Hinokitiol (β-thujaplicin) is a natural monoterpenoid found in the wood of trees in the family

Cupressaceae Cupressaceae is a conifer family, the cypress family, with worldwide distribution. The family includes 27–30 genera (17 monotypic), which include the junipers and redwoods, with about 130–140 species in total. They are monoecious, subdioeci ...

. It is a tropolone derivative and one of the thujaplicins. Hinokitiol is used in oral and skin care products, and is a

food additive Food additives are substances added to food to preserve Taste, flavor or enhance taste, appearance, or other sensory qualities. Some additives have been used for centuries as part of an effort to preserve food, for example vinegar (pickling), sal ...

used in

Japan Japan ( ja, 日本, or , and formally , ''Nihonkoku'') is an island country in East Asia. It is situated in the northwest Pacific Ocean, and is bordered on the west by the Sea of Japan, while extending from the Sea of Okhotsk in the n ...

History

Hinokitiol was discovered by a Japanese chemist Tetsuo Nozoe in 1936. It was isolated from the

essential oil An essential oil is a concentrated hydrophobic liquid containing volatile (easily evaporated at normal temperatures) chemical compounds from plants. Essential oils are also known as volatile oils, ethereal oils, aetheroleum, or simply as the o ...

component of the

heartwood Wood is a porous and fibrous structural tissue found in the stems and roots of trees and other woody plants. It is an organic materiala natural composite of cellulose fibers that are strong in tension and embedded in a matrix of lignin t ...

of '' Taiwanese hinoki'', from which the compound ultimately adopted its name. Hinokitiol is the first non- benzenoid aromatic compound identified. The compound has a heptagonal molecular structure and was first synthesyzed by Ralph Raphael in 1951. 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". Taiwanese hinoki is native to

East Asian East Asia is the eastern region of Asia, which is defined in both geographical and ethno-cultural terms. The modern states of East Asia include China, Japan, Mongolia, North Korea, South Korea, and Taiwan. China, North Korea, South Korea ...

countries, particularly to

and

Taiwan Taiwan, officially the Republic of China (ROC), is a country in East Asia, at the junction of the East and South China Seas in the northwestern Pacific Ocean, with the People's Republic of China (PRC) to the northwest, Japan to the no ...

. Hinokitiol has also been found in other trees of the ''

'' family, including ''Thuja plicata'' Donn ex D. Don which is common in the

Pacific Northwest The Pacific Northwest (sometimes Cascadia, or simply abbreviated as PNW) is a geographic region in western North America bounded by its coastal waters of the Pacific Ocean to the west and, loosely, by the Rocky Mountains to the east. Thou ...

. Woods that are rich in hinokitiol were used by people of ancient

for creating long-standing buildings, such as the Konjiki-dō, a japanese national treasure, one of the buildings of

Chūson-ji is a Buddhist temple in the town of Hiraizumi in southern Iwate Prefecture, Japan. It is the head temple of the Tendai sect in Tōhoku region of northern Honshu. The temple claims it was founded in 850 by Ennin, the third chief abbot of the sect ...

complex, a temple in

Iwate Prefecture is a prefecture of Japan located in the Tōhoku region of Honshu. It is the second-largest Japanese prefecture at , with a population of 1,210,534 (as of October 1, 2020). Iwate Prefecture borders Aomori Prefecture to the north, Akita Prefectu ...

. It kept it from harm against

insects Insects (from Latin ') are pancrustacean hexapod invertebrates of the class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body (head, thorax and abdomen), three pairs of j ...

