O3226c[43]55(3S,5R,6S,7E)-Megasfigma-7-ene-3,5,6,9-tetrolC13H24O4244s, w[8, 42]56(3S,5S,6S,9R)-3,6-Dihydroxy-5,6-dihydro-β-ionolC13H24O3228w[42]57Wilsonol HC13H24O5260s, w[8]58Wilsonol IC13H24O3228w[42]59Wilsonol JC13H24O3228w[42]60Wilsonol KC13H22O3226w[42]61Wilsonol LC13H22O3226w[42]62(3R,9S)-Megastigman-5-ene-3,9-diol 3-O-β-d-glucopyranosideC19H34O7374w[42]63(3S,4R,9R)-3,4,9-Trihydroxymegastigman-5-eneC13H24O3228w[42]64Apocynol AC13H20O3224w[42]65Blumenol AC13H20O3224c, p[43, 44]66DehydrovomifoliolC13H18O3222c[43]67(3S,5R,6S,9S)-3,6,9-Trihydroxymegastigman-7-ene 3-O-β-d-glucopyranosideC19H34O8390c[19]68(1R,2R)-4-[(3S)-3-Hydroxybutyl]-3,3,5-trimethylcyclohex-4-ene-1,2-diolC13H24O3228c[45]69(3S,5R,6S,7E)-3,5,6-Trihydroxy-7-megastigmen-9-oneC13H22O4242c[46]70Grasshopper ketoneC13H20O3224c[43]71Asicariside B1C18H30O8374s[8]72CaryophyllaneCaryophyllene oxideC15H24O220o, s[9, 16]73trans-CaryophylleneC15H24204c[47]74Humulane(2E,9E)-6,7-cis-Dihydroxyhumulan-2,9-dieneC15H26O2238c[46]75α-HumuleneC15H24204g[10]76CadinaneCinnamoid BC15H24O3252c[48, 49]77Cinnamoid CC15H24O3252c[48, 49]78MustakoneC15H24O3252c[46]79Oxyphyllenodiol AC14H22O3238s[50]80Oxyphyllenodiol BC14H22O3238s[50]81(-)-15-HydroxytmuurololC15H26O2238c[49]8215-Hydroxy-α-cadinolC15H26O2238c[49]83β-CadineneC15H24204z[11]84δ-CadineneC15H24204c, d, o, z[10–13]85α-MuuroleneC15H24204c, d[14]86α-CadinolC15H26O222c, d[14]87α-CalacoreneC15H20200c, o, z[11, 12]88CalameneneC15H22202z[11]89Eudesmane4(15)-Eudesmene-1β,7,11-triolC15H26O3254c[51]901β,6α-Dihydroxyeudesm-4(15)-eneC15H26O2238c[51]911α,6β-Dihydroxy-5,10-bis-epi-eudesm-15-carboxaldehyde-6-O-β-d-glucopyranosideC21H36O9433s[8]921β,4β,11-Trihydroxyl-6β-gorgonaneC15H28O3256c[51]93Cinnamosim BC15H24O4270c[51]94Cinnamosim AC15H24O3252c[51]951β,7-Dihydroxyl opposit-4(15)-eneC15H26O2238c[51]961β,11-Dihydroxyl opposit-4(15)-eneC15H26O2238c[51]97Guaiane4α-10α-Dihydroxy-5β-H-guaja-6-eneC15H26O2238c[51]98AlpinenoneC15H26O2238t[52]99α-BulneseneC15H24204c[53]100GuaiolC15H26O222g[10]101AromadendraneAromadendrane-4β,10α-diolC15H26O2238c[51]102Aromadendrane-4α,10α-diolC15H26O2238c[51]1031-Epimeraromadendrane-4β,10α-DiolC15H26O2238c[51]104EspatulenolC15H24O220c[14]105SpathulenolC15H24O220o[12]106(–)-IsoledeneC15H24204c[53]107Bisabolaneβ-BisaboleneC15H24204c[14]108α-BisabololC15H26O2238c[14]109CurcumeneC15H22202c, o[14]110GermacraneGermacrene DC15H28208c[47]111CedraneCedreneC15H24204c[20]112Others3S-(+)-9-OxonerolidolC16H26O234d[21]1132,6,11-Trimethyldodeca-2,6,10-trieneC15H26206q[54]114(+)-(6S,7E,9Z)-Abscisic esterC16H22O4278w[42]115GibberodioneC15H24O2236s[55]116(+)-Abscisic acidC15H20O4264b, s[56, 57]117Caryolane-1,9β-diolC15H26O2238c[46, 51]118Vlovane-2β,9α-diolC15H26O2238c[46]119Cinnamoid AC15H26O2238c[48, 49]120Cinnamoid DC15H24O2236c[48, 49]121Cinnamoid EC15H22O2234c[48, 49]122(-)-15-Hydroxy-T-muurololC15H22O2218c[13]123α-CubebeneC15H24204c[53]124α-CopaeneC15H24204c, o, z[11, 12]1251-(3-Indolyl)-2,3-dihydroxypropan-1-oneC15H26O2238c[43]126Patchouli alcoholC15H26O222c[53]Figure 2
The structures of sesquiterpenes fromCinnamomum.
(a)(b)There are 28 ionone sesquiterpenoids (44–71) among these constituents, which are the most abundant sesquiterpene skeletons from the genus Cinnamomum. Although ionone sesquiterpenes are common in natural products, this class of compounds from Cinnamomum has its special features, which are demonstrated as follows: (1) C-4 is connected to a hydroxyl group in some compounds, including 44–46, 48, 49, 51–53, 57, and 63. (2) The methyl group attached to C-5 is hydroxylated, such as compounds 47, 58–61, and 64. (3) The hydroxyl group of C-3 was removed in compound 51. (4) C-2 was connected to a hydroxyl group, such as compounds 51 and 68.Compounds72 and 73 belong to caryophyllane sesquiterpenes. Compounds 74 and 75 belong to humulane sesquiterpenes with an eleven-membered ring. Compounds 97–100 are guaiane sesquiterpenes, among which 98 was further cyclized on the basis of this structure and has exerted potent antitumor activity.Cadinane sesquiterpenes include compounds76–88. The methyl groups attached to the C-9 positions of 79 and 80 were degraded, and both of them are derived from C. subavenium. In compounds 81 and 82, which were isolated from C. cassia, the hydrogen at the C-10 position was hydroxylated. In addition, compounds 83–88 are common in the volatile oils of Cinnamomum plants.Eudesmane sesquiterpenes include compounds89–96. Compound 92 is a rearranged sesquiterpene, with its isopropanol group migrating from C-7 to C-6. Furthermore, 94–96 are also rearranged sesquiterpenes, with one carbon migrating to form a cyclopentane instead of cyclohexane. Interestingly, the compounds above were all derived from C. cassia.Compounds101–106 are aromadendrane sesquiterpenes. Furthermore, compounds 107–111 are the common components of the volatile oils in Cinnamomum plants. Among these, 107–109 are bisabolane sesquiterpenes, while 110 and 111 belong to germacrane and cedrane sesquiterpenes, respectively. Compound 117 is the result of the further cyclization based on the caryophyllane skeleton, and 118 was formed through the migration of one carbon atom based on the structure of 117.In 2014, Yan et al. separated cinnamonoid A (119) from C. cassia with an unprecedented skeleton, which may be derived from cadinane sesquiterpenes. The possible biosynthesis pathway of 119 was carried out by the cleavage of C-5 and C-6, followed by the construction of C-4 with C-6 and C-5 with C-10. Furthermore, compounds 120–122 are rearranged cadinane sesquiterpenes with the cleavage of C-9 and C-4.Some sesquiterpenoids were reported to show significant anti-inflammatory effects. Tung et al. confirmed that the essential oil ofC. osmophloeum twig exhibited a potent inhibition on NO production in LPS-stimulated RAW 264.7 macrophage cells. The anti-inflammatory effects of some constituents from essential oils were also evaluated. Compound 72 (54.0%) exhibited stronger inhibition activities than twig essential oil (48.3%) at the concentration of 10 μg/mL, while 117 exhibited an activity similar to that of twig essential oil, with inhibition rates of 46.1 and 50.9%, respectively [12]. In addition, Guoruoluo et al. evaluated some sesquiterpenoids for the antimicrobial activities. Compounds including 89, 90, 93–95, 97, 101, 102, and 117 showed significant antimicrobial activities against Candida albicans with inhibitory zone diameters ranging from 8 to 11 mm. Moreover, 90, 101, and 117 have exhibited moderate inhibitory effects on Escherichia coli and Staphylococcus aureus with inhibitory zone diameters ranging from 7 to 11 mm [51]. In another antibacterial assay, the activities of 79 and 80 against Candida glabrata were also evaluated, and the MIC values were 187.6 and 177.5, respectively [58].


