Taxodone is a naturally occurring

diterpenoid Diterpenes are a class of terpenes composed of four isoprene units, often with the molecular formula C20H32. They are biosynthesized by plants, animals and fungi via the HMG-CoA reductase pathway, with geranylgeranyl pyrophosphate being a primar ...

found in ''

Taxodium distichum ''Taxodium distichum'' (baldcypress, bald-cypress, bald cypress, swamp cypress; ; ''cipre'' in Louisiana) is a deciduous conifer in the family Cupressaceae. It is native to the southeastern United States. Hardy and tough, this tree adapts to a ...

'' (bald cypress), ''

Rosmarinus officinalis ''Salvia rosmarinus'' (), commonly known as rosemary, is a shrub with fragrant, evergreen, needle-like leaves and white, pink, purple, or blue flowers. It is a member of the sage family, Lamiaceae. The species is native to the Mediterranean r ...

'' (rosemary), several

salvia ''Salvia'' () is the largest genus of plants in the sage family Lamiaceae, with just under 1,000 species of shrubs, Herbaceous plant, herbaceous Perennial plant, perennials, and Annual plant, annuals. Within the Lamiaceae, ''Salvia'' is part o ...

species and other plants, along with its oxidized rearrangement product, taxodione. Taxodone and taxodione exhibit

anticancer An anticarcinogen (also known as a carcinopreventive agent) is a substance that counteracts the effects of a carcinogen or inhibits the development of cancer. Anticarcinogens are different from anticarcinoma agents (also known as anticancer or ant ...

antibacterial An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...

antioxidant Antioxidants are Chemical compound, compounds that inhibit Redox, oxidation, a chemical reaction that can produce Radical (chemistry), free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants ...

antifungal An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as ...

insecticide Insecticides are pesticides used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. The major use of insecticides is in agriculture, but they are also used in home and garden settings, i ...

, and

antifeedant Antifeedants are organic compounds produced by plants to repel herbivores through distaste or toxicity. These chemical compounds are typically classified as secondary metabolites in that they are not essential for the metabolism of the plant, but ...

activities.

Discovery

Taxodone was first isolated in 1968 from the seeds of ''

'' (Bald Cypress) by S. Morris Kupchan and coworkers. They reported the structure determination and basic chemistry of taxodone and its oxidized rearrangement product, taxodione. Taxodone occurs naturally in the form of (+)-taxodone.

Occurrence

Taxodone and/or taxodione have been identified in several plants besides ''

'' including: ''

'' (Rosemary), '' Salvia barrelieri'', ''

Metasequoia glyptostroboides ''Metasequoia glyptostroboides'', the dawn redwood, is a fast-growing, endangered deciduous pinophyta, conifer. It is the sole living species of the genus ''Metasequoia'', one of three genera in the subfamily Sequoioideae of the family (botany), ...

'' (Dawn Redwood), '' Salvia munzii'' (San Diego Sage), ''

Salvia moorcroftiana ''Salvia moorcroftiana'' is a herbaceous perennial native to the Himalayas, Himalayan mountains from Pakistan to western Nepal, and is especially common in the Kashmir valley#Kashmir valley, Kashmir Valley. It grows between 5,000 and 9,000 feet e ...

'', '' Salvia staminea'', ''

Salvia clevelandii ''Salvia clevelandii'', the fragrant sage, blue sage, Jim sage, Cleveland sage, and Cleveland's blue sage is a perennial plant of family Lamiaceae native to Southern California and northern Baja California, growing below elevation in Califor ...

'' (Cleveland Sage), '' Salvia hypargeia'', '' Salvia broussonetii'', ''Salvia montbretii'', ''Salvia nipponica'', ''

Salvia verbenaca ''Salvia verbenaca'', also known as wild clary or wild sage, is native to the British Isles, the Mediterranean region in Southern Europe, North Africa, and Near East, and in the Caucasus. It can be found as an introduced species that has natural ...