, wood-rotting fungi, and molds for a long time of about 840 years. Additionally, there are some old famous Buddhist temples and

Shinto shrines A is a structure whose main purpose is to house ("enshrine") one or more '' kami'', the deities of the Shinto religion. Overview Structurally, a Shinto shrine typically comprises several buildings. The ''honden''Also called (本殿, meani ...

using trees, later known to contain hinokitiol. Beginning in the 2000s, the biological properties of hinokitiol have become of research interest, focusing on its biological properties. And the resistance of

cypress Cypress is a common name for various coniferous trees or shrubs of northern temperate regions that belong to the family Cupressaceae. The word ''cypress'' is derived from Old French ''cipres'', which was imported from Latin ''cypressus'', the l ...

trees to

wood decay A wood-decay or xylophagous fungus is any species of fungus that digests moist wood, causing it to rot. Some species of wood-decay fungi attack dead wood, such as brown rot, and some, such as ''Armillaria'' (honey fungus), are parasitic and col ...

was the leading reason prompting to study their chemical content and to find the substances responsible for those properties.

Natural occurrence

Hinokitiol has been found in the

hardwoods Hardwood is wood from dicot trees. These are usually found in broad-leaved temperate and tropical forests. In temperate and boreal latitudes they are mostly deciduous, but in tropics and subtropics mostly evergreen. Hardwood (which comes from ...

of the trees of the ''

'' family, including ''

Chamaecyparis obtusa ''Chamaecyparis obtusa'' (Japanese cypress, hinoki cypress or hinoki; ja, 檜 or , ) is a species of cypress native to central Japan in East Asia, and widely cultivated in the temperate northern hemisphere for its high-quality timber and or ...

'' (Hinoki cypress), ''

Thuja plicata ''Thuja plicata'' is an evergreen coniferous tree in the cypress family Cupressaceae, native to western North America. Its common name is western redcedar (western red cedar in the UK), and it is also called Pacific redcedar, giant arborvitae, w ...

'' (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 ''Chamaecyparis lawsoniana'', known as Port Orford cedar or Lawson cypress, is a species of conifer in the genus ''Chamaecyparis'', family Cupressaceae. It is native to Oregon and northwestern California, and grows from sea level up to in the v ...

'' (Port Orford cedar), ''

Chamaecyparis taiwanensis ''Chamaecyparis taiwanensis'' (Taiwan cypress; ) is a species of cypress, native to the mountains of Taiwan, where it grows at altitudes of 1300–2800 m.Rushforth, K. (1987). ''Conifers''. Helm . Description It is a slow-growing coniferous tre ...

'' (Taiwan cypress), '' Chamaecyparis thyoides'' (Atlantic white cedar), '' Cupressus arizonica'' (Arizona cypress), ''

Cupressus macnabiana ''Cupressus macnabiana'' (MacNab cypress or Shasta cypress) is a species of cypress in western North America. Distribution ''Cupressus macnabiana'' is endemic to northern California. ''Cupressus macnabiana'' is one of the most widely distribut ...

'' (MacNab cypress), ''

Cupressus macrocarpa ''Hesperocyparis macrocarpa'' is a coniferous tree. It is commonly known as the Monterey cypress and is one of several species of cypress trees endemic to California. The Monterey cypress is found naturally only on the Central Coast of Califor ...

'' (Monterey cypress), ''

Juniperus chinensis ''Juniperus chinensis'', the Chinese juniper (圆柏, 桧) is a species of plant in the cypress family (botany), family Cupressaceae, native species, native to China, Myanmar, Japan, Korea and the Russian Far East. Growing tall, it is a very va ...

'' (Chinese juniper), '' Juniperus communis'' (Common juniper), '' Juniperus californica'' (California juniper), '' Juniperus occidentalis'' (Western juniper), ''

Juniperus oxycedrus ''Juniperus oxycedrus'', vernacularly called Cade, cade juniper, prickly juniper, prickly cedar, or sharp cedar, is a species of juniper, native across the Mediterranean region from Algeria and Portugal, north to southern France, east to westernm ...

'' (Cade), ''

Juniperus sabina ''Juniperus sabina'', the savin juniper or savin, is a species of juniper native to the mountains of central and southern Europe and western and central Asia, from Spain to eastern Siberia, typically growing at altitudes of .Farjon, A. (2005). ...