### 2.3. Diterpenes

A total of 55 diterpenes were isolated fromCinnamomum plants (Table 3 and Figure 3). Most of these were derived from C. cassia (127–178), and 179 was derived from C. kotoense and C. philippinense. Nine new diterpene skeletons were found from this species, including ryanodane (cinncassiol B type), 11,12-seco-ryanodane (cinncassiol A type), 7,8-seco-ryanodane (cinncassiol C type), isoryanodane (cinncassiol D type), 10,13-cyclo-12,13-seco-isoryanodane (cinncassiol E type), 12,13-seco-isoryanodane (cinncassiol F type), 11,12-seco-isoryanodane (cinncassiol G type), 6,10-cyclo-12,13-seco-isoryanodane (cinnamomane), and 11,14-cyclo-8,14:12,13-di-seco-isoryanodane (cassiabudane).Table 3
Diterpenes from the genusCinnamomum.
No.TypeCompoundMolecular formulaMolecular weightReferences127Cinncassiol ACinncassiol AC20H30O7382[46, 49]128Cinncassiol A 19-O-β-d-glucopyranosideC26H40O12544[59, 60]129AnhydrocinnzeylanineC22H32O7408[49]130EpianhydrocinnzeylanolC20H30O6366[61]1311-Acetylcinncassiol AC22H32O8424[59]1322,3-DehydroanhydrocinnzeylanineC22H30O7406[59]133Cinncassiol HC20H30O7382[61]134Cinncassiol BCinnzeylanolC20H32O7384[61]135CinnzeylanineC22H34O8427[61]136Cinncassiol BC20H32O8400[46]137RyanodolC20H32O8400[46]138Ryanodol 14-monoacetateC22H34O9442[46]13918-HydroxycinnzeylanineC22H34O9442[59]140CinnzeylanoneC20H30O7382[46]141Cinncassiol CCinncassiol C1C26H38O12542[62]142Cinncassiol C1-19-O-β-d-glucopyranosideC20H28O7380[63]143Cinncassiol C2C20H28O6364[63]144Cinncassiol C3C20H30O7382[63]145Cinncassiol DCinncassiol D1C26H42O10515[64, 65]146Cinncassiol D1 glucosideC20H32O5352[64, 65]1471-Hydroxycinncassiol D1C20H32O6368[45]148Cinncassiol D2C20H32O6368[64]149Cinncassiol D2 glucosideC26H42O11531[64]150Cinncassiol D3C20H32O5352[64]151Cinncassiol D3-2-O-monoacetateC24H36O8452[46]152(18S)-3-Dehydroxycinncassiol D3C20H32O5352[45]153(18S)-3-Dehydroxycinncassiol D3 glucosideC26H42O10515[45]154(18S)-3,5-Didehydroxy-1,8-dihydroxy-cinncassiol D3C20H32O6368[45]155(18S)-3-Dehydroxy-8-hydroxy-cinncassiol D3C20H32O6368[45]156Cinncassiol D4C20H32O5352[66]157Cinncassiol D4 glucosideC26H42O10515[67]158Cinncassiol D4-2-O-monoacetateC22H34O6395[46]15918-HydroxyperseanolC20H32O8400[67, 68]160PerseanolC20H32O7384[67, 68]16116-O-β-d-Glucopyranosyl-perseanolC26H42O13563[45]16219-Dehydroxy-13-hydroxy-cinncassiol D1C20H32O6368[45]163(E)-3-Dehydroxy-13(18)-ene-19-O-β-d-glucopyranosyl-cinncassia D3C26H40O10513[45]164Cinncassiol ECinncassiol EC20H30O8398[67]165Cinncassiol FCinncassiol FC20H30O8398[67]166Cinncassiol GCinncassiol GC20H30O7382[67]16716-O-β-d-Glucopyranosyl-19-deoxycinncassiol GC26H40O12545[67]168Cinnamomol CC20H30O6366[45]169Cinnamomol DC20H30O5350[45]170Cinnamomol EC20H30O6366[45]171Cinnamomol FC17H24O4292[45]17213-O-β-d-Glucopyranosyl-cinnamomol FC23H34O9455[45]173CinnamomaneCinnamomol AC20H30O8398[68]174Cinnamomol BC20H30O9414[68]175CassiabudaneCassiabudanol AC21H32O8412[69]176Cassiabudanol BC20H30O8398[69]177OthersCinnacasolC20H30O7382[70]178CinnacasideC26H40O12545[70]179PhytolC20H40O297[54, 71]Figure 3
The structures of diterpenes fromCinnamomum.Among these nine skeletons, the representative compounds of the cinncassiol A-G types were127, 136, 141, 143–145, 148, 150, and 164–166. Furthermore, the typical constituents of cinnamomane-type diterpenes were 173 and 174, while those of cassiabudane-type diterpenes were 175 and 176.The biogenetic relationships of the nine diterpene skeletons were proposed by Zhou et al. (Figure4) [69]. Cinncassiol B type (134–140), that is, renolane-type diterpenes, is a 6/5/5/6/5 pentacyclic skeleton with a ketal structure. The two oxygen atoms connected to C-11 were, respectively, connected to hydrogen and C-6. In addition, cinncassiol A-type diterpenes (127–133) have a lactone skeleton produced by the cleavage of the bond between C-11 and C-12, and the formation of the carbon-oxygen double bond at C-11 in cinncassiol B-type diterpenes. The linkage between C-7 and C-8 was cleaved, and two carbonyl groups were formed at the two positions in the cinncassiol B type to produce a diketone skeleton, cinncassiol C type (141–144). Cinncassiol D-type diterpenes (145–163) are isorinolone diterpenes, which have a pentacyclic ring skeleton produced by the migration of the bond between C-5 and C-6 of cinncassiol B-type diterpenes to the C-1 position. Similarly, cinncassiol G-type diterpenes were formed by the migration of 5,6-bond to C-1 in cinncassiol A-type diterpenes.Figure 4
Biogenetic relationships of diterpene carbon skeletons fromCinnamomum.The possible biosynthetic pathway of cassiabudane diterpenes was proposed by Zhou et al. [69]. These were formed from 18-hydroxyperseanol (159), an isoryanodane diterpenoid, by the cleavage of the 12,13-bond and migration of the 14,8-bond to C-11 through a series of retro-aldol, aldol, and oxidation reactions.According to the research conducted by Zeng et al. [67], isoryanodane diterpenoid perseanol (160) is the plausible biosynthetic precursor of cinncassiol F (165) and cinncassiol G (166), and biosynthetic pathways have been proposed. These were, respectively, formed by the cleavage of the 12,13-bond and 11,12-bond from 160 through a series of reactions under the catalysis of acid. In addition, Zhou et al. [68] proposed that cinnamomane diterpenoids are also generated from perseanol (160) through a series of retro-aldol, aldol, and oxidation reactions.Some diterpenes ofCinnamomum have been reported to demonstrate immunomodulatory potency, covering immunostimulative and immunosuppressive activities.Zhou et al. reported that the cassiabudane diterpenes175 and 176 showed strong immunostimulative activity. Both of these significantly promoted the expansion of ConA-induced murine T cells with enhancement rates of 10.38 and 19.96%, respectively, at a dose of 0.3906 μM and enhanced the proliferation of LPS-induced murine B cells with enhancement rates of 52.13 and 55.06%, respectively, at the same dose [69]. In another assay conducted by Zhou et al., cinnamomane diterpenes 173 and 174 could promote the proliferation of ConA-induced murine T cells with enhancement rates of 59 and 64%, respectively, at the concentration of 0.3906 μM [68]. By comparing the results, we found that cinnamomane diterpenes exhibited stronger immunostimulative effects than cassiabudane diterpenes, showing that the 6,10-cyclo-12,13-seco-isoryanodane skeleton could probably promote the activity. In addition, a hydroxyl group connected to C-2 in cinnamomane diterpenes could enhance their immunostimulative activity and C-13 connecting to a hydroxyl group in cassiabudane diterpenes exerted stronger effect compared with connecting to a methoxy group.In the ConA/LPS-induced splenocyte proliferation assay conducted by Zeng et al., cinncassiol G (166) inhibited 94.5% of ConA-induced murine T-cell proliferation at a dose of 100 μM, showing strong immunosuppressive activity. More importantly, 166 and 177 exhibited significant inhibitory effects on T-cell proliferation even at 50 μM, with inhibition rates of 86.1% and 58.8%, respectively. It was also concluded that the 11,6-lactone moiety plays an important role in immunosuppressive activity, which accounts for the stronger inhibition of 166 compared to that of 177 [67]. According to the research by Zhou et al., some diterpenes, including 145, 152, 154, 168–170, 173, and 174, could significantly promote ConA-induced murine T-cell proliferation, with proliferation rates of up to 78% at five different concentrations (0.391 to 100 μM). When the concentration was lower than 25 μM, compounds 168 and 169 appeared to promote proliferation. However, these appeared to inhibit the growth at the concentration of 100 μM [45].In addition, some diterpenes have been reported to exert anti-inflammatory activities. He et al. reported that compounds127, 129, 130, 133, 134, and 135 had a good performance of inhibiting NO production, with IC50 values ranging from 72.3 to 81.8 μM [61].


### 2.4. Triterpenes

Two triterpenes were obtained from theCinnamomum genus, including squalene (180) from C. kotoense, C. philippinense, and C. subavenium, and oleanolic acid (181) from C. camphora (Table 4 and Figure 5).Table 4
Triterpenes from the genusCinnamomum.
No.CompoundMolecular formulaMolecular weightOriginReferences180SqualeneC30H50410k, q, s[54, 71]181Oleanolic acidC30H48O3456d[62]Figure 5
The structures of triterpenes fromCinnamomum.


