Thujaplicin

Last updated
Thujaplicin
Alpha-thujaplicin tautomers.png
α-Thujaplicin
Beta-thujaplicin tautomers.png
β-Thujaplicin (hinokitiol)
Gamma-thujaplicin tautomers.png
γ-Thujaplicin
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
EC Number
  • β:207-880-7
PubChem CID
UNII
  • α:InChI=1S/C10H12O2/c1-7(2)8-5-3-4-6-9(11)10(8)12/h3-7H,1-2H3,(H,11,12)
    Key: TUFYVOCKVJOUIR-UHFFFAOYSA-N
  • β:InChI=1S/C10H12O2/c1-7(2)8-4-3-5-9(11)10(12)6-8/h3-7H,1-2H3,(H,11,12)
    Key: FUWUEFKEXZQKKA-UHFFFAOYSA-N
  • γ:InChI=1S/C10H12O2/c1-7(2)8-3-5-9(11)10(12)6-4-8/h3-7H,1-2H3,(H,11,12)
    Key: WKEWHSLZDDZONF-UHFFFAOYSA-N
  • α:CC(C)C1=C(C(=O)C=CC=C1)O
  • β:CC(C)C1=CC(=O)C(=CC=C1)O
  • γ:CC(C)C1=CC=C(C(=O)C=C1)O
Properties
C10H12O2
Molar mass 164.204 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Thujaplicin (isopropyl cycloheptatrienolone) is any of three isomeric tropolone-related natural products 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]

Contents

History

Thuja plicata Donn ex D. Don (Western red cedar) - a tree belonging to the Cupressaceae family from which thujaplicins were first purified Thuja plicata Vancouver.jpg
Thuja plicata Donn ex D. Don (Western red cedar) – a tree belonging to the Cupressaceae family from which thujaplicins were first purified

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]

Occurrence and isolation

Tjujaplicins are found in the heartwood of the conifer trees belonging to 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). [8] [9] [10] [11]

Thujaplicins can be produced in plant cell suspension cultures, [12] [13] or can be extracted from wood using solvents and ultrasonication. [14]

Biosynthesis

Thujaplicins can be synthesized by cycloaddition of isopropylcyclopentadiene 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 regioselectively by several steps, and from troponeirontricarbonyl complex by few steps. [15] [16] The synthesis pathway of β-thujaplicin from troponeirontricarbonyl complex is found below:

Biosynthesis of beta-thujaplicin from troponeirontricarbonyl complex.svg

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

Biosynthesis of beta-thujaplicin through electroreductive alkylation.svg

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

Biosynthesis of beta-thujaplicin from 2-isopropylcyclohexanone.svg

The synthesis pathway of β-thujaplicin through oxyallyl cation [4+3] cyclization (Noyori's synthesis) is shown below:

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

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 ]

Beta-thujaplicin aromaticity.png

Biological properties

Insecticidal and pesticidal activity

Thujaplicins are shown to act against Reticulitermes speratus (Japanese termites), Coptotermes formosanus (super termites), Dermatophagoides farinae (dust mites), Tyrophagus putrescentiae (mould mites), Callosobruchus chinensis (adzuki bean weevil), Lasioderma serricorne (cigarette beetle). [9] [22] [11]

Hinokitiol has also shown some larvicidal activities against Aedes aegypti (yellow fever mosquito) and Culex pipiens (common house mosquito), and anti-plasmodial activities against Plasmodium falciparum and Plasmodium berghei . [11]

Antioxidant activity

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, including also thujaplicinol, 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]

Veterinary medicine

Due to its antifungal activity against Malassezia pachydermatis , it is used in eardrop formulations for external otitis in dogs. [27] [28]

Agriculture

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]

Food additive

Thujaplicins are used as food additives in Japan. [30] Due to its suppressive activity on food browning and the inhibitory activity against bacteria and fungi causing food spoilage (such as Clostridium perfringens , Alternaria alternata , Aspergillus niger , Botrytis cinerea , Fusobacterium species, Monilinia fructicola and Rhizopus stolonifer ), hinokitiol is also used in food packaging as a shelf-life extending agent. [31] [32] [33] Thujaplicinol, a tropolone, is also used in Japan as a food additive in small amount.

See also

Related Research Articles

<i>Cedrus</i> Genus of plants (coniferous trees)

Cedrus, with the common English name cedar, is a genus of coniferous trees in the plant family Pinaceae. They are native to the mountains of the western Himalayas and the Mediterranean region, occurring at altitudes of 1,500–3,200 m (4,900–10,500 ft) in the Himalayas and 1,000–2,200 m (3,300–7,200 ft) in the Mediterranean.

<span class="mw-page-title-main">Juniper</span> Genus of plants

Junipers are coniferous trees and shrubs in the genus Juniperus of the cypress family Cupressaceae. Depending on the taxonomy, between 50 and 67 species of junipers are widely distributed throughout the Northern Hemisphere, from the Arctic, south to tropical Africa, throughout parts of western, central and southern Asia, east to eastern Tibet in the Old World, and in the mountains of Central America. The highest-known juniper forest occurs at an altitude of 4,900 metres (16,100 ft) in southeastern Tibet and the northern Himalayas, creating one of the highest tree lines on earth.

Cypress is a common name for various coniferous trees or shrubs from the Cupressus genus of the Cupressaceae family, typically found in warm-temperate and subtropical regions of Asia, Europe, and North America.

