Chemistry:Hinokitiol

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Hinokitiol[1]
Skeletal formula of hinokitiol
Ball-and-stick model of the hinokitiol molecule
Names
Preferred IUPAC name
2-Hydroxy-6-(propan-2-yl)cyclohepta-2,4,6-trien-1-one
Other names
β-Thujaplicin; 4-Isopropyltropolone
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
UNII
Properties
C10H12O2
Molar mass 164.204 g·mol−1
Appearance Colorless to pale yellow crystals
Melting point 50 to 52 °C (122 to 126 °F; 323 to 325 K)
Boiling point 140 °C (284 °F; 413 K) at 10 mmHg
1.2 g/L (0 °C)
Solubility in ethanol 20 g/L[2]
Solubility in dimethyl sulfoxide 30 g/L[2]
Solubility in dimethylformamide 12.5 g/L[2]
Hazards
Flash point 140 °C (284 °F; 413 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Hinokitiol (β-thujaplicin) is a natural monoterpenoid found in the wood of trees in the family Cupressaceae. It is a tropolone derivative and one of the thujaplicins.[3] Hinokitiol is used in oral and skin care products,[4][5] and is a food additive used in Japan .[6]

History

Hinokitiol was discovered by a Japanese chemist Tetsuo Nozoe in 1936. It was isolated from the essential oil component of the heartwood of Taiwanese hinoki, from which the compound ultimately adopted its name.[7] Hinokitiol is the first non-benzenoid aromatic compound identified.[8] The compound has a heptagonal molecular structure and was first synthesized by Ralph Raphael in 1951.[9] Due to its iron-chelating activity, hinokitiol has been called an "Iron Man molecule" in the scientific media, which is ironic because Tetsuo is translated into English as "Iron Man".[10] Taiwanese hinoki is native to East Asian countries, particularly to Japan and Taiwan.[11] Hinokitiol has also been found in other trees of the Cupressaceae family, including Thuja plicata Donn ex D. Don which is common in the Pacific Northwest.

Woods that are rich in hinokitiol were used by people of ancient Japan for creating long-standing buildings, such as the Konjiki-dō, a japanese national treasure, one of the buildings of Chūson-ji complex, a temple in Iwate Prefecture. It kept it from harm against insects, wood-rotting fungi, and molds for a long time of about 840 years. Additionally, there are some old famous Buddhist temples and Shinto shrines using trees, later known to contain hinokitiol.[12] Beginning in the 2000s, the biological properties of hinokitiol have become of research interest, focusing on its biological properties.[10] And the resistance of cypress trees to wood decay was the leading reason prompting to study their chemical content and to find the substances responsible for those properties.[13]

Natural occurrence

Hinokitiol has been found in the heartwood of the conifer trees of 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).[14][15][16][17]

Its concentration in the trees are 0.1-0.2% in Chamaecyparis taiwanensis (2 mg of hinokitiol per 1 g of dry sawdust), 0.04% in Juniperus cedrus and Thujopsis dolabrata var. hondai (0.4 mg of hinokitiol per 1 g of dry sawdust), and 0.02% in Chamaecyparis obtusa (0.2 mg of hinokitiol per 1 g of dry sawdust).[7][18]

There are three naturally found thujaplicins: α-thujaplicin, β-thujaplicin (hinokitiol) and γ-thujaplicin. Hinokitiol is the most common isomer and it appears to be the only isomer that exerts all biological activities attributed to thujaplicins.[19][20]

Chemical synthesis

There are different pathways to synthesize thujaplicins. Hinokitiol, as other thujaplicins, can be synthesized by cycloaddition of isopropylcyclopentadiene and dichloro ketene, 1,3-dipolar cycloaddition of 5-isopropyl-1-methyl-3-oxidopyridinium, ring expansion of 2-isopropylcyclohexanone, regiocontrolled hydroxylation of oxyallyl (4+3) cycloadducts, regioselectively from (R)-(+)-limonene, and from troponeirontricarbonyl complex.[21][22] Hinokitiol can also be isolated through plant cell suspension cultures,[23][24] or readily extracted from the wood with chemical solvents and ultrasonication.[25]

(1) Synthesis of hinokitiol from troponeirontricarbonyl complex:

Biosynthesis of beta-thujaplicin from troponeirontricarbonyl complex.svg

(2) Synthesis of hinokitiol by electro-reductive alkylation of substituted cycloheptatrienes:

