Caryophyllene

Caryophyllene

Names
Preferred IUPAC name (1R,4E,9S)-4,11,11-Trimethyl-8-methylidenebicyclo[7.2.0]undec-4-ene
Other names β-Caryophyllene trans-(1R,9S)-8-Methylene-4,11,11-trimethylbicyclo[7.2.0]undec-4-ene
Identifiers
CAS Number	87-44-5^Y
3D model (JSmol)	Interactive image
ChEBI	CHEBI:10357^Y
ChEMBL	ChEMBL445740^Y
ChemSpider	4444848^Y
DrugBank	DB16854
ECHA InfoCard	100.001.588
EC Number	201-746-1
KEGG	C09629
PubChem CID	5281515
UNII	BHW853AU9H^Y
CompTox Dashboard (EPA)	DTXSID8024739
InChI InChI=1S/C15H24/c1-11-6-5-7-12(2)13-10-15(3,4)14(13)9-8-11/h6,13-14H,2,5,7-10H2,1,3-4H3/b11-6+/t13-,14-/m1/s1^Y Key: NPNUFJAVOOONJE-GFUGXAQUSA-N^Y InChI=1/C15H24/c1-11-6-5-7-12(2)13-10-15(3,4)14(13)9-8-11/h6,13-14H,2,5,7-10H2,1,3-4H3/b11-6+/t13-,14-/m1/s1 Key: NPNUFJAVOOONJE-GFUGXAQUBC
SMILES C1(=C)\CC/C=C(/CC[C@@H]2[C@@H]1CC2(C)C)C
Properties
Chemical formula	C15H24
Molar mass	204.357 g·mol^−1
Density	0.9052 g/cm^3 (17 °C)[1]
Boiling point	262–264 °C (504–507 °F; 535–537 K)[2]
Hazards
GHS labelling:[1]
Pictograms
Signal word	Warning
Hazard statements	H304, H317
Precautionary statements	P261, P272, P280, P301+P316, P302+P352, P321, P331, P333+P317, P362+P364, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Y verify (what is ^YN ?) Infobox references

Caryophyllene (/ˌkærioʊˈfɪliːn/), more formally (−)-β-caryophyllene (BCP), is a natural bicyclic sesquiterpene that occurs widely in nature. Caryophyllene is notable for having a cyclobutane ring, as well as a trans-double bond in a 9-membered ring, both rarities in nature. ^[3]

Production

Caryophyllene can be produced synthetically,^[4] but it is invariably obtained from natural sources because it is widespread. It is a constituent of many essential oils, especially clove oil, the oil from the stems and flowers of Syzygium aromaticum (cloves), the essential oil of Cannabis sativa, copaiba, rosemary, and hops.^[3] It is usually found as a mixture with isocaryophyllene (the cis double bond isomer) and α-humulene (obsolete name: α-caryophyllene), a ring-opened isomer.

Caryophyllene is one of the chemical compounds that contributes to the aroma of black pepper.^[5]

Basic research

β-Caryophyllene is under basic research for its potential action as an agonist of the cannabinoid receptor type 2 (CB₂ receptor).^[6] In other basic studies, β-caryophyllene has a binding affinity of K_i = 155 nM at the CB₂ receptors.^[7]

β-Caryophyllene has the highest cannabinoid activity compared to the ring opened isomer α-caryophyllene humulene which may modulate CB₂ activity.^[8] To compare binding, cannabinol binds to the CB₂ receptors as a partial agonist with an affinity of K_i = 126.4 nM,^[9] while delta-9-tetrahydrocannabinol binds to the CB₂ receptors as a partial agonist with an affinity of K_i = 36 nM.^[10]

Safety

Caryophyllene has been given generally recognized as safe (GRAS) designation by the FDA and is approved by the FDA for use as a food additive, typically for flavoring.^[11][12] Rats given up to 700 mg/kg daily for 90 days did not produce any significant toxic effects.^[13] Caryophyllene has an LD₅₀ of 5,000 mg/kg in mice.^[14][15]

Metabolism and derivatives

14-Hydroxycaryophyllene oxide (C₁₅H₂₄O₂) was isolated from the urine of rabbits treated with (−)-caryophyllene (C₁₅H₂₄). The X-ray crystal structure of 14-hydroxycaryophyllene (as its acetate derivative) has been reported.^[16]

The metabolism of caryophyllene progresses through (−)-caryophyllene oxide (C₁₅H₂₄O) since the latter compound also afforded 14-hydroxycaryophyllene (C₁₅H₂₄O) as a metabolite.^[17]

Caryophyllene (C₁₅H₂₄) → caryophyllene oxide (C₁₅H₂₄O) → 14-hydroxycaryophyllene (C₁₅H₂₄O) → 14-hydroxycaryophyllene oxide (C₁₅H₂₄O₂).

