Chemistry:Thujaplicin

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Thujaplicin
Alpha-thujaplicin tautomers.png
α-Thujaplicin
Beta-thujaplicin tautomers.png
β-Thujaplicin (hinokitiol)
Gamma-thujaplicin tautomers.png
γ-Thujaplicin
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
EC Number
  • β: 207-880-7
UNII
Properties
C10H12O2
Molar mass 164.204 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references
Tracking categories (test):

Thujaplicins (isopropyl cycloheptatrienolones) are a series of tropolone-related chemical substances that have been isolated from the softwoods of the trees of Cupressaceae family.[1] These compounds are known for their antibacterial, antifungal, and antioxidant properties.[2][3] They were the first natural tropolones to be made synthetically.[4]

History

Thuja plicata Donn ex D. Don (Western red cedar) – a tree belonging to the Cupressaceae family from which thujaplicins were first purified

Thujaplicins were discovered in the mid-1930s and purified from the heartwood of Thuja plicata Donn ex D. Don, commonly called as Western red cedar tree.[5] These compounds were also identified in the constituents of Chamaecyparis obtusa, another species from the Cupressaceae family. C. obtusa is native to East Asian countries including Japan and Taiwan, and is also known as Taiwan hinoki, from which the β-thujaplicin was first isolated in 1936 and received its name, hinokitiol. Thujaplicins were the first natural tropolones to be made synthetically, by Ralph Raphael and colleagues, and the β-thujaplicin was the first non-benzenoid aromatic compound identified, by Tetsuo Nozoe and colleagues.[4][5] The resistance of the heartwood of the tree to decay was the main reason prompting to investigate its content and identify the compounds responsible for antimicrobial properties.[4] β-thujaplicin gained more scientific interest beginning in the 2000s.[6] Later, iron-binding activity of β-thujaplicin was discovered and the molecule has been ironically nicknamed as “Iron Man molecule”,[7] because the first name of Tetsuo Nozoe can be translated into English as “Iron Man”.[6]

Occurrence and isolation

Tjujaplicins are found in the heartwood of the conifer trees belonging to the Cupressaceae family, including Chamaecyparis obtusa (Hinoki cypress), Thuja plicata (Western red cedar), Thujopsis dolabrata var. hondai (Hinoki asunaro), Juniperus cedrus (Canary Islands juniper), Cedrus atlantica (Atlas cedar), Cupressus lusitanica (Mexican white cedar), Chamaecyparis lawsoniana (Port Orford cedar), Chamaecyparis taiwanensis (Taiwan cypress), Chamaecyparis thyoides (Atlantic white cedar), Cupressus arizonica (Arizona cypress), Cupressus macnabiana (MacNab cypress), Cupressus macrocarpa (Monterey cypress), Juniperus chinensis (Chinese juniper), Juniperus communis (Common juniper), Juniperus californica (California juniper), Juniperus occidentalis (Western juniper), Juniperus oxycedrus (Cade), Juniperus sabina (Savin juniper), Calocedrus decurrens (California incense-cedar), Calocedrus formosana (Taiwan incense-cedar), Platycladus orientalis (Chinese thuja), Thuja occidentalis (Northern white-cedar), Thuja standishii (Japanese thuja), Tetraclinis articulata (Sandarac).[8][9][10][11]

Thujaplicins can be produced in plant cell suspension cultures,[12][13] or can be extracted from wood using solvents and ultrasonication.[14]

Biosynthesis

Thujaplicins can be synthesized by cycloaddition of isopropylcyclopentadiene and dichloroketene, 1,3-dipolar cycloaddition of 5-isopropyl-1-methyl-3-oxidopyridinium, ring expansion of 2-isopropylcyclohexanone, regiocontrolled hydroxylation of oxyallyl (4+3) cycloadducts, from (R)-(+)-limonene regioselectively by several steps, and from troponeirontricarbonyl complex by few steps.[15][16] The synthesis pathway of β-thujaplicin from troponeirontricarbonyl complex is found below:

Biosynthesis of beta-thujaplicin from troponeirontricarbonyl complex.svg

The synthesis pathway of β-thujaplicin by electro-reductive alkylation of substituted cycloheptatrienes is shown below:

Biosynthesis of beta-thujaplicin through electroreductive alkylation.svg

The synthesis pathway of β-thujaplicin through ring expansion of 2-isopropylcyclohexanone is shown below:

Biosynthesis of beta-thujaplicin from 2-isopropylcyclohexanone.svg

The synthesis pathway of β-thujaplicin through oxyallyl cation [4+3] cyclization (Noyori's synthesis) is shown below:

Biosynthesis of β-thujaplicin through oxyallyl cation (4+3) cyclization.svg

Chemistry

Thujaplicins belong to tropolones containing an unsaturated seven-membered carbon ring. Thujaplicins are monoterpenoids that are cyclohepta-2,4,6-trien-1-one substituted by a hydroxy group at position 2 and an isopropyl group at positions 3, 4 or 5.[17] These compounds are enols and cyclic ketones. They derive from a hydride of a cyclohepta-1,3,5-triene. Thujaplicins are soluble in organic solvents and aqueous buffers. Hinokitiol is soluble in ethanol, dimethyl sulfoxide, dimethylformamide with a solubility of 20, 30 and 12.5 mg/ml, respectively.[18] β-thujaplicin provides acetone on vigorous oxidation and gives the saturated monocyclic diol upon catalytic hydrogenation.[19] It is stable to alkali and acids, forming salts or remaining unchanged, but does not convert to catechol derivatives. The complexes made of iron and tropolones display high thermodynamic stability and has shown to have a stronger binding constant than the transferrin-iron complex.[20]

There are three isomers of thujaplicin, with the isopropyl group positioned progressively further from the two oxygen atoms around the ring: α-thujaplicin, β-thujaplicin, and γ-thujaplicin.[4] β-Thujaplicin, also called hinokitiol, is the most common in nature.[21] Each exists in two tautomeric forms, swapping the hydroxyl hydrogen to the other oxygen, meaning the two oxygen substituents do not have distinct "carbonyl" vs "hydroxyl" identities. The extent of this exchange is that the tropolone ring is aromatic with an overall cationic nature, and the oxygen–hydrogen–oxygen region has an anionic nature.[citation needed]

Beta-thujaplicin aromaticity.png

Biological properties

Insecticidal and pesticidal activity

Thujaplicins are shown to act against Reticulitermes speratus (Japanese termites), Coptotermes formosanus (super termites), Dermatophagoides farinae (dust mites), Tyrophagus putrescentiae (mould mites), Callosobruchus chinensis (adzuki bean weevil), Lasioderma serricorne (cigarette beetle).[9][22][11]

Hinokitiol has also shown some larvicidal activities against Aedes aegypti (yellow fever mosquito) and Culex pipiens (common house mosquito), and anti-plasmodial activities against Plasmodium falciparum and Plasmodium berghei.[11]

Antioxidant activity

Chelating and ionophore activity

Thujaplicins, as other tropolones, demonstrate chelating activity, acting as an ionophore by binding different metal ions.[23]

Anti-browning activity

Tropolone and thujaplicins exhibit potent suppressive activity on enzymatic browning due to inhibition of polyphenol oxidase and tyrosinase. This have been shown in experiments on different vegetables, fruits, mushrooms, plants and other agricultural products.[11] Prevention of darkening has also been elicited on seafood products.[24]

Applications

Skin care and cosmetics

Owing to their antibacterial activities against various microbes colonizing and affecting the skin, thujaplicins are used in skin care and hair growth products,[25] and are especially popular in Eastern Asia.[citation needed]

Oral care

Hinokitiol is used in various oral care products, including toothpastes and oral sprays.[25][26]

Veterinary medicine

Due to its antifungal activity against Malassezia pachydermatis, it is used in eardrop formulations for external otitis in dogs.[27][28]

Agriculture

Considering their antifungal activity against many plant-pathogenic fungi, and pesticidal and insecticidal properties, the role of thujaplicins in agriculture is evolving, including their use in the management of different plant diseases and for controlling the postharvest decay.[9][29]

Food additive

Thujaplicins are used as food additives in Japan.[30] Due to its suppressive activity on food browning and the inhibitory activity against bacteria and fungi causing food spoilage (such as Clostridium perfringens, Alternaria alternata, Aspergillus niger, Botrytis cinerea, Fusobacterium species, Monilinia fructicola and Rhizopus stolonifer), hinokitiol is also used in food packaging as a shelf-life extending agent.[31][32][33]