'' (Savin juniper), '' Calocedrus decurrens'' (California incense-cedar), ''

Calocedrus formosana ''Calocedrus formosana'' (syn. ''C. macrolepis'' var. ''formosana'' (Florin) W.C.Cheng & L.K.Fu; Taiwan Incense-cedar; or ) is a conifer endemic to Taiwan.Farjon, A. (2005). ''Monograph of Cupressaceae and Sciadopitys''. Royal Botanic Gardens, ...

'' (Taiwan incense-cedar), ''

Platycladus orientalis ''Platycladus'' is a monotypic genus of evergreen coniferous trees in the cypress family Cupressaceae, containing only one species, ''Platycladus orientalis'', also known as Chinese thuja, Oriental arborvitae, Chinese arborvitae, biota or Ori ...

'' (Chinese thuja), ''

Thuja occidentalis ''Thuja occidentalis'', also known as northern white-cedar, eastern white-cedar, or arborvitae, is an evergreen coniferous tree, in the cypress family Cupressaceae, which is native to eastern Canada and much of the north-central and northeastern ...

'' (Northern white-cedar), '' Thuja standishii'' (Japanese thuja), ''

Tetraclinis articulata ''Tetraclinis'' (also called arar, araar or Sictus tree) is a genus of evergreen coniferous trees in the cypress family Cupressaceae, containing only one species, ''Tetraclinis articulata'', also known as Thuja articulata, Its concentration in the trees are 0.1-0.2% in ''

'' (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 ''

'' (0.2 mg of hinokitiol per 1 g of dry sawdust). 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.

Chemical synthesis

There are different pathways to synthesize thujaplicins. Hinokitiol, as other thujaplicins, can be synthesized by

cycloaddition In organic chemistry, a cycloaddition is a chemical reaction in which "two or more unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity" ...

of isopropyl

cyclopentadiene Cyclopentadiene is an organic compound with the formula C5H6.LeRoy H. Scharpen and Victor W. Laurie (1965): "Structure of cyclopentadiene". ''The Journal of Chemical Physics'', volume 43, issue 8, pages 2765-2766. It is often abbreviated CpH beca ...

and dichloro ketene, 1,3-dipolar cycloaddition of 5-isopropyl-1-methyl-3-oxidopyridinium, ring expansion of 2-isopropylcyclohexanone, regiocontrolled

hydroxylation In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a ...

of oxyallyl (4+3) cycloadducts, regioselectively from (''R'')-(+)-

limonene Limonene is a colorless liquid aliphatic hydrocarbon classified as a cyclic monoterpene, and is the major component in the oil of citrus fruit peels. The -isomer, occurring more commonly in nature as the fragrance of oranges, is a flavoring a ...

, and from troponeirontricarbonyl complex. Hinokitiol can also be isolated through plant cell suspension cultures, or readily extracted from the wood with chemical

solvents A solvent (s) (from the Latin '' solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a solution. A solvent is usually a liquid but can also be a solid, a gas, or a supercritical fluid. Water is a solvent for ...

and

ultrasonication image:Sonicator.jpg, A sonicator at the Weizmann Institute of Science during sonicationSonication is the act of applying sound energy to agitate particles in a sample, for various purposes such as the extraction of multiple compounds from plants, m ...

. (1) Synthesis of hinokitiol from troponeirontricarbonyl complex: Biosynthesis of beta-thujaplicin from troponeirontricarbonyl complex

(2) Synthesis of hinokitiol by electro-reductive alkylation of substituted cycloheptatrienes: Biosynthesis of beta-thujaplicin through electroreductive alkylation

Biosynthesis of beta-thujaplicin through electroreductive alkylation

(3) Synthesis of hinokitiol through ring expansion of 2-isopropylcyclohexanone: Biosynthesis of beta-thujaplicin from 2-isopropylcyclohexanone

Biosynthesis of beta-thujaplicin from 2-isopropylcyclohexanone

(4) Synthesis of hinokitiol through oxyallyl cation +3cyclization (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 In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

at position 2 and an isopropyl group at position 4. It is a

enol In organic chemistry, alkenols (shortened to enols) are a type of reactive structure or intermediate in organic chemistry that is represented as an alkene ( olefin) with a hydroxyl group attached to one end of the alkene double bond (). T ...

and a cyclic

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double b ...