Biosynthesis of beta-thujaplicin through electroreductive alkylation.svg

(3) Synthesis of hinokitiol through ring expansion of 2-isopropylcyclohexanone:

Biosynthesis of beta-thujaplicin from 2-isopropylcyclohexanone.svg

(4) Synthesis of hinokitiol through oxyallyl cation [4+3] cyclization (Noyori's synthesis):

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

Chemistry

Hinokitiol is a tropolone derivative containing an unsaturated seven-membered carbon ring. It is a monoterpenoid – cyclohepta-2,4,6-trien-1-one substituted by a hydroxy group at position 2 and an isopropyl group at position 4.[26][27][28] It is a enol and a cyclic ketone. It derives from a hydride of a cyclohepta-1,3,5-triene. Thujaplicins are soluble in organic solvents and aqueous buffers.[2] Hinokitiol provides acetone on vigorous oxidation and gives the saturated monocyclic diol upon catalytic hydrogenation.[7] It is stable to alkali and acids, forming salts or remaining unchanged, but does not convert to catechol derivatives. Hinokitiol, as other thujaplicins and tropolones, reversibly binds metal ions. It forms complex salts with metal ions.

Ionophore

Main page: Physics:Ionophore

Hinokitiol, as other tropolones, reversibly binds metal ions (i.e. Zn2+, Fe2+, Cu2+, Co2+, Mn2+, Ag2+) and form complex salts. It is considered as a broad-spectrum metallophore, and an efficient iron-chelating agent.[17] The iron complex with hinokitiol with the formula (C10H11O2)3Fe is called hinokitin. Hinoki oil is rich in hinokitin which has an appearance of dark red crystals.[7] 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.[29] It is believed that metal-binding activity may be the principal mechanism of action underlying the most part of its biological activities, especially binding iron, zinc, and copper ions.[20] By binding different metal ions and serving as an ionophore, it accelerates the intracellular uptake of those ions and increases their intracellular levels, thus influencing on different biological activities. It is shown that a synergistic effect in some biological activities and settings may occur when ionophores are combined with the ions they bind.[30] As an ionophore, its molecule has an hydrophilic center and a hydrophobic part. The hydrophobic part interacts with biological membranes. The hydrophilic center binds metal ions and form ionophore-ion complexes.

Biological properties

Hinokitiol and other thujaplicins have been mainly investigated in in-vitro studies and animal models for their possible biological properties, such as antimicrobial, antifungal, antiviral, antiproliferative, anti-inflammatory, antiplasmodial effects.[10][17][20] However, no evidence exists from clinical studies to support these findings. It has also shown to have insecticidal, pesticidal and antibrowning effects. The vast majority of these properties are thought to be due to the metal ion-binding activity. Hinokitiol appeared to exert all in-vitro activities attributed to thujaplicins.[20]

Hinokitiol has been shown to possess inhibitory effects on Chlamydia trachomatis and may be clinically useful as a topical drug.[31][10]

Safety

The safety of hinokitiol has been tested in rats and no carcinogenic effect to rats was found.[32] In 2006, hinokitiol was categorized under the Domestic substances list (DSL) in Canada as non-persistent, non-bioaccumulative and non-toxic to aquatic organisms.[33]

Uses

Skin and oral care products

Hinokitiol is used in a range of consumer products intended for skin care, such as soaps, skin lotions, eyelid cleanser, shampoos and hair tonics;[4][34][35] for oral care, such as toothpastes, breath sprays.[4][5][36]

In April 2020, Advance Nanotek, an Australian producer of zinc oxide, filed a joint patent application with AstiVita Limited, for an anti-viral composition that included oral care products.[37]

Insect repellent

Main page: Chemistry:Insect repellent

Hinokitiol is found to have insecticidal and pesticidal activities against crop-damaging termites (Reticulitermes speratus, Coptotermes formosanus) and beetles (Lasioderma serricorne, Callosobruchus chinensis).[15][38][17] It has also shown to act against certain mites (Dermatophagoides farinae, Tyrophagus putrescentiae) and mosquito larvae (Aedes aegypti, Culex pipiens). Hinokitiol is supplemented in commercial tick and insect repellents.[19]