References

  1. ↑ ERDTMAN, HOLGER; GRIPENBERG, JARL (May 1948). "Antibiotic Substances from the Heart Wood of Thuja plicata Don". Nature 161 (4097): 719. doi:10.1038/161719a0. PMID 18860272. Bibcode: 1948Natur.161..719E. 
  2. ↑ Chedgy, Russell J.; Lim, Young Woon; Breuil, Colette (May 2009). "Effects of leaching on fungal growth and decay of western redcedar". Canadian Journal of Microbiology 55 (5): 578–586. doi:10.1139/W08-161. PMID 19483786. 
  3. ↑ Chedgy, R. (2010). Secondary Metabolites of Western Red Cedar (Thuja plicata). Lambert Academic Publishing. ISBN 978-3-8383-4661-8. 
  4. ↑ 4.0 4.1 4.2 4.3 Cook, J. W.; Raphael, R. A.; Scott, A. I. (1951). "149. Tropolones. Part II. The synthesis of α-, β-, and γ-thujaplicins". J. Chem. Soc.: 695–698. doi:10.1039/JR9510000695. 
  5. ↑ 5.0 5.1 Nakanishi, Koji (June 2013). "Tetsuo Nozoe's "Autograph Books by Chemists 1953-1994": An Essay". The Chemical Record 13 (3): 343–352. doi:10.1002/tcr.201300007. PMID 23737463. 
  6. ↑ 6.0 6.1 "Hinokitiol" (in en). https://www.acs.org/content/acs/en/molecule-of-the-week/archive/h/hinokitiol.html. 
  7. ↑ Service, Robert (11 May 2017). "Iron Man molecule restores balance to cells". Science. doi:10.1126/science.aal1178. 
  8. ↑ Okabe, T; Saito, K (1994). "Antibacterial and preservative effects of natural Hinokitiol (beta-Thujaplicin) extracted from wood". Acta Agriculturae Zhejiangensis 6 (4): 257–266. https://europepmc.org/article/cba/269244. 
  9. ↑ 9.0 9.1 9.2 Morita, Yasuhiro; Matsumura, Eiko; Okabe, Toshihiro; Fukui, Toru; Shibata, Mitsunobu; Sugiura, Masaaki; Ohe, Tatsuhiko; Tsujibo, Hiroshi et al. (2004). "Biological Activity of α-Thujaplicin, the Isomer of Hinokitiol". Biological & Pharmaceutical Bulletin 27 (6): 899–902. doi:10.1248/bpb.27.899. PMID 15187442. 
  10. ↑ Rebia, Rina Afiani; binti Sadon, Nurul Shaheera; Tanaka, Toshihisa (22 November 2019). "Natural Antibacterial Reagents (Centella, Propolis, and Hinokitiol) Loaded into Poly[(R)-3-hydroxybutyrate-co-(R)-3-hydroxyhexanoate Composite Nanofibers for Biomedical Applications"]. Nanomaterials 9 (12): 1665. doi:10.3390/nano9121665. PMID 31766678. 
  11. ↑ 11.0 11.1 11.2 11.3 Saniewski, Marian; Horbowicz, Marcin; Kanlayanarat, Sirichai (10 September 2014). "The Biological Activities of Troponoids and Their Use in Agriculture A Review". Journal of Horticultural Research 22 (1): 5–19. doi:10.2478/johr-2014-0001. 
  12. ↑ Zhao, J.; Fujita, K.; Yamada, J.; Sakai, K. (1 April 2001). "Improved β-thujaplicin production in Cupressus lusitanica suspension cultures by fungal elicitor and methyl jasmonate". Applied Microbiology and Biotechnology 55 (3): 301–305. doi:10.1007/s002530000555. PMID 11341310. 
  13. ↑ Yamada, J.; Fujita, K.; Sakai, K. (April 2003). "Effect of major inorganic nutrients on β-thujaplicin production in a suspension culture of Cupressus lusitanica cells". Journal of Wood Science 49 (2): 172–175. doi:10.1007/s100860300027. Bibcode: 2003JWSci..49..172Y. 
  14. ↑ Chedgy, Russell J.; Daniels, C.R.; Kadla, John; Breuil, Colette (1 March 2007). "Screening fungi tolerant to Western red cedar (Thuja plicata Donn) extractives. Part 1. Mild extraction by ultrasonication and quantification of extractives by reverse-phase HPLC". Holzforschung 61 (2): 190–194. doi:10.1515/HF.2007.033. 
  15. ↑ Soung, Min-Gyu; Matsui, Masanao; Kitahara, Takeshi (September 2000). "Regioselective Synthesis of β- and γ-Thujaplicins". Tetrahedron 56 (39): 7741–7745. doi:10.1016/S0040-4020(00)00690-6. 
  16. ↑ Liu, Na; Song, Wangze; Schienebeck, Casi M.; Zhang, Min; Tang, Weiping (December 2014). "Synthesis of naturally occurring tropones and tropolones". Tetrahedron 70 (49): 9281–9305. doi:10.1016/j.tet.2014.07.065. PMID 25400298. 
  17. ↑ "2,4,6-Cycloheptatrien-1-one, 2-hydroxy-3-(1-methylethyl)-" (in en). PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/80297. 
