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]
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]
The synthesis pathway of β-thujaplicin by electro-reductive alkylation of substituted cycloheptatrienes is shown below:
The synthesis pathway of β-thujaplicin through ring expansion of 2-isopropylcyclohexanone is shown below:
The synthesis pathway of β-thujaplicin through oxyallyl cation [4+3] cyclization (Noyori's synthesis) is shown below:
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]
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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]
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]
^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. PMID19483786.
^Chedgy, R. (2010). Secondary Metabolites of Western Red Cedar (Thuja plicata). Lambert Academic Publishing. ISBN978-3-8383-4661-8.
^ abcdCook, 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.
^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. PMID11341310. S2CID25767209.
^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. S2CID95994935.
^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.
^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.
^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. PMID17950018.
^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. Bibcode:1993NZJCH..21..165A. doi:10.1080/01140671.1993.9513763.
^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. S2CID202995336.
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