Thujaplicins (

isopropyl In organic chemistry, propyl is a three-carbon alkyl substituent with chemical formula for the linear form. This substituent form is obtained by removing one hydrogen atom attached to the terminal carbon of propane. A propyl substituent is often ...

cycloheptatrienolones) are a series of

tropolone Tropolone is an organic compound with the chemical formula . It is a pale yellow solid that is soluble in organic solvents. The compound has been of interest to research chemists because of its unusual electronic structure and its role as a ligan ...

-related chemical substances that have been isolated from the hardwoods of the trees of '' Cupressaceae'' family. These compounds are known for their antibacterial, antifungal, and antioxidant properties. They were the first natural tropolones to be made synthetically.

History

Thujaplicins were discovered in the mid-1930s and purified from 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 ''Thuja plicata'' Donn ex D. Don, commonly called as Western red cedar tree. 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 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 nort ...

, 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

s to be made synthetically, by

Ralph Raphael Ralph Alexander Raphael (1 January 1921 – 27 April 1998) was a British organic chemist, well known for his use of acteylene derivatives in the synthesis of natural products with biological activity. Early life and education Ralph Raphael ...

and colleagues, and the β-thujaplicin was the first non-benzenoid aromatic compound identified, by Tetsuo Nozoe and colleagues. The resistance of the heartwood of the tree to

decay Decay may refer to: Science and technology * Bit decay, in computing * Software decay, in computing * Distance decay, in geography * Decay time (fall time), in electronics Biology * Decomposition of organic matter * Tooth decay (dental caries ...

was the main reason prompting to investigate its content and identify the compounds responsible for antimicrobial properties. β-thujaplicin gained more scientific interest beginning in the 2000s. Later, iron-binding activity of β-thujaplicin was discovered and the molecule has been ironically nicknamed as “Iron Man molecule”, because the first name of Tetsuo Nozoe can be translated into English as “Iron Man”.

Occurrence and isolation

Tjujaplicins are found in the hardwoods of the trees belonging to the '' Cupressaceae'' family, including '' Chamaecyparis obtusa'' (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 ''Juniperus cedrus'', the Canary Islands juniper, is a species of juniper, native to the western Canary Islands (Tenerife, La Palma, Gran Canaria, Gomera) and Madeira (''J. cedrus'' Webb & Berthel. subsp. ''maderensis'' (Menezes) Rivas Mart ''et ...

'' (Canary Islands juniper), ''

Cedrus atlantica ''Cedrus atlantica'', the Atlas cedar, is a species of tree in the pine family Pinaceae, native to the Rif and Atlas Mountains of Morocco (Middle Atlas, High Atlas), and to the Tell Atlas in Algeria.Gaussen, H. (1964). Genre ''Cedrus''. Les ...

'' (Atlas cedar), ''

Cupressus lusitanica ''Cupressus lusitanica'', the Mexican cedar or cedar-of-Goa, is a species of cypress native to Mexico and Central America (Guatemala, El Salvador and Honduras). It has also been introduced to Belize, Costa Rica and Nicaragua, growing at altitu ...

'' (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'' (Taiwan cypress), ''

Chamaecyparis thyoides ''Chamaecyparis thyoides'' (Atlantic white cedar, Atlantic white cypress, southern white cedar, whitecedar, or false-cypress), a species of ''Cupressaceae'', is native to the Atlantic coast of North America and is found from southern Maine to ...

'' (Atlantic white cedar), ''

Cupressus arizonica ''Cupressus arizonica'', the Arizona cypress, is a North American species of tree in the cypress family Cupressaceae, native to the southwestern United States and Mexico. Populations may be scattered rather than in large, dense stands. Descripti ...

'' (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 distribute ...

'' (MacNab cypress), '' Cupressus macrocarpa'' (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 ''Juniperus communis'', the common juniper, is a species of small tree or shrub in the cypress family Cupressaceae. An evergreen conifer, it has the largest geographical range of any woody plant, with a circumpolar distribution throughout the coo ...

'' (Common juniper), ''

Juniperus californica ''Juniperus californica'', the California juniper, is a species of juniper native to southwestern North America. Description ''Juniperus californica'' is a shrub or small tree reaching , but rarely up to tall. The bark is ashy gray, typically ...

'' (California juniper), ''

Juniperus occidentalis ''Juniperus occidentalis'', known as the western juniper, is a shrub or tree native to the Western United States, growing in mountains at altitudes of and rarely down to . It is listed as Least Concern on the IUCN Red List because it is a widesp ...