. It derives from a hydride of a cyclohepta-1,3,5-triene. Thujaplicins are soluble in organic solvents and aqueous buffers. Hinokitiol provides acetone on vigorous oxidation and gives the saturated monocyclic diol upon catalytic hydrogenation. 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

Hinokitiol, as other tropolones, reversibly binds metal ions (i.e. Zn²⁺, Fe²⁺, Cu²⁺, Co²⁺, Mn²⁺, Ag²⁺) and form complex

salts In chemistry, a salt is a chemical compound consisting of an ionic assembly of positively charged cations and negatively charged anions, which results in a compound with no net electric charge. A common example is table salt, with positively c ...

. It is considered as a broad-spectrum metallophore, and an efficient

iron Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in ...

chelating agent Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate (multiple bonded) ligand and a single central metal atom. These ligands a ...

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

Safety

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

Uses

Skin and oral care products

Hinokitiol is used in a range of consumer products intended for skin care, such as

soap Soap is a salt of a fatty acid used in a variety of cleansing and lubricating products. In a domestic setting, soaps are surfactants usually used for washing, bathing, and other types of housekeeping. In industrial settings, soaps are us ...

skin lotion Lotion is a low-viscosity topical preparation intended for application to the skin. By contrast, creams and gels have higher viscosity, typically due to lower water content. Lotions are applied to external skin with bare hands, a brush, a clean ...

s, eyelid cleanser, shampoos and hair tonics; for oral care, such as

toothpaste Toothpaste is a paste or gel dentifrice used with a toothbrush to clean and maintain the aesthetics and health of teeth. Toothpaste is used to promote oral hygiene: it is an abrasive that aids in removing dental plaque and food from the teeth, ...

s, breath sprays. 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.

Insect repellent

Hinokitiol is found to have

insecticidal Insecticides are substances used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. Insecticides are used in agriculture, medicine, industry and by consumers. Insecticides are claimed t ...

and

pesticidal Pesticides are substances that are meant to control pests. This includes herbicide, insecticide, nematicide, molluscicide, piscicide, avicide, rodenticide, bactericide, insect repellent, animal repellent, microbicide, fungicide, and lamprici ...

activities against crop-damaging

termite Termites are small insects that live in colonies and have distinct castes ( eusocial) and feed on wood or other dead plant matter. Termites comprise the infraorder Isoptera, or alternatively the epifamily Termitoidae, within the order Blat ...

s (''

Reticulitermes speratus ''Reticulitermes speratus'', the Japanese termite, is a species of subterranean termite found in Japan, North Korea, and South Korea. It eats decayed wood. It is adapted to withstand the cold temperatures of the temperate regions it inhabits. T ...

'', ''

Coptotermes formosanus The Formosan termite (''Coptotermes formosanus'') is a species of termite local to southern China and introduced to Taiwan (formerly known as Formosa, where it gets its name), Japan, South Africa, Sri Lanka, Hawaii, and the continental United Sta ...

'') and beetles (''

Lasioderma serricorne ''Lasioderma serricorne'', commonly known as the cigarette beetle, cigar beetle, or tobacco beetle, is an insect very similar in appearance to the drugstore beetle (''Stegobium paniceum'') and the common furniture beetle (''Anobium punctatum''). ...

'', ''

Callosobruchus chinensis ''Callosobruchus chinensis'' is a common species of beetle found in the bean weevil subfamily, and is known to be a pest to many stored legumes. Although it is commonly known as the adzuki bean weevil it is in fact not a true weevil, belonging in ...