## 2.1. Monoterpenes

A total of 43 monoterpenes have been reported fromCinnamomum (Table 1 and Figure 1), including 24 cyclic monoterpenes (1–17, 37–43) and 19 acyclic monoterpenes (18–36). Among these cyclic monoterpenes, compounds 1–13 are menthane monoterpenes, which are the most abundant types in the genus Cinnamomum. In addition, compounds 6–12 are the common constituents in the volatile oils of Cinnamomum plants. Compounds 14 and 15 are camphane monoterpenes and camphor (15), along with linalool (29) and eucalyptol (41), is one of the main components of volatile oil in C. camphora. Compounds 16 and 17 belong to the pinane-type monoterpenes, which are common in volatile oils. Monoterpenes 18–36 are laurane-type monoterpenes. Among these, compounds 18–24 have a geranylphenylacetate skeleton connected to glucose. Compounds 18–21, 23, and 24 were further cyclized to form a tetrahydrofuran ring. Interestingly, these compounds were only isolated from C. cassia and are the characteristic compounds for this species. Extracted from C. inunctum, compounds 25–27 were monoterpene lactones. Based on this structure, the original hydroxyl groups at the C-4 and C-7 positions of compound 27 were further cyclized to form a rare spironolactone structure. Obtained from C. camphora, compound 33 is an acyclic monoterpene with one carbon degraded and has shown strong anti-inflammatory activity. Compounds 37 and 38 are normonoterpenes from C. reticulatum, with one carbon degraded. Subamone (43), which was obtained from C. subavenium, has a cycloheptanone skeleton and has strong antitumor activity.Table 1
Monoterpenes from the genusCinnamomum.
No.TypeCompoundMolecular formulaMolecular weightOriginReferences1Menthane(3R,4R)-p-Menth-1-ene-3,4-diol 3-O-β-d-glucopyranosideC16H28O7332s[8]2(3R,4S,6R)-p-Menth-1-ene-3,6-diol 3-O-β-d -glucopyranosideC16H28O7332s[8]3(4R)-p-Menthane-1,2α,8-triolC10H20O3188s[8]4CarvacrolC10H14O150s[9]5ThymolC10H14O150s[9]6α-TerpineolC10H18O154c, d, g, o[10–12]7α-PhellandreneC10H16136d, g[10, 13]8α-TerpineneC10H16136d, g[10, 13]9p-CymeneC10H14134g[10]10TerpinoleneC10H16136d, g[10, 13]11Terpinen-4-olC10H18O154g[10]12LimoneneC10H16136g, z[10, 11]13(1R,2R,4S,6S)-4-(2-Hydroxypropan-2-yl)-1-methyl-7-oxabicy clo[4.1.0]heptan-2-olC10H18O3186c[14]14CamphaneBorneolC10H18O154c, g, z, o[10–12]15CamphorC10H16O152c, d, g[10, 13]16Pinaneα-PineneC10H16136d, g, z[10, 11]17β-PineneC10H16136c, d, g[10, 11]18LauraneCinnacasside AC25H36O11512c[15–17]19Cinnacasside BC25H36O11512c[15–17]20Cinnacasside CC25H36O11512c[15–17]21Cinnacasside DC25H36O11512c[15]22Cinnacasside EC25H38O11514c[15]23Cinnacasside FC26H40O12544c[17]24Cinnacasside GC26H40O12545c[17]255-(2,3-Dihydroxy-3-methylbutyl)-4-hydroxy-4-methyldihydrofuran-2(3H)-oneC10H18O5218i[18]265-(2,3-Dihydroxy-3-methylbutyl)-4-methylfuran-2(5H)-oneC10H16O4200i[18]278-Hydroxy-4,7,7-trimethyl-9-1,6-dioxaspiro[4.4]non-3-en-2-oneC10H14O4198i[18]28trans-Linalool-3,6-oxide-β-d-glucopyranosideC16H28O7332c[19]29LinaloolC10H18O154c, d[19, 20]303,7-Dimethyl-1-octene-3,6,7-triolC10H20O3188c[19]313,7-Dimethyl-oct-1-en-3,6,7-triol-6-O-β-d-glucopyranosideC16H30O8350c[19]32(6R)-Geraniol-6,7-diolC10H20O3188c[19]336-Hydroxy-6-methyl-4,7-octadien-2-oneC9H14O2154d[21]34β-OcimeneC10H16136d[13]35β-MyrceneC10H16136g[10]36Geranyl acetateC12H20O2196c[20]37NormonoterpenesReticuoneC9H14O3170r[22]38(3,3-Dimethylcyclohex-1-ene-1,4-diyl) dimethanolC15H26O7318c[14]39Othersα-ThujeneC10H16136d, g[10]40SabineneC10H16136d, g[10]41EucalyptolC10H18O154d, g[10, 13]42CampheneC10H16136c, d, g[13, 20]43SubamoneC10H16O2168s[23, 24]Note: b:C. burmannii; c: C. cassia; d: C. camphora; g: C. glanduliferum; i: C. inunctum; k: C. kotoense; o: C. osmophloeum; p: C. parthenoxylon; q: C. philippinense; r: C. reticulatum; s: C. subavenium; t: C. tenuifolium; w: C. wilsonii; z: C. zeylanicum. The same is given in Figure 1.Figure 1
The structures of monoterpenes fromCinnamomum.Some monoterpenes fromCinnamomum plants have shown potent antimicrobial activities. Carvacrol (4) showed a broad spectrum of antibacterial activity against both Gram-positive and Gram-negative bacteria [25]. The antimicrobial activity of compound 4 against numerous bacteria was studied and it showed a high inhibitory effect against all these strains, including Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumonia, Escherichia coli, Klebsiella pneumonia, Enterobacter spp., Serratia spp., and Proteus mirabilis [26]. Furthermore, 4 is also effective against various fungi, such as Aspergillus niger, Aspergillus flavus, Alternaria alternata, Penicillium rubrum, Trichoderma viride, Candida spp., and dermatophytes [27]. The antibacterial activity of