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 in the Himalayas and 1,000–2,200 m in the Mediterranean.

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 latinisation of the Greek κυπάρισσος (kyparissos). Cypress trees are a large classification of conifers, encompassing the trees and shrubs from the cypress family (Cupressaceae) and many others with the word cypress in their common name. Many cypress trees have needle-like, evergreen foliage and acorn-like seed cones.

<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.

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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.

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Callophrys gryneus, the juniper hairstreak or olive hairstreak, is a butterfly native to North America. It belongs in the family Lycaenidae.

<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

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<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

  1. ↑ ERDTMAN, HOLGER; GRIPENBERG, JARL (May 1948). "Antibiotic Substances from the Heart Wood of Thuja plicata Don". Nature. 161 (4097): 719. Bibcode:1948Natur.161..719E. doi: 10.1038/161719a0 . PMID   18860272. S2CID   4074514.
  2. ↑ 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. PMID   19483786.
  3. ↑ Chedgy, R. (2010). Secondary Metabolites of Western Red Cedar (Thuja plicata). Lambert Academic Publishing. ISBN   978-3-8383-4661-8.
  4. 1 2 3 4 Cook, 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.
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  7. ↑ Service, Robert (11 May 2017). "Iron Man molecule restores balance to cells". Science. doi:10.1126/science.aal1178.
  8. ↑ Okabe, T; Saito, K (1994). "Antibacterial and preservative effects of natural Hinokitiol (beta-Thujaplicin) extracted from wood". Acta Agriculturae Zhejiangensis. 6 (4): 257–266.
  9. 1 2 3 Morita, Yasuhiro; Matsumura, Eiko; Okabe, Toshihiro; Fukui, Toru; Shibata, Mitsunobu; Sugiura, Masaaki; Ohe, Tatsuhiko; Tsujibo, Hiroshi; Ishida, Nakao; Inamori, Yoshihiko (2004). "Biological Activity of α-Thujaplicin, the Isomer of Hinokitiol". Biological & Pharmaceutical Bulletin. 27 (6): 899–902. doi: 10.1248/bpb.27.899 . PMID   15187442.
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  12. ↑ 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. PMID   11341310. S2CID   25767209.
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  22. ↑ INAMORI, Yoshihiko; SAKAGAMI, Yoshikazu; MORITA, Yasuhiro; SHIBATA, Mistunobu; SUGIURA, Masaaki; KUMEDA, Yuko; OKABE, Toshihiro; TSUJIBO, Hiroshi; ISHIDA, Nakao (2000). "Antifungal Activity of Hinokitiol-Related Compounds on Wood-Rotting Fungi and Their Insecticidal Activities". Biological & Pharmaceutical Bulletin. 23 (8): 995–997. doi: 10.1248/bpb.23.995 . PMID   10963310.
  23. ↑ 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.
  24. ↑ 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. PMID   17950018.
  25. 1 2 "Hinokitiol | 499-44-5". www.chemicalbook.com.
  26. ↑ Suzuki, Joichiro; Tokiwa, Tamami; Mochizuki, Maho; Ebisawa, Masato; Nagano, Takatoshi; Yuasa, Mohei; Kanazashi, Mikimoto; Gomi, Kazuhiro; Arai, Takashi (2008). "Effects of a newly designed toothbrush for the application of periodontal disease treatment medicine (HinoporonTM) on the plaque removal and the improvement of gingivitis". Nihon Shishubyo Gakkai Kaishi (Journal of the Japanese Society of Periodontology). 50 (1): 30–38. doi: 10.2329/perio.50.030 .
  27. ↑ NAKANO, Yasuyuki; MATSUO, Saburo; TANI, Hiroyuki; SASAI, Kazumi; BABA, Eiichiroh (2006). "Therapeutic Effects of β-Thujaplicin Eardrops on Canine Malassezia-Related Otitis Externa". Journal of Veterinary Medical Science. 68 (4): 373–374. doi: 10.1292/jvms.68.373 . PMID   16679729.
  28. ↑ NAKANO, Yasuyuki; WADA, Makoto; TANI, Hiroyuki; SASAI, Kazumi; BABA, Eiichiroh (2005). "Effects of β-Thujaplicin on Anti-Malassezia pachydermatis Remedy for Canine Otitis Externa". Journal of Veterinary Medical Science. 67 (12): 1243–1247. doi: 10.1292/jvms.67.1243 . PMID   16397383.
  29. ↑ 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.
  30. ↑ "The Japan Food chemical Research Faundation". www.ffcr.or.jp.
  31. ↑ L. Brody, Aaron; Strupinsky, E. P.; Kline, Lauri R. (2001). Active Packaging for Food Applications (1 ed.). CRC Press. ISBN   9780367397289.
  32. ↑ MITSUBOSHI, SAORI; OBITSU, RIE; MURAMATSU, KANAKO; FURUBE, KENTARO; YOSHITAKE, SHIGEHIRO; KIUCHI, KAN (2007). "Growth Inhibitory Effect of Shelf Life Extending Agents on Bacillus subtilis IAM 1026". Biocontrol Science. 12 (2): 71–75. doi: 10.4265/bio.12.71 . PMID   17629249.
  33. ↑ 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. S2CID   202995336.
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