Caryophyllene oxide,^[18] in which the alkene group of caryophyllene has become an epoxide, is the component responsible for cannabis identification by drug-sniffing dogs^[19][20] and is also an approved food additive, often as flavoring.^[12] Caryophyllene oxide may have negligible cannabinoid activity.^[21]

Natural sources

The approximate quantity of caryophyllene in the essential oil of each source is given in square brackets ([ ]):

• Cannabis (Cannabis sativa) [3.8–37.5% of cannabis flower essential oil]^[22]
• Black caraway (Carum nigrum) [7.8%]^[23]
• Cloves (Syzygium aromaticum) [1.7–19.5% of clove bud essential oil]^[24]
• Hops (Humulus lupulus)^[25] [5.1–14.5%]^[26]
• Basil (Ocimum spp.)^[27] [5.3–10.5% O. gratissimum; 4.0–19.8% O. micranthum]^[28]
• Oregano (Origanum vulgare)^[29] [4.9–15.7%]^[30][31]
• Black pepper (Piper nigrum) [7.29%]^[5]
• Lavender (Lavandula angustifolia) [4.62–7.55% of lavender oil]^[32][33]
• Rosemary (Rosmarinus officinalis)^[34] [0.1–8.3%]^{[citation needed]}
• True cinnamon (Cinnamomum verum) [6.9–11.1%]^[35]
• Malabathrum (Cinnamomum tamala) [25.3%]^[36]
• Ylang-ylang (Cananga odorata) [3.1–10.7%]
• Copaiba oil (Copaifera)^[37][38]

Biosynthesis

Caryophyllene is a common sesquiterpene among plant species. It is biosynthesized from the common terpene precursors dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP). First, single units of DMAPP and IPP are reacted via an S_N1-type reaction with the loss of pyrophosphate, catalyzed by the enzyme GPPS2, to form geranyl pyrophosphate (GPP). This further reacts with a second unit of IPP, also via an S_N1-type reaction catalyzed by the enzyme IspA, to form farnesyl pyrophosphate (FPP). Finally, FPP undergoes QHS1 enzyme-catalyzed intramolecular cyclization to form caryophyllene.^[39]

Biosynthesis of caryophyllene

Compendial status

• Food Chemicals Codex^[40][41]

Further reading

• Ghelardini, C.; Galeotti, N.; Di Cesare Mannelli, L.; Mazzanti, G.; Bartolini, A. (2001). "Local anaesthetic activity of beta-caryophyllene". Farmaco. 56 (5–7): 387–389. doi:10.1016/S0014-827X(01)01092-8. hdl:2158/397975. PMID 11482764.

Notes and references

1. SciFinder Record, CAS Registry Number 87-44-5
2. Baker, R. R. (2004). "The pyrolysis of tobacco ingredients". Journal of Analytical and Applied Pyrolysis. 71 (1): 223–311. Bibcode:2004JAAP...71..223B. doi:10.1016/s0165-2370(03)00090-1.
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4. Corey, E. J.; Mitra, R. B.; Uda, H. (1964). "Total Synthesis of d,l-Caryophyllene and d,l-Isocaryophyllene". Journal of the American Chemical Society. 86 (3): 485–492. Bibcode:1964JAChS..86..485C. doi:10.1021/ja01057a040.
5. Jirovetz, L.; Buchbauer, G.; Ngassoum, M. B.; Geissler, M. (November 2002). "Aroma compound analysis of Piper nigrum and Piper guineense essential oils from Cameroon using solid-phase microextraction–gas chromatography, solid-phase microextraction–gas chromatography–mass spectrometry and olfactometry". Journal of Chromatography A. 976 (1–2): 265–275. doi:10.1016/S0021-9673(02)00376-X. PMID 12462618.
6. Ceccarelli, Ilaria; Fiorenzani, Paolo; Pessina, Federica; Pinassi, Jessica; Aglianò, Margherita; Miragliotta, Vincenzo; Aloisi, Anna Maria (18 August 2020). "The CB2 Agonist β-Caryophyllene in Male and Female Rats Exposed to a Model of Persistent Inflammatory Pain". Frontiers in Neuroscience. 14: 850. doi:10.3389/fnins.2020.00850. PMC 7461959. PMID 33013287.
7. Alberti, Thaís Barbosa; Barbosa, Wagner Luiz Ramos; Vieira, José Luiz Fernandes; Raposo, Nádia Rezende Barbosa; Dutra, Rafael Cypriano (1 April 2017). "(−)-β-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis". International Journal of Molecular Sciences. 18 (4): 691. doi:10.3390/ijms18040691. PMC 5412277. PMID 28368293.
8. Hashiesh, Hebaallah Mamdouh; Sharma, Charu; Goyal, Sameer N.; Sadek, Bassem; Jha, Niraj Kumar; Kaabi, Juma Al; Ojha, Shreesh (1 August 2021). "A focused review on CB2 receptor-selective pharmacological properties and therapeutic potential of β-caryophyllene, a dietary cannabinoid". Biomedicine & Pharmacotherapy. 140: 111639. doi:10.1016/j.biopha.2021.111639. PMID 34091179. S2CID 235362290.
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    •  • Adams, T.B.; Gavin, C. Lucas; McGowen, M.M.; Waddell, W.J.; Cohen, S.M.; Feron, V.J.; Marnett, L.J.; Munro, I.C.; Portoghese, P.S.; Rietjens, I.M.C.M.; Smith, R.L. (2011). "The FEMA GRAS assessment of aliphatic and aromatic terpene hydrocarbons used as flavor ingredients". Food and Chemical Toxicology. 49 (10). Elsevier BV: 2471–2494. doi:10.1016/j.fct.2011.06.011. ISSN 0278-6915. PMID 21726592. S2CID 207734236.
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