Thujaplicins are a series of tropolone-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 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, 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. 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. 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, Thuja plicata, Thujopsis dolabrata var. hondai, Juniperus cedrus, Cedrus atlantica, Cupressus lusitanica, Chamaecyparis lawsoniana, Chamaecyparis taiwanensis, Chamaecyparis thyoides, Cupressus arizonica, Cupressus macnabiana, Cupressus macrocarpa, Juniperus chinensis, Juniperus communis, Juniperus californica, Juniperus occidentalis, Juniperus oxycedrus, Juniperus sabina, Calocedrus decurrens, Calocedrus formosana, Platycladus orientalis, Thuja occidentalis, Thuja standishii, Tetraclinis articulata. Thujaplicins can be produced in plant cell suspension cultures, or can be extracted from wood using solvents and ultrasonication.
Classification
Thujaplicins belong to tropolones containing an unsaturated seven-membered carbon ring. There are three naturally occurring monocyclic tropolones described: α-thujaplicin, β-thujaplicin, and γ-thujaplicin.
Biological properties
Antibacterial and antifungal activity
Thujaplicins have shown to display bacteriostatic or bactericidal activity against a broad spectrum of Gram-positive and Gram-negative bacterias and fungicidal activity against various human- and plant-pathogenic species of fungi and yeasts. However, these antimicrobial and antifungal properties were elicited predominantly on in-vitro studies and the clinical or agricultural value of these findings are mainly unknown as in-vivo studies are lacking. β-thujaplicin has shown a paradoxical zone phenomenon when it inhibits the bacterial growth at a lower concentration, then promotes the growth at a higher concentration followed by full inhibition at even higher concentrations. This phenomenon has been shown to be inhibited by addition of zinc-containing compounds, such as zinc oxide.
Antiviral activity
β-thujaplicin has been investigated for antiviral features and has demonstrated in-vitro inhibitory activity against several viruses, including rhinovirus, coxsackievirus and mengovirus, affecting viral replication in the infected cells, importantly due to aiding the transport of zinc ions into the cells thus increasing their intracellular concentration.
Anti-inflammatory activity
Thujaplicins also possess anti-inflammatory activities characterized by inhibition of the key inflammatory pathways and markers, such as TNF-α and NF-κB.
Thujaplicins are shown to act against Reticulitermes speratus, Coptotermes formosanus, Dermatophagoides farinae, Tyrophagus putrescentiae, Callosobruchus chinensis, Lasioderma serricorne. Hinokitiol has also shown some larvicidal activities against Aedes aegypti and Culex pipiens, and anti-plasmodial activities against Plasmodium falciparum and Plasmodium berghei.
Antioxidant activity
activity is one of the leading reasons for ongoing research on thujaplicins. β-thujaplicin and its derivatives produce neuroprotective activity on hippocampal neurons preventing their death from stress-triggered cell death. They also show antioxidant activity on skin cells by inhibiting ultraviolet B-induced apoptosis in the setting of sunburn.
Chelating and ionophore activity
Thujaplicins, as other tropolones, demonstrate chelating activity by binding different metal ions.
Anti-browning activity
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. Prevention of darkening has also been elicited on seafood products.
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. They are suggested to improve skin condition in atopic dermatitis, especially providing more relief when used combined with zinc compounds.They are also proposed to have a beneficial effect in sunburn by inhibiting ultraviolet B-induced apoptosis in sunburn cells.
Oral care
Hinokitiol is used in various oral care products, including toothpastes and oral sprays.
Cancer research
There is limited preliminary data from an in-vitro study showing that β-thujaplicin can suppress breast cancercell proliferation, inhibit the cell growth and regulate the estrogen sensitivity in breast tissue. A recent study proved that β-thujaplicin can induce autophagic cell death, apoptosis and cell cycle arrest in liver cancer cells. Another recent study has shown novel anti-cancer properties, including β-thujaplicin participating in sensitizing cancer cells to radiotherapy and inhibiting homologous recombination-mediated DNA repair in tumor cells. They also exhibit strong cytotoxicity on cancer cells by inducing autophagic and apoptotic processes documented both by in-vitro and animal studies.
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, 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.