<span class="mw-page-title-main">Cupressaceae</span> Cypress family of conifers

Cupressaceae is a conifer family, the cypress, with worldwide distribution. The family includes 27–30 genera, which include the junipers and redwoods, with about 130–140 species in total. They are monoecious, subdioecious or (rarely) dioecious trees and shrubs up to 116 m (381 ft) tall. The bark of mature trees is commonly orange- to red-brown and of stringy texture, often flaking or peeling in vertical strips, but smooth, scaly or hard and square-cracked in some species.

<i>Callitropsis nootkatensis</i> Species of conifer

Callitropsis nootkatensis, formerly known as Cupressus nootkatensis, is a species of tree in the cypress family native to the coastal regions of northwestern North America. This species goes by many common names including: Nootka cypress, yellow cypress, Alaska cypress, Nootka cedar, yellow cedar, Alaska cedar, and Alaska yellow cedar. The specific epithet nootkatensis is derived from the species being from the area of Nootka Sound on the west coast of Vancouver Island, Canada. Both locations are named for the older European name Nootka, given the Nuu-chah-nulth First Nation.

<i>Thuja plicata</i> Species of conifer

Thuja plicata is a large evergreen coniferous tree in the family Cupressaceae, native to the Pacific Northwest of North America. Its common name is western redcedar in the U.S. or western red cedar in the UK, and it is also called pacific red cedar, giant arborvitae, western arborvitae, just cedar, giant cedar, or shinglewood. It is not a true cedar of the genus Cedrus. T. plicata is the largest species in the genus Thuja, growing up to 70 metres (230 ft) tall and 7 m (23 ft) in diameter. It mostly grows in areas that experience a mild climate with plentiful rainfall, although it is sometimes present in drier areas on sites where water is available year-round, such as wet valley bottoms and mountain streamsides. The species is shade-tolerant and able to establish in forest understories and is thus considered a climax species. It is a very long-lived tree, with some specimens reaching ages of well over 1,000 years.

<i>Chamaecyparis obtusa</i> Tree, a species of cypress

Chamaecyparis obtusa 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 ornamental qualities, with many cultivars commercially available.

<span class="mw-page-title-main">Sister Mary Grace Burns Arboretum</span> Botanical garden in Lakewood Township, New Jersey, United States

The Sister Mary Grace Burns Arboretum, on the campus of Georgian Court University, in Lakewood Township, New Jersey, United States, was once the landscaped park for the winter home of George Jay Gould, millionaire son of railroad tycoon Jay Gould.

<span class="mw-page-title-main">Ralph Raphael</span> British chemist

Ralph Alexander Raphael was a British organic chemist, well known for his use of acteylene derivatives in the synthesis of natural products with biological activity.

<span class="mw-page-title-main">Tropolone</span> Chemical compound

Tropolone is an organic compound with the chemical formula C7H5(OH)O. 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 ligand precursor. Although not usually prepared from tropone, it can be viewed as its derivative with a hydroxyl group in the 2-position.

<span class="mw-page-title-main">Hinokitiol</span> Chemical compound

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 used in Japan.

<span class="mw-page-title-main">Totarol</span> Chemical compound

Totarol is a naturally produced diterpene that is bioactive as totarol. It was first isolated by McDowell and Easterfield from the heartwood of Podocarpus totara, a conifer tree found in New Zealand. Podocarpus totara was investigated for unique molecules due to the tree's increased resistance to rotting. Recent studies have confirmed totarol's unique antimicrobial and therapeutic properties. Consequently, totarol is a candidate for a new source of drugs and has been the goal of numerous syntheses.

<i>Cinara cupressi</i> Species of true bug

Cinara cupressi, the cypress aphid, is a brownish soft-bodied aphid. It sucks sap from twigs of conifers, and can cause damage to the tree, ranging from discoloring of the affected twig to the death of the tree. This insect appears to have originated in the Middle East and has been increasing its range and is considered to be an invasive species in Africa and Europe. It has been included in the List of the world's 100 worst invasive species.

<span class="mw-page-title-main">Cedrol</span> Chemical compound

Cedrol is a sesquiterpene alcohol found in the essential oil of conifers, especially in the genera Cupressus (cypress) and Juniperus (juniper). It has also been identified in Origanum onites, a plant related to oregano. Its main uses are in the chemistry of aroma compounds. It makes up about 19% of cedarwood oil Texas and 15.8% of cedarwood oil Virginia.

<span class="mw-page-title-main">Mihrabat Nature Park</span> Nature park in Beykoz, Istanbul, Turkey

Mihrabat Nature Park is a nature park located on the Asian part in Beykoz district of Istanbul Province, Turkey.

<span class="mw-page-title-main">Tetsuo Nozoe</span>

Tetsuo Nozoe was a Japanese organic chemist. He is known for the discovery of hinokitiol, a seven-membered aromatic compound, and studying non-benzenoid aromatic compounds.

<span class="mw-page-title-main">Thujaplicinol</span> A natural terpenoid belonging to tropolones

Thujaplicinol is either of two isomeric tropolone-related natural products. They are found in tree species primarily in bark, needles, xylem, of the family of Cupressaceae like the Cupressus, Thuja, Juniperus and Thujopsis. The thujaplicinols are structurally equivalent to the thujaplicins with an additional hydroxyl group. They belong to the class of natural terpenoids having two free hydroxyl groups at C3 and C5 position.

References

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