compounds 4 and 9 (a precursor of 4) was studied against the foodborne microorganism V. cholerae. Compound 4 exerted a good inhibitory effect against V. cholerae, while 9 exhibited a weak activity. However, it was interesting to find that the inhibitory effects were enhanced when the two compounds were used together, showing a synergistic effect [28]. According to the findings both 16 and 29 exerted antibacterial activity against E. faecalis and S. aureus, and 16 showed antifungal activity against C. albicans. Similarly, compound 7 was effective against Ae. aegypti and Ae. albopictus [29], as well as Culex pipiens molestus [30].The antioxidant activities of some monoterpenes were evaluated. The assessment on antioxidant capacity of carvacrol (4) showed that 4 at the doses of 25 (49.79 IU/mg) and 50 mg/kg (52.43 IU/mg) enhanced the level of hippocampal SOD activity in ischemic rats, when compared with the ischemic group (42.9 IU/mg). In the DPPH assay, the percentage of oxidant inhibition was significantly increased in the ischemic group treated with 4 at doses of 25 (41.5%) and 50 mg/kg (36.83%), when compared to the untreated ischemic group (11.29%) [31]. Hakimi et al. confirmed that three doses of compound 4 (25, 50, and 100 mg/kg) could significantly increase the thiol content and improve the activities of both CAT and SOD compared with LPS groups in the hippocampus of rats [32]. In the trolox equivalent antioxidant capacity assay, the antioxidant effects of compounds 4 and 5 were evaluated and compared to that of the synthetic antioxidant trolox. Both compounds have exerted significant antioxidant activity similar to trolox, and the capacity of 4 has been proven to be higher than that of its isomer thymol at the same concentration [25]. Moreover, the antioxidant potential of p-cymene (9) was evaluated in the hippocampus of adult mice. The treatment with 9 at a concentration of 50 mg/kg (0.42 ± 0.03) has produced a significant decrease in lipid peroxidation 65.54%, when compared with the control group. Furthermore, compound 9 at all tested doses (50, 100, and 150 mg/kg) could significantly decrease the nitrite content and produce an increase in SOD and catalase activities [33].Some monoterpenes were reported to show significant anti-inflammatory effects. Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme in prostaglandin biosynthesis, which plays a key role in inflammation. In human macrophage-like U937 cells, compound4 was shown to suppress the LPS-induced expression of COX-2 and activate the peroxisome proliferator-activated receptors (PPAR) α and γ [34]. Furthermore, 4 could also inhibit the production and actions of NO [25]. Moreover, NF-κB has been reported to play an important role in the inflammatory response and LPS/GalN-induced liver injury [35]. The effects of linalool (29) on NF-κB expression were assessed, and it was found that 29 could significantly inhibit LPS-induced p65 NF-κB translocation into the nucleus and IκBα degradation. In addition to the NF-κB inhibition, compound 29 could also induce antioxidant defense via Nrf2 activating and consequently protect against LPS/GalN-induced liver injury [36]. Other than this, another study demonstrated that 29 protected against CS-induced lung inflammation through inhibiting CS-induced NF-κB activation [37].The anticancer activity of linalool (29) against human prostate cancer (DU145) cells was evaluated by the MTT assay and it was observed that 4.36%, 11.54%, 21.88%, and 15.54% of the cells underwent early apoptosis after treatment with 0, 20, 40, and 80 μM of 29, respectively [38]. In addition, Okumura et al. confirmed that terpinolene (10) could markedly reduce the expression of protein kinase AKT, which can mediate cell proliferation and survival signals, and contribute to cancer progression [39].In an immunosuppression assay, Zeng et al. found that monoterpenes18, 19, and 23 exhibited potent immunosuppressive activities against murine lymphocytes. Compound 23 inhibited the proliferation of T cells and B cells with an inhibitory ratio of 36.1% and 20.3%, respectively, at a concentration of 400 μM [17]. In another assay, the effect of α-terpineol (6) on the generation of nitric oxide in macrophages induced by LPS was evaluated. The nitrite production induced by LPS in these cells was reduced at all concentrations of compound 4 tested (1, 10, and 100 μg/mL) [40]. Rufino et al. reported that α-pinene (16) could decrease NO production in a dose-dependent manner in primary human chondrocytes, showing the highest inhibition of NO production at a dose of 200 μg/mL, with a decrease to 31.5% relative to cells treated with IL-1β alone [41].