Food preservative

In experimental studies hinokitiol has been shown to act against Botrytis cinerea, a necrotrophic fungus causing gray mold in many plant species and known to damage horticultural crops. Thus it has been suggested to be used for post-harvest waxing to prevent post-harvest decay.[17][39] Hinokitiol is a registered food additive in Japan.[6] Hinokitiol appears to suppress food browning through inhibiting browning enzymes, particularly tyrosinase and other polyphenol oxidases by chelating copper ions.[17] This effect has been shown on different vegetables, fruits, mushrooms, flowers, plants, other agricultural products and seafood.[40] Due to the latter effects, hinokitiol is used in food packaging as a shelf-life extending agent.[41]

Wood preservative

Main page: Chemistry:Wood preservation

Hinokitiol is one of the chemical compounds isolated from trees, known as extractives, responsible for natural durability of certain trees. Hinokitiol is found in the heartwood of naturally durable trees belonging to the Cupressaceae family.[13][42] These compounds give the wood natural resistance to decay and insect attacks due to their fungicidal, insecticidal and pesticidal activities. Thereby, hinokitiol, as some other natural extractives, is suggested to be used as a wood preservative for timber treatment.[18]

Research directions

Iron transport

Researchers screening a library of small biomolecules for signs of iron transport found that hinokitiol restored cell functionality. Further work by the team suggested a mechanism by which hinokitiol restores or reduces cell iron.[43]

Cancer research

Different in-vitro studies have investigated the effects of hinokitiol on various tumor cell lines.