''). It has also shown to act against certain mites ('' Dermatophagoides farinae'', '' Tyrophagus putrescentiae'') and mosquito larvae (''

Aedes aegypti ''Aedes aegypti'', the yellow fever mosquito, is a mosquito that can spread dengue fever, chikungunya, Zika fever, Mayaro and yellow fever viruses, and other disease agents. The mosquito can be recognized by black and white markings on its l ...

'', '' Culex pipiens''). Hinokitiol is supplemented in commercial tick and

insect repellent An insect repellent (also commonly called "bug spray") is a substance applied to skin, clothing, or other surfaces to discourage insects (and arthropods in general) from landing or climbing on that surface. Insect repellents help prevent and cont ...

Food preservative

In experimental studies hinokitiol has been shown to act against ''

Botrytis cinerea ''Botrytis cinerea'' is a necrotrophic fungus that affects many plant species, although its most notable hosts may be wine grapes. In viticulture, it is commonly known as "botrytis bunch rot"; in horticulture, it is usually called "grey mould" or ...

'', a necrotrophic fungus causing gray mold in many plant species and known to damage

horticultural Horticulture is the branch of agriculture that deals with the art, science, technology, and business of plant cultivation. It includes the cultivation of fruits, vegetables, nuts, seeds, herbs, sprouts, mushrooms, algae, flowers, seaweeds and no ...

crop A crop is a plant that can be grown and harvested extensively for profit or subsistence. When the plants of the same kind are cultivated at one place on a large scale, it is called a crop. Most crops are cultivated in agriculture or hydropon ...

s. Thus it has been suggested to be used for post-harvest waxing to prevent post-harvest decay. Hinokitiol is a registered

in Japan. Hinokitiol appears to suppress food browning through inhibiting browning enzymes, particularly tyrosinase and other

polyphenol oxidase Polyphenol oxidase (PPO; also polyphenol oxidase i, chloroplastic), an enzyme involved in fruit browning, is a tetramer that contains four atoms of copper per molecule. PPO may accept monophenols and/or ''o''-diphenols as substrates. The ...

s by chelating

copper Copper is a chemical element with the symbol Cu (from la, cuprum) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pink ...

ions. This effect has been shown on different vegetables, fruits, mushrooms, flowers, plants, other agricultural products and seafood. Due to the latter effects, hinokitiol is used in

food packaging Food packaging is a packaging system specifically designed for food and represents one of the most important aspects among the processes involved in the food industry, as it provides protection from chemical, biological and physical alteratio ...

as a

shelf-life Shelf life is the length of time that a commodity may be stored without becoming unfit for use, consumption, or sale. In other words, it might refer to whether a commodity should no longer be on a pantry shelf (unfit for use), or no longer on a ...

extending agent.

Wood preservative

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

of naturally durable trees belonging to the ''

'' family. 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 Wood easily degrades without sufficient preservation. Apart from structural wood preservation measures, there are a number of different chemical preservatives and processes (also known as "timber treatment", "lumber treatment" or "pressure treat ...

for

timber Lumber is wood that has been processed into dimensional lumber, including beams and planks or boards, a stage in the process of wood production. Lumber is mainly used for construction framing, as well as finishing (floors, wall panels, w ...

treatment.

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.

Cancer research

Different ''in-vitro'' studies have investigated the effects of hinokitiol on various tumor

cell line An immortalised cell line is a population of cells from a multicellular organism which would normally not proliferate indefinitely but, due to mutation, have evaded normal cellular senescence and instead can keep undergoing division. The cell ...

References

External links

Hinokitiol
at PubChem
β-Thujaplicin
at

Sigma-Aldrich Sigma-Aldrich (formally MilliporeSigma) is an American chemical, life science, and biotechnology company that is owned by the German chemical conglomerate Merck Group. Sigma-Aldrich was created in 1975 by the merger of Sigma Chemical Company a ...

Hinokitiol
at ChemicalBook {{Terpenoids Isopropyl compounds Monoterpenes Tropolones Non-benzenoid aromatic carbocycles Ionophores Chelating agents Skin care Oral hygiene Food additives Preservatives