'' (Wild Clary), '' Salvia lanigera'', '' Salvia prionitis'', '' Salvia deserta'', ''Salvia phlomoides'', and ''

Plectranthus ''Plectranthus'' is a genus of about 85 species of flowering plants from the sage family, Lamiaceae, found mostly in southern and tropical Africa and Madagascar. Common names include spur-flower. ''Plectranthus'' species are herbaceous perennial ...

hereroensis'' Taxodone, taxodione and their reaction products have been used as archeological and geological biomarkers. Analogs of taxodone and taxodione have also been isolated. 2-hydroxy taxodone and 2-hydroxy-taxodione have been found in '' Salvia texana'' (Texas Sage). 5,6-Didehydro-7-hydroxy-taxodone was found in '' Salvia munzii''. 7-Hydroxytaxodione, 7,7‘-bistaxodione, and 11,11‘-didehydroxy-7,7‘-dihydroxytaxodione were found in ''Salvia montbretti''.

Activity

Taxodone and taxodione possess ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

'' activity against Walker intramuscular

carcinosarcoma Carcinosarcomas are malignant tumors that consist of a Mixed tumor, mixture of carcinoma (or epithelial cancer) and sarcoma (or mesenchymal/connective tissue cancer). Carcinosarcomas are rare tumors, and can arise in diverse organs, such as the ski ...

256 in rats (25 and 40 mg/kg, respectively) and ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'' activity against cells derived from human

carcinoma Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesoder ...

of the

nasopharynx The pharynx (: pharynges) is the part of the throat behind the mouth and nasal cavity, and above the esophagus and trachea (the tubes going down to the stomach and the lungs respectively). It is found in vertebrates and invertebrates, though its ...

(KB) (ED₅₀ = 0.6 and 3 ug/ml respectively). Taxodone and taxodione exhibit

activity against wood decay fungi, with taxodione being especially active against ''

Trametes versicolor ''Trametes versicolor''also known as ''Coriolus versicolor'' and ''Polyporus versicolor''is a common polypore mushroom found throughout the world. Owing to its shape being similar to that of a wild turkey's tail feathers, ''T. versicolor ...

'' and '' Fomitopsis palustris''. Taxodione exhibited the highest

activity among the tested

s from the roots of '' Salvia barrelieri''. Taxodone showed potent

effects against foodborne

pathogenic In biology, a pathogen (, "suffering", "passion" and , "producer of"), in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ. The term ...

bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...

, such as ''

Listeria monocytogenes ''Listeria monocytogenes'' is the species of pathogenic bacteria that causes the infection listeriosis. It is a facultative anaerobic bacterium, capable of surviving in the presence or absence of oxygen. It can grow and reproduce inside the ho ...

'' ATCC 19166, ''

Salmonella typhimurium ''Salmonella enterica'' subsp. ''enterica'' is a subspecies of ''Salmonella enterica'', the rod-shaped, flagellated, aerobic, Gram-negative bacterium. Many of the pathogenic serovars of the ''S. enterica'' species are in this subspecies, includin ...

'' KCTC 2515, '' Salmonella enteritidis'' KCTC 2021, ''

Escherichia coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Escherichia'' that is commonly fo ...

'' ATCC 8739, ''

'' O157:H7 ATCC 43888, ''

Enterobacter aerogenes ''Enterobacter'' is a genus of common Gram-negative, facultatively anaerobic, rod-shaped, non-spore-forming bacteria of the family Enterobacteriaceae. Cultures are found in soil, water, sewage, feces and gut environments. It is the type genu ...

'' KCTC 2190, ''

Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often posi ...

'' ATCC 6538 and ''

'' KCTC 1916 Taxodone showed potent termicidal activity against the subterranean

termite Termites are a group of detritivore, detritophagous Eusociality, eusocial cockroaches which consume a variety of Detritus, decaying plant material, generally in the form of wood, Plant litter, leaf litter, and Humus, soil humus. They are dist ...

, ''Reticulitermes speratus'' Kolbe. Taxodione depresses neuronal GABAA receptor-operated Cl-current (IGABA). Taxodione may have potential in treatment of cardiovascular disease. The use of taxodone and taxodione to inhibit hair growth has been patented. Treatment of benign prostate enlargement with taxodone has also been patented.

Chemistry

Taxodone was the first isolated example of a

quinone methide A quinone methide is a type of conjugated organic compound that contain a cyclohexadiene with a carbonyl and an exocyclic methylidene or extended alkene unit. It is analogous to a quinone, but having one of the double bonded oxygens replaced with ...

with a

labile Lability refers to the degree that something is likely to undergo change. It is the opposite ( antonym) of stability. Biochemistry In reference to biochemistry, this is an important concept as far as kinetics is concerned in metalloprotein ...

hydrogen Hydrogen is a chemical element; it has chemical symbol, symbol H and atomic number 1. It is the