## 2.2. Sesquiterpenes

A total of 83 sesquiterpenoids (44–126) were isolated from Cinnamomum plants, which contain multiple structural types (Table 2 and Figure 2).Table 2
Sesquiterpenes from the genusCinnamomum.
No.TypeCompoundMolecular formulaMolecular weightOriginReferences44InoneWilsonol AC13H24O4244w[42]45Wilsonol BC13H24O4244w[42]46Wilsonol CC13H22O4242w[42]47Wilsonol DC13H24O3228w[42]48(3S,4S,5S,6S,9S)-Wilsonol EC13H26O3230w[42]49(3S,4S,5S,6S,9R)-Wilsonol EC13H26O3230w[42]50Wilsonol FC13H26O3230w[42]51Wilsonol GC13H24O4244s, w[8, 42]52(3S,4S,5S,6S,9S)-3,4-Dihydroxy-5,6-dihydro-β-ionolC13H24O3228w[42]53Lasianthionoside AC19H32O9404w[42]54BoscialinC13H22O3226c[43]55(3S,5R,6S,7E)-Megasfigma-7-ene-3,5,6,9-tetrolC13H24O4244s, w[8, 42]56(3S,5S,6S,9R)-3,6-Dihydroxy-5,6-dihydro-β-ionolC13H24O3228w[42]57Wilsonol HC13H24O5260s, w[8]58Wilsonol IC13H24O3228w[42]59Wilsonol JC13H24O3228w[42]60Wilsonol KC13H22O3226w[42]61Wilsonol LC13H22O3226w[42]62(3R,9S)-Megastigman-5-ene-3,9-diol 3-O-β-d-glucopyranosideC19H34O7374w[42]63(3S,4R,9R)-3,4,9-Trihydroxymegastigman-5-eneC13H24O3228w[42]64Apocynol AC13H20O3224w[42]65Blumenol AC13H20O3224c, p[43, 44]66DehydrovomifoliolC13H18O3222c[43]67(3S,5R,6S,9S)-3,6,9-Trihydroxymegastigman-7-ene 3-O-β-d-glucopyranosideC19H34O8390c[19]68(1R,2R)-4-[(3S)-3-Hydroxybutyl]-3,3,5-trimethylcyclohex-4-ene-1,2-diolC13H24O3228c[45]69(3S,5R,6S,7E)-3,5,6-Trihydroxy-7-megastigmen-9-oneC13H22O4242c[46]70Grasshopper ketoneC13H20O3224c[43]71Asicariside B1C18H30O8374s[8]72CaryophyllaneCaryophyllene oxideC15H24O220o, s[9, 16]73trans-CaryophylleneC15H24204c[47]74Humulane(2E,9E)-6,7-cis-Dihydroxyhumulan-2,9-dieneC15H26O2238c[46]75α-HumuleneC15H24204g[10]76CadinaneCinnamoid BC15H24O3252c[48, 49]77Cinnamoid CC15H24O3252c[48, 49]78MustakoneC15H24O3252c[46]79Oxyphyllenodiol AC14H22O3238s[50]80Oxyphyllenodiol BC14H22O3238s[50]81(-)-15-HydroxytmuurololC15H26O2238c[49]8215-Hydroxy-α-cadinolC15H26O2238c[49]83β-CadineneC15H24204z[11]84δ-CadineneC15H24204c, d, o, z[10–13]85α-MuuroleneC15H24204c, d[14]86α-CadinolC15H26O222c, d[14]87α-CalacoreneC15H20200c, o, z[11, 12]88CalameneneC15H22202z[11]89Eudesmane4(15)-Eudesmene-1β,7,11-triolC15H26O3254c[51]901β,6α-Dihydroxyeudesm-4(15)-eneC15H26O2238c[51]911α,6β-Dihydroxy-5,10-bis-epi-eudesm-15-carboxaldehyde-6-O-β-d-glucopyranosideC21H36O9433s[8]921β,4β,11-Trihydroxyl-6β-gorgonaneC15H28O3256c[51]93Cinnamosim BC15H24O4270c[51]94Cinnamosim AC15H24O3252c[51]951β,7-Dihydroxyl opposit-4(15)-eneC15H26O2238c[51]961β,11-Dihydroxyl opposit-4(15)-eneC15H26O2238c[51]97Guaiane4α-10α-Dihydroxy-5β-H-guaja-6-eneC15H26O2238c[51]98AlpinenoneC15H26O2238t[52]99α-BulneseneC15H24204c[53]100GuaiolC15H26O222g[10]101AromadendraneAromadendrane-4β,10α-diolC15H26O2238c[51]102Aromadendrane-4α,10α-diolC15H26O2238c[51]1031-Epimeraromadendrane-4β,10α-DiolC15H26O2238c[51]104EspatulenolC15H24O220c[14]105SpathulenolC15H24O220o[12]106(–)-IsoledeneC15H24204c[53]107Bisabolaneβ-BisaboleneC15H24204c[14]108α-BisabololC15H26O2238c[14]109CurcumeneC15H22202c, o[14]110GermacraneGermacrene DC15H28208c[47]111CedraneCedreneC15H24204c[20]112Others3S-(+)-9-OxonerolidolC16H26O234d[21]1132,6,11-Trimethyldodeca-2,6,10-trieneC15H26206q[54]114(+)-(6S,7E,9Z)-Abscisic esterC16H22O4278w[42]115GibberodioneC15H24O2236s[55]116(+)-Abscisic acidC15H20O4264b, s[56, 57]117Caryolane-1,9β-diolC15H26O2238c[46, 51]118Vlovane-2β,9α-diolC15H26O2238c[46]119Cinnamoid AC15H26O2238c[48, 49]120Cinnamoid DC15H24O2236c[48, 49]121Cinnamoid EC15H22O2234c[48, 49]122(-)-15-Hydroxy-T-muurololC15H22O2218c[13]123α-CubebeneC15H24204c[53]124α-CopaeneC15H24204c, o, z[11, 12]1251-(3-Indolyl)-2,3-dihydroxypropan-1-oneC15H26O2238c[43]126Patchouli alcoholC15H26O222c[53]Figure 2
The structures of sesquiterpenes fromCinnamomum.
