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]
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]
(1) Synthesis of hinokitiol from troponeirontricarbonyl complex:
(2) Synthesis of hinokitiol by electro-reductive alkylation of substituted cycloheptatrienes:
(3) Synthesis of hinokitiol through ring expansion of 2-isopropylcyclohexanone:
(4) Synthesis of hinokitiol through oxyallyl cation [4+3] cyclization (Noyori's synthesis):
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.
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]
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]
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 horticulturalcrops. Thus it has been suggested to be used for post-harvestwaxing 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]
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.
^Chedgy RJ, Lim YW, Breuil C (May 2009). "Effects of leaching on fungal growth and decay of western redcedar". Canadian Journal of Microbiology. 55 (5): 578–86. doi:10.1139/W08-161. PMID19483786.
^Archer, Mary D.; Haley, Christopher D. (2007). The 1702 Chair of Chemistry at Cambridge : Transformation and Change. Cambridge Univ Pr. p. 243. ISBN9780521030854.
^ abCook, 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.
^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. PMID6954070. S2CID43256591.
^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. PMID19859983.
^Chedgy R (2010). Secondary metabolites of Western red cedar (Thuja plicata): their biotechnological applications and role in conferring natural durability. LAP Lambert Academic Publishing. ISBN978-3-8383-4661-8.
^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. PMID18465297. S2CID11746050.
^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. PMID20308878. S2CID12971210.
^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. S2CID208583176.
^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.
^L. Brody, Aaron; Strupinsky, E. P.; Kline, Lauri R. (2001). Active Packaging for Food Applications (1 ed.). CRC Press. ISBN9780367397289.
^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. S2CID16934998.