  18. ↑ "Hinokitiol - Product Information". Cayman Chemical. https://www.caymanchem.com/pdfs/17538.pdf. 
  19. ↑ "Tetsuo Nozoe (1902−1996)". European Journal of Organic Chemistry 2004 (4): 899–928. February 2004. doi:10.1002/ejoc.200300579. 
  20. ↑ Hendershott, Lynn; Gentilcore, Rita; Ordway, Frederick; Fletcher, James; Donati, Robert (May 1982). "Tropolone: A lipid solubilizing agent for cationic metals". European Journal of Nuclear Medicine 7 (5): 234–236. doi:10.1007/BF00256471. PMID 6954070. 
  21. ↑ Bentley, Ronald (2008). "A fresh look at natural tropolonoids". Nat. Prod. Rep. 25 (1): 118–138. doi:10.1039/B711474E. PMID 18250899. 
  22. ↑ INAMORI, Yoshihiko; SAKAGAMI, Yoshikazu; MORITA, Yasuhiro; SHIBATA, Mistunobu; SUGIURA, Masaaki; KUMEDA, Yuko; OKABE, Toshihiro; TSUJIBO, Hiroshi et al. (2000). "Antifungal Activity of Hinokitiol-Related Compounds on Wood-Rotting Fungi and Their Insecticidal Activities.". Biological & Pharmaceutical Bulletin 23 (8): 995–997. doi:10.1248/bpb.23.995. PMID 10963310. 
  23. ↑ Pietra, Francesco (August 1973). "Seven-membered conjugated carbo- and heterocyclic compounds and their homoconjugated analogs and metal complexes. Synthesis, biosynthesis, structure, and reactivity". Chemical Reviews 73 (4): 293–364. doi:10.1021/cr60284a002. 
  24. ↑ Aladaileh, Saleem; Rodney, Peters; Nair, Sham V.; Raftos, David A. (December 2007). "Characterization of phenoloxidase activity in Sydney rock oysters (Saccostrea glomerata)". Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology 148 (4): 470–480. doi:10.1016/j.cbpb.2007.07.089. PMID 17950018. 
  25. ↑ 25.0 25.1 "Hinokitiol | 499-44-5". https://www.chemicalbook.com/ChemicalProductProperty_EN_CB8714323.htm. 
  26. ↑ Suzuki, Joichiro; Tokiwa, Tamami; Mochizuki, Maho; Ebisawa, Masato; Nagano, Takatoshi; Yuasa, Mohei; Kanazashi, Mikimoto; Gomi, Kazuhiro et al. (2008). "Effects of a newly designed toothbrush for the application of periodontal disease treatment medicine (HinoporonTM) on the plaque removal and the improvement of gingivitis.". Nihon Shishubyo Gakkai Kaishi (Journal of the Japanese Society of Periodontology) 50 (1): 30–38. doi:10.2329/perio.50.030. 
  27. ↑ NAKANO, Yasuyuki; MATSUO, Saburo; TANI, Hiroyuki; SASAI, Kazumi; BABA, Eiichiroh (2006). "Therapeutic Effects of β-Thujaplicin Eardrops on Canine Malassezia-Related Otitis Externa". Journal of Veterinary Medical Science 68 (4): 373–374. doi:10.1292/jvms.68.373. PMID 16679729. 
  28. ↑ NAKANO, Yasuyuki; WADA, Makoto; TANI, Hiroyuki; SASAI, Kazumi; BABA, Eiichiroh (2005). "Effects of β-Thujaplicin on Anti-Malassezia pachydermatis Remedy for Canine Otitis Externa". Journal of Veterinary Medical Science 67 (12): 1243–1247. doi:10.1292/jvms.67.1243. PMID 16397383. 
  29. ↑ Aharoni, Y.; Copel, A.; Fallik, E. (June 1993). "Hinokitiol (β-thujaplicin), for postharvest decay control on 'Galia' melons". New Zealand Journal of Crop and Horticultural Science 21 (2): 165–169. doi:10.1080/01140671.1993.9513763. Bibcode: 1993NZJCH..21..165A. 
  30. ↑ "The Japan Food chemical Research Faundation". https://www.ffcr.or.jp/en/tenka/list-of-existing-food-additives/list-of-existing-food-additives.html. 
  31. ↑ L. Brody, Aaron; Strupinsky, E. P.; Kline, Lauri R. (2001). Active Packaging for Food Applications (1 ed.). CRC Press. ISBN 9780367397289. 
  32. ↑ MITSUBOSHI, SAORI; OBITSU, RIE; MURAMATSU, KANAKO; FURUBE, KENTARO; YOSHITAKE, SHIGEHIRO; KIUCHI, KAN (2007). "Growth Inhibitory Effect of Shelf Life Extending Agents on Bacillus subtilis IAM 1026". Biocontrol Science 12 (2): 71–75. doi:10.4265/bio.12.71. PMID 17629249. 
  33. ↑ Vanitha, Thiraviam; Thammawong, Manasikan; Umehara, Hitomi; Nakamura, Nobutaka; Shiina, Takeo (3 September 2019). "Effect of hinokitiol impregnated sheets on shelf life and quality of "KEK-1" tomatoes during storage". Packaging Technology and Science 32 (12): 641–648. doi:10.1002/pts.2479. 



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