(a)(b)There are 28 ionone sesquiterpenoids (44–71) among these constituents, which are the most abundant sesquiterpene skeletons from the genus Cinnamomum. Although ionone sesquiterpenes are common in natural products, this class of compounds from Cinnamomum has its special features, which are demonstrated as follows: (1) C-4 is connected to a hydroxyl group in some compounds, including 44–46, 48, 49, 51–53, 57, and 63. (2) The methyl group attached to C-5 is hydroxylated, such as compounds 47, 58–61, and 64. (3) The hydroxyl group of C-3 was removed in compound 51. (4) C-2 was connected to a hydroxyl group, such as compounds 51 and 68.Compounds72 and 73 belong to caryophyllane sesquiterpenes. Compounds 74 and 75 belong to humulane sesquiterpenes with an eleven-membered ring. Compounds 97–100 are guaiane sesquiterpenes, among which 98 was further cyclized on the basis of this structure and has exerted potent antitumor activity.Cadinane sesquiterpenes include compounds76–88. The methyl groups attached to the C-9 positions of 79 and 80 were degraded, and both of them are derived from C. subavenium. In compounds 81 and 82, which were isolated from C. cassia, the hydrogen at the C-10 position was hydroxylated. In addition, compounds 83–88 are common in the volatile oils of Cinnamomum plants.Eudesmane sesquiterpenes include compounds89–96. Compound 92 is a rearranged sesquiterpene, with its isopropanol group migrating from C-7 to C-6. Furthermore, 94–96 are also rearranged sesquiterpenes, with one carbon migrating to form a cyclopentane instead of cyclohexane. Interestingly, the compounds above were all derived from C. cassia.Compounds101–106 are aromadendrane sesquiterpenes. Furthermore, compounds 107–111 are the common components of the volatile oils in Cinnamomum plants. Among these, 107–109 are bisabolane sesquiterpenes, while 110 and 111 belong to germacrane and cedrane sesquiterpenes, respectively. Compound 117 is the result of the further cyclization based on the caryophyllane skeleton, and 118 was formed through the migration of one carbon atom based on the structure of 117.In 2014, Yan et al. separated cinnamonoid A (119) from C. cassia with an unprecedented skeleton, which may be derived from cadinane sesquiterpenes. The possible biosynthesis pathway of 119 was carried out by the cleavage of C-5 and C-6, followed by the construction of C-4 with C-6 and C-5 with C-10. Furthermore, compounds 120–122 are rearranged cadinane sesquiterpenes with the cleavage of C-9 and C-4.Some sesquiterpenoids were reported to show significant anti-inflammatory effects. Tung et al. confirmed that the essential oil ofC. osmophloeum twig exhibited a potent inhibition on NO production in LPS-stimulated RAW 264.7 macrophage cells. The anti-inflammatory effects of some constituents from essential oils were also evaluated. Compound 72 (54.0%) exhibited stronger inhibition activities than twig essential oil (48.3%) at the concentration of 10 μg/mL, while 117 exhibited an activity similar to that of twig essential oil, with inhibition rates of 46.1 and 50.9%, respectively [12]. In addition, Guoruoluo et al. evaluated some sesquiterpenoids for the antimicrobial activities. Compounds including 89, 90, 93–95, 97, 101, 102, and 117 showed significant antimicrobial activities against Candida albicans with inhibitory zone diameters ranging from 8 to 11 mm. Moreover, 90, 101, and 117 have exhibited moderate inhibitory effects on Escherichia coli and Staphylococcus aureus with inhibitory zone diameters ranging from 7 to 11 mm [51]. In another antibacterial assay, the activities of 79 and 80 against Candida glabrata were also evaluated, and the MIC values were 187.6 and 177.5, respectively [58].