'' (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'' (Savin juniper), ''

Calocedrus decurrens ''Calocedrus decurrens'', with the common names incense cedar and California incense-cedar (syn. ''Libocedrus decurrens'' Torr.), is a species of coniferous tree native to western North America. It is the most widely known species in the genus, ...

'' (California incense-cedar), '' Calocedrus formosana'' (Taiwan incense-cedar), '' Platycladus orientalis'' (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 ''Thuja standishii'' (Japanese thuja; Japanese: , ) is a species of thuja, an evergreen coniferous tree in the cypress family Cupressaceae. It is native to southern Japan, where it occurs on the islands of Honshū and Shikoku. It is a medium- ...

'' (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, Thujaplicins can be produced in plant cell suspension cultures, or can be extracted from wood using solvents and ultrasonication.

Biosynthesis

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". T ...

of isopropyl cyclopentadiene 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 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 ...

regioselectively by several steps, and from troponeirontricarbonyl complex by few steps. The synthesis pathway of β-thujaplicin from troponeirontricarbonyl complex is found below:
Biosynthesis of beta-thujaplicin from troponeirontricarbonyl complex

Biosynthesis of beta-thujaplicin from troponeirontricarbonyl complex

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

Biosynthesis of beta-thujaplicin through electroreductive alkylation

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

Biosynthesis of beta-thujaplicin from 2-isopropylcyclohexanone

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

Chemistry

Thujaplicins belong to tropolones containing an unsaturated seven-membered carbon ring. Thujaplicins are

monoterpenoids Monoterpenes are a class of terpenes that consist of two isoprene units and have the molecular formula C10H16. Monoterpenes may be linear (acyclic) or contain rings (monocyclic and bicyclic). Modified terpenes, such as those containing oxygen funct ...

that are cyclohepta-2,4,6-trien-1-one substituted by a hydroxy group at position 2 and an

isopropyl group In organic chemistry, propyl is a three-carbon alkyl substituent with chemical formula for the linear form. This substituent form is obtained by removing one hydrogen atom attached to the terminal carbon of propane. A propyl substituent is often ...

at positions 3, 4 or 5. These compounds are

enols 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 (). The t ...

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 Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an alcohol with the chemical formula . Its formula can be also written as or (an ethyl group linked to a ...

, dimethyl sulfoxide,

dimethylformamide Dimethylformamide is an organic compound with the formula ( CH3)2NC(O)H. Commonly abbreviated as DMF (although this initialism is sometimes used for dimethylfuran, or dimethyl fumarate), this colourless liquid is miscible with water and the maj ...

with a solubility of 20, 30 and 12.5 mg/ml, respectively. β-thujaplicin 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. 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. There are three isomers of thujaplicin, with the

positioned progressively further from the two oxygen atoms around the ring: α-thujaplicin, β-thujaplicin, and γ-thujaplicin. β-Thujaplicin, also called

hinokitiol 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. Hinokitiol is used in oral and skin care products, and is a food additive us ...

, is the most common in nature. Each exists in two

tautomer Tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert. The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hyd ...

ic forms, swapping the

hydroxyl 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 hydro ...

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

ring is

aromatic In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...

with an overall cationic nature, and the oxygen–hydrogen–oxygen region has an anionic nature. : Beta-thujaplicin aromaticity

Biological properties

Antibacterial and antifungal activity

Antiviral activity

Anti-inflammatory activity

Insecticidal and pesticidal activity

Thujaplicins are shown to act against ''

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 ...

'' (Japanese termites), '' Coptotermes formosanus'' (super termites), '' Dermatophagoides farinae'' (dust mites), '' Tyrophagus putrescentiae'' (mould mites), '' Callosobruchus chinensis'' (adzuki bean weevil), '' Lasioderma serricorne'' (cigarette beetle). Hinokitiol has also shown some larvicidal activities against ''

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 le ...

'' (yellow fever mosquito) and ''

Culex pipiens ''Culex pipiens'', commonly referred to as the common house mosquito, is a species of mosquito. House mosquitoes are some of the most common mosquitoes in the United States. More specifically, ''Culex pipiens'' is considered as the northern hous ...