See also

References

  1. ↑ β-Thujaplicin at Sigma-Aldrich
  2. ↑ 2.0 2.1 2.2 2.3 "Hinokitiol - Product Information". Cayman Chemical. https://www.caymanchem.com/pdfs/17538.pdf. 
  3. ↑ "Effects of leaching on fungal growth and decay of western redcedar". Canadian Journal of Microbiology 55 (5): 578–86. May 2009. doi:10.1139/W08-161. PMID 19483786. 
  4. ↑ 4.0 4.1 4.2 "Hinokitiol | 499-44-5". https://www.chemicalbook.com/ChemicalProductProperty_EN_CB8714323.htm. 
  5. ↑ 5.0 5.1 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. 
  6. ↑ 6.0 6.1 "The Japan Food chemical Research Faundation". https://www.ffcr.or.jp/en/tenka/list-of-existing-food-additives/list-of-existing-food-additives.html. 
  7. ↑ 7.0 7.1 7.2 7.3 "Tetsuo Nozoe (1902−1996)". European Journal of Organic Chemistry 2004 (4): 899–928. February 2004. doi:10.1002/ejoc.200300579. 
  8. ↑ 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. 
  9. ↑ Archer, Mary D.; Haley, Christopher D. (2007). The 1702 Chair of Chemistry at Cambridge : Transformation and Change.. Cambridge Univ Pr. p. 243. ISBN 9780521030854. 
  10. ↑ 10.0 10.1 10.2 10.3 "Hinokitiol" (in en). https://www.acs.org/content/acs/en/molecule-of-the-week/archive/h/hinokitiol.html. 
  11. ↑ Farjon, A. (2005). Monograph of Cupressaceae and Sciadopitys. Kew: Royal Botanic Gardens. ISBN 1-84246-068-4. 
  12. ↑ Inamori, Yoshihiko; Morita, Yasuhiro; Sakagami, Yoshikazu; Okabe, Toshihoro; Ishida, Nakao (2006). "The Excellence of Aomori Hiba (Hinokiasunaro) in Its Use as Building Materials of Buddhist Temples and Shinto Shrines". Biocontrol Science 11 (2): 49–54. doi:10.4265/bio.11.49. PMID 16789546. 
  13. ↑ 13.0 13.1 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. 
  14. ↑ 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. 
  15. ↑ 15.0 15.1 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. 
  16. ↑ 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. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 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. 
  18. ↑ 18.0 18.1 Hu, Junyi; Shen, Yu; Pang, Song; Gao, Yun; Xiao, Guoyong; Li, Shujun; Xu, Yingqian (December 2013). "Application of hinokitiol potassium salt for wood preservative". Journal of Environmental Sciences 25: S32–S35. doi:10.1016/S1001-0742(14)60621-5. PMID 25078835. 
  19. ↑ 19.0 19.1 Bentley, Ronald (2008). "A fresh look at natural tropolonoids". Nat. Prod. Rep. 25 (1): 118–138. doi:10.1039/B711474E. PMID 18250899. 
  20. ↑ 20.0 20.1 20.2 20.3 Falcone, Eric (5 October 2016). "Investigating the Antiproliferative Activity of Synthetic Troponoids". Doctoral Dissertations. https://opencommons.uconn.edu/dissertations/1302. 
  21. ↑ 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. 
  22. ↑ 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. 
  23. ↑ 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. 
  24. ↑ 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. 
  25. ↑ 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. 
  26. ↑ "2,4,6-Cycloheptatrien-1-one, 2-hydroxy-3-(1-methylethyl)-" (in en). PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/80297. 
  27. ↑ "Hinokitiol" (in en). PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/Hinokitiol. 
  28. ↑ "gamma-Thujaplicin" (in en). PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/12649. 
  29. ↑ 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. 
  30. ↑ Ding, Wei-Qun; Lind, Stuart E. (November 2009). "Metal ionophores – An emerging class of anticancer drugs". IUBMB Life 61 (11): 1013–1018. doi:10.1002/iub.253. PMID 19859983. 
  31. ↑ Chedgy, Russell (2010). Secondary metabolites of Western red cedar (Thuja plicata): their biotechnological applications and role in conferring natural durability.. LAP Lambert Academic Publishing. ISBN 978-3-8383-4661-8. 
  32. ↑ IMAI, Norio; DOI, Yuko; NABAE, Kyoko; TAMANO, Seiko; HAGIWARA, Akihiro; KAWABE, Mayumi; ICHIHARA, Toshio; OGAWA, Kumiko et al. (2006). "LACK OF HINOKITIOL (BETA-THUJAPLICIN) CARCINOGENICITY IN F344/DuCrj RATS". The Journal of Toxicological Sciences 31 (4): 357–370. doi:10.2131/jts.31.357. PMID 17077589. 
  33. ↑ Secretariat, Treasury Board of Canada. "Detailed categorization results of the Domestic Substances List - Open Government Portal". https://open.canada.ca/data/en/dataset/1d946396-cf9a-4fa1-8942-4541063bfba4. 
  34. ↑ Hwang, S. L.; Kim, J.-C. (January 2008). "In vivo hair growth promotion effects of cosmetic preparations containing hinokitiol-loaded poly(ε-caprolacton) nanocapsules". Journal of Microencapsulation 25 (5): 351–356. doi:10.1080/02652040802000557. PMID 18465297. 
  35. ↑ Gilbard, Jeffrey P; Douyon, Yanick; Huson, Robert B (May 2010). "Time-Kill Assay Results for a Linalool-Hinokitiol-Based Eyelid Cleanser for Lid Hygiene". Cornea 29 (5): 559–563. doi:10.1097/ICO.0b013e3181bd9f79. PMID 20308878. 
  36. ↑ Kumbargere Nagraj, Sumanth; Eachempati, Prashanti; Uma, Eswara; Singh, Vijendra Pal; Ismail, Noorliza Mastura; Varghese, Eby (11 December 2019). "Interventions for managing halitosis". Cochrane Database of Systematic Reviews 2019 (12): CD012213. doi:10.1002/14651858.CD012213.pub2. PMID 31825092. 
  37. ↑ "IP Australia: AusPat". http://pericles.ipaustralia.gov.au/ols/auspat/applicationDetails.do?applicationNo=2020900820. 
  38. ↑ 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. 
  39. ↑ Wang, Ying; Liu, Xiaoyun; Chen, Tong; Xu, Yong; Tian, Shiping (January 2020). "Antifungal effects of hinokitiol on development of Botrytis cinerea in vitro and in vivo". Postharvest Biology and Technology 159: 111038. doi:10.1016/j.postharvbio.2019.111038. 
  40. ↑ 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. 
  41. ↑ L. Brody, Aaron; Strupinsky, E. P.; Kline, Lauri R. (2001). Active Packaging for Food Applications (1 ed.). CRC Press. ISBN 9780367397289. 
  42. ↑ Singh, Tripti; Singh, Adya P. (September 2012). "A review on natural products as wood protectant". Wood Science and Technology 46 (5): 851–870. doi:10.1007/s00226-011-0448-5. 
  43. ↑ "Restored iron transport by a small molecule promotes absorption and hemoglobinization in animals". Science 356 (6338): 608–616. May 2017. doi:10.1126/science.aah3862. PMID 28495746. Bibcode: 2017Sci...356..608G. 

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