## 2.3. Diterpenes

A total of 55 diterpenes were isolated fromCinnamomum plants (Table 3 and Figure 3). Most of these were derived from C. cassia (127–178), and 179 was derived from C. kotoense and C. philippinense. Nine new diterpene skeletons were found from this species, including ryanodane (cinncassiol B type), 11,12-seco-ryanodane (cinncassiol A type), 7,8-seco-ryanodane (cinncassiol C type), isoryanodane (cinncassiol D type), 10,13-cyclo-12,13-seco-isoryanodane (cinncassiol E type), 12,13-seco-isoryanodane (cinncassiol F type), 11,12-seco-isoryanodane (cinncassiol G type), 6,10-cyclo-12,13-seco-isoryanodane (cinnamomane), and 11,14-cyclo-8,14:12,13-di-seco-isoryanodane (cassiabudane).Table 3
Diterpenes from the genusCinnamomum.
No.TypeCompoundMolecular formulaMolecular weightReferences127Cinncassiol ACinncassiol AC20H30O7382[46, 49]128Cinncassiol A 19-O-β-d-glucopyranosideC26H40O12544[59, 60]129AnhydrocinnzeylanineC22H32O7408[49]130EpianhydrocinnzeylanolC20H30O6366[61]1311-Acetylcinncassiol AC22H32O8424[59]1322,3-DehydroanhydrocinnzeylanineC22H30O7406[59]133Cinncassiol HC20H30O7382[61]134Cinncassiol BCinnzeylanolC20H32O7384[61]135CinnzeylanineC22H34O8427[61]136Cinncassiol BC20H32O8400[46]137RyanodolC20H32O8400[46]138Ryanodol 14-monoacetateC22H34O9442[46]13918-HydroxycinnzeylanineC22H34O9442[59]140CinnzeylanoneC20H30O7382[46]141Cinncassiol CCinncassiol C1C26H38O12542[62]142Cinncassiol C1-19-O-β-d-glucopyranosideC20H28O7380[63]143Cinncassiol C2C20H28O6364[63]144Cinncassiol C3C20H30O7382[63]145Cinncassiol DCinncassiol D1C26H42O10515[64, 65]146Cinncassiol D1 glucosideC20H32O5352[64, 65]1471-Hydroxycinncassiol D1C20H32O6368[45]148Cinncassiol D2C20H32O6368[64]149Cinncassiol D2 glucosideC26H42O11531[64]150Cinncassiol D3C20H32O5352[64]151Cinncassiol D3-2-O-monoacetateC24H36O8452[46]152(18S)-3-Dehydroxycinncassiol D3C20H32O5352[45]153(18S)-3-Dehydroxycinncassiol D3 glucosideC26H42O10515[45]154(18S)-3,5-Didehydroxy-1,8-dihydroxy-cinncassiol D3C20H32O6368[45]155(18S)-3-Dehydroxy-8-hydroxy-cinncassiol D3C20H32O6368[45]156Cinncassiol D4C20H32O5352[66]157Cinncassiol D4 glucosideC26H42O10515[67]158Cinncassiol D4-2-O-monoacetateC22H34O6395[46]15918-HydroxyperseanolC20H32O8400[67, 68]160PerseanolC20H32O7384[67, 68]16116-O-β-d-Glucopyranosyl-perseanolC26H42O13563[45]16219-Dehydroxy-13-hydroxy-cinncassiol D1C20H32O6368[45]163(E)-3-Dehydroxy-13(18)-ene-19-O-β-d-glucopyranosyl-cinncassia D3C26H40O10513[45]164Cinncassiol ECinncassiol EC20H30O8398[67]165Cinncassiol FCinncassiol FC20H30O8398[67]166Cinncassiol GCinncassiol GC20H30O7382[67]16716-O-β-d-Glucopyranosyl-19-deoxycinncassiol GC26H40O12545[67]168Cinnamomol CC20H30O6366[45]169Cinnamomol DC20H30O5350[45]170Cinnamomol EC20H30O6366[45]171Cinnamomol FC17H24O4292[45]17213-O-β-d-Glucopyranosyl-cinnamomol FC23H34O9455[45]173CinnamomaneCinnamomol AC20H30O8398[68]174Cinnamomol BC20H30O9414[68]175CassiabudaneCassiabudanol AC21H32O8412[69]176Cassiabudanol BC20H30O8398[69]177OthersCinnacasolC20H30O7382[70]178CinnacasideC26H40O12545[70]179PhytolC20H40O297[54, 71]Figure 3
The structures of diterpenes fromCinnamomum.Among these nine skeletons, the representative compounds of the cinncassiol A-G types were127, 136, 141, 143–145, 148, 150, and 164–166. Furthermore, the typical constituents of cinnamomane-type diterpenes were 173 and 174, while those of cassiabudane-type diterpenes were 175 and 176.The biogenetic relationships of the nine diterpene skeletons were proposed by Zhou et al. (Figure4) [69]. Cinncassiol B type (134–140), that is, renolane-type diterpenes, is a 6/5/5/6/5 pentacyclic skeleton with a ketal structure. The two oxygen atoms connected to C-11 were, respectively, connected to hydrogen and C-6. In addition, cinncassiol A-type diterpenes (127–133) have a lactone skeleton produced by the cleavage of the bond between C-11 and C-12, and the formation of the carbon-oxygen double bond at C-11 in cinncassiol B-type diterpenes. The linkage between C-7 and C-8 was cleaved, and two carbonyl groups were formed at the two positions in the cinncassiol B type to produce a diketone skeleton, cinncassiol C type (141–144). Cinncassiol D-type diterpenes (145–163) are isorinolone diterpenes, which have a pentacyclic ring skeleton produced by the migration of the bond between C-5 and C-6 of cinncassiol B-type diterpenes to the C-1 position. Similarly, cinncassiol G-type diterpenes were formed by the migration of 5,6-bond to C-1 in cinncassiol A-type diterpenes.Figure 4
Biogenetic relationships of diterpene carbon skeletons fromCinnamomum.The possible biosynthetic pathway of cassiabudane diterpenes was proposed by Zhou et al. [69]. These were formed from 18-hydroxyperseanol (159), an isoryanodane diterpenoid, by the cleavage of the 12,13-bond and migration of the 14,8-bond to C-11 through a series of retro-aldol, aldol, and oxidation reactions.According to the research conducted by Zeng et al. [67], isoryanodane diterpenoid perseanol (160) is the plausible biosynthetic precursor of cinncassiol F (165) and cinncassiol G (166), and biosynthetic pathways have been proposed. These were, respectively, formed by the cleavage of the 12,13-bond and 11,12-bond from 160 through a series of reactions under the catalysis of acid. In addition, Zhou et al. [68] proposed that cinnamomane diterpenoids are also generated from perseanol (160) through a series of retro-aldol, aldol, and oxidation reactions.Some diterpenes ofCinnamomum have been reported to demonstrate immunomodulatory potency, covering immunostimulative and immunosuppressive activities.Zhou et al. reported that the cassiabudane diterpenes175 and 176 showed strong immunostimulative activity. Both of these significantly promoted the expansion of ConA-induced murine T cells with enhancement rates of 10.38 and 19.96%, respectively, at a dose of 0.3906 μM and enhanced the proliferation of LPS-induced murine B cells with enhancement rates of 52.13 and 55.06%, respectively, at the same dose [69]. In another assay conducted by Zhou et al., cinnamomane diterpenes 173 and 174 could promote the proliferation of ConA-induced murine T cells with enhancement rates of 59 and 64%, respectively, at the concentration of 0.3906 μM [68]. By comparing the results, we found that cinnamomane diterpenes exhibited stronger immunostimulative effects than cassiabudane diterpenes, showing that the 6,10-cyclo-12,13-seco-isoryanodane skeleton could probably promote the activity. In addition, a hydroxyl group connected to C-2 in cinnamomane diterpenes could enhance their immunostimulative activity and C-13 connecting to a hydroxyl group in cassiabudane diterpenes exerted stronger effect compared with connecting to a methoxy group.In the ConA/LPS-induced splenocyte proliferation assay conducted by Zeng et al., cinncassiol G (166) inhibited 94.5% of ConA-induced murine T-cell proliferation at a dose of 100 μM, showing strong immunosuppressive activity. More importantly, 166 and 177 exhibited significant inhibitory effects on T-cell proliferation even at 50 μM, with inhibition rates of 86.1% and 58.8%, respectively. It was also concluded that the 11,6-lactone moiety plays an important role in immunosuppressive activity, which accounts for the stronger inhibition of 166 compared to that of 177 [67]. According to the research by Zhou et al., some diterpenes, including 145, 152, 154, 168–170, 173, and 174, could significantly promote ConA-induced murine T-cell proliferation, with proliferation rates of up to 78% at five different concentrations (0.391 to 100 μM). When the concentration was lower than 25 μM, compounds 168 and 169 appeared to promote proliferation. However, these appeared to inhibit the growth at the concentration of 100 μM [45].In addition, some diterpenes have been reported to exert anti-inflammatory activities. He et al. reported that compounds127, 129, 130, 133, 134, and 135 had a good performance of inhibiting NO production, with IC50 values ranging from 72.3 to 81.8 μM [61].