'' (common house mosquito), and anti-plasmodial activities against '' Plasmodium falciparum'' and ''

Plasmodium berghei ''Plasmodium berghei'' is a species in the genus ''Plasmodium'' subgenus '' Vinckeia''. It is a protozoan parasite that causes malaria in certain rodents. Originally, isolated from thicket rats in Central Africa, ''P. berghei'' is one of four ' ...

''.

Antioxidant activity

Chelating and ionophore activity

Thujaplicins, as other tropolones, demonstrate

chelating 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 are ...

activity, acting as an

ionophore In chemistry, an ionophore () is a chemical species that reversibly binds ions. Many ionophores are lipid-soluble entities that transport ions across the cell membrane. Ionophores catalyze ion transport across hydrophobic membranes, such as liq ...

by binding different metal ions.

Anti-browning activity

Tropolone Tropolone is an organic compound with the chemical formula . It is a pale yellow solid that is soluble in organic solvents. The compound has been of interest to research chemists because of its unusual electronic structure and its role as a ligan ...

and thujaplicins exhibit potent suppressive activity on

enzymatic browning Browning is the process of food turning brown due to the chemical reactions that take place within. The process of browning is one of the chemical reactions that take place in food chemistry and represents an interesting research topic regardin ...

due to inhibition of

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 ...

and

tyrosinase Tyrosinase is an oxidase that is the rate-limiting enzyme for controlling the production of melanin. The enzyme is mainly involved in two distinct reactions of melanin synthesis otherwise known as the Raper Mason pathway. Firstly, the hydroxy ...

. This have been shown in experiments on different vegetables, fruits, mushrooms, plants and other agricultural products. Prevention of darkening has also been elicited on seafood products.

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, and are especially popular in Eastern Asia.

Oral care

Hinokitiol is used in various oral care products, including toothpastes and oral sprays.

Veterinary medicine

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

Agriculture

Considering their antifungal activity against many plant-pathogenic

fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...

, 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 lamp ...

and

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 ...

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.

Food additive

Thujaplicins are used as food additives in Japan. Due to its suppressive activity on

food browning Browning is the process of food turning brown due to the chemical reactions that take place within. The process of browning is one of the chemical reactions that take place in food chemistry and represents an interesting research topic regarding ...

and the inhibitory activity against bacteria and fungi causing

food spoilage Food spoilage is the process where a food product becomes unsuitable to ingest by the consumer. The cause of such a process is due to many outside factors as a side-effect of the type of product it is, as well as how the product is packaged and s ...

(such as ''

Clostridium perfringens ''Clostridium perfringens'' (formerly known as ''C. welchii'', or ''Bacillus welchii'') is a Gram-positive, rod-shaped, anaerobic, spore-forming pathogenic bacterium of the genus ''Clostridium''. ''C. perfringens'' is ever-present in nature an ...

'', ''

Alternaria alternata ''Alternaria alternata'' is a fungus which has been recorded causing leaf spot and other diseases on over 380 host species of plant. It is an opportunistic pathogen on numerous hosts causing leaf spots, rots and blights on many plant parts. It ...

'', ''

Aspergillus niger ''Aspergillus niger'' is a mold classified within the ''Nigri'' section of the ''Aspergillus'' genus. The ''Aspergillus'' genus consists of common molds found throughout the environment within soil and water, on vegetation, in fecal matter, on de ...

'', ''

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" o ...

'', ''

Fusobacterium ''Fusobacterium'' is a genus of anaerobic, Gram-negative, non-sporeforming bacteria belonging to Gracilicutes. Individual cells are slender, rod-shaped bacilli with pointed ends. Strains of ''Fusobacterium'' cause several human diseases, includi ...

'' species, ''

Monilinia fructicola ''Monilinia fructicola'' is a species of fungus in the order Helotiales. A plant pathogen, it is the causal agent of brown rot of stone fruits. Stone fruit (summer fruit) Stone fruits such as apricot and peaches originated in China and spread t ...

'' and ''

Rhizopus stolonifer ''Rhizopus stolonifer'' is commonly known as white bread mold. It is a member of ''Zygomycota'' and considered the most important species in the genus '' Rhizopus''. It is one of the most common fungi in the world and has a global distribution a ...

''), hinokitiol is also 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.

References

{{Terpenoids Tropolones Monoterpenes Isopropyl compounds Non-benzenoid aromatic carbocycles Ionophores Chelating agents Antifungals Fungicides Antiviral drugs Insecticides Pesticides Skin care Oral hygiene Antioxidants Food additives