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 .
History
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.
Hinokitiol is the first non-
benzenoid aromatic compound identified.
The compound has a heptagonal molecular structure and was first synthesized 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 countries, particularly to
Japan and
Taiwan.
Hinokitiol has also been found in other trees of the
Cupressaceae family, including
Thuja plicata 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 Mold for a long time of about 840 years. Additionally, there are some old famous Buddhist temples and Shinto shrine using trees, later known to contain hinokitiol.
Natural occurrence
Hinokitiol has been found in the heartwood of the conifer trees of the
Cupressaceae family, including
Chamaecyparis obtusa (Hinoki cypress),
Thuja plicata (Western red cedar),
Thujopsis (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).
Its concentration in the trees are 0.1-0.2% in Chamaecyparis taiwanensis (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 Chamaecyparis obtusa (0.2 mg of hinokitiol per 1 g of dry sawdust).
There are three naturally found : 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 of isopropyl
cyclopentadiene and dichloro ketene, 1,3-dipolar cycloaddition of 5-isopropyl-1-methyl-3-oxidopyridinium, ring expansion of 2-isopropylcyclohexanone, regiocontrolled
hydroxylation of oxyallyl (4+3) cycloadducts,
Regioselectivity from (
R)-(+)-
limonene, and from troponeirontricarbonyl complex.
Hinokitiol can also be isolated through plant cell suspension cultures,
or readily extracted from the wood with chemical
solvents and
ultrasonication.
(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
Monoterpene –
Tropone substituted by a
hydroxy group at position 2 and an
Propyl group at position 4.
It is a
enol and a cyclic
ketone. It derives from a hydride of a
Cycloheptatriene. 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
, reversibly binds metal ions (i.e.
Zinc2+,
Iron2+,
Copper2+,
Cobalt2+,
Manganese2+,
Silver2+) and form complex salts. It is considered as a broad-spectrum
Ionophore, and an efficient
iron-
Chelation.
The iron complex with hinokitiol with the formula (C
10H
11O
2)
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
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
,
,
Eyewash,
shampoos and
Hair care;
for oral care, such as
,
.
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
Insecticide and
Pesticide activities against crop-damaging
(
Reticulitermes speratus,
Coptotermes formosanus) and beetles (
Lasioderma serricorne,
Callosobruchus chinensis).
It has also shown to act against certain mites (
Dermatophagoides farinae,
Tyrophagus putrescentiae) and mosquito larvae (
Aedes aegypti,
Culex pipiens). Hinokitiol is supplemented in commercial tick and
.
Food preservative
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
Horticulture . Thus it has been suggested to be used for
Postharvest Fruit waxing to prevent post-harvest decay.
Hinokitiol is a registered
food additive in Japan.
Hinokitiol appears to suppress
food browning through inhibiting browning enzymes, particularly tyrosinase and other polyphenol oxidases by chelating
copper 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 as a
shelf-life 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
heartwood of naturally durable trees belonging to the
Cupressaceae 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 for
timber 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 culture.
See also
External links