## 2.4. Triterpenes

Two triterpenes were obtained from theCinnamomum genus, including squalene (180) from C. kotoense, C. philippinense, and C. subavenium, and oleanolic acid (181) from C. camphora (Table 4 and Figure 5).Table 4
Triterpenes from the genusCinnamomum.
No.CompoundMolecular formulaMolecular weightOriginReferences180SqualeneC30H50410k, q, s[54, 71]181Oleanolic acidC30H48O3456d[62]Figure 5
The structures of triterpenes fromCinnamomum.


## 3. Conclusion

The medicinal value of the genusCinnamomum has attracted much attention around the world, and many studies have been conducted. Most importantly, terpenes are the most abundant in the genus Cinnamomum, with various novel skeletons and significant biological activities, including immunomodulatory, anti-inflammatory, antimicrobial, antioxidant, and anticancer activities. In the present review, the research progress on chemical structures and biological effects of terpenes from Cinnamomum has been summarized. This can not only increase the understanding of the genus Cinnamomum, but also promote the better use of plants and further development of new drugs. Nevertheless, research on Cinnamomum remains incomplete, and more investigations are needed in the future.First, chemical research onCinnamomum plants has focused on only a few species like C. cassia and C. subavenium. Some other plants have gradually become research hotspots, but are only limited to the study of volatile oils. Cinnamomum plants have great economic and medicinal value and need to be further explored in future studies. Second, the diterpenes from Cinnamomum have shown significant immunomodulatory activities according to the findings. However, this only stays in the stage of cell activity in vitro. Thus, further pharmaceutical and in vivo activity experiments can be performed to promote the development of new drugs.



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*Source: 5097542-2020-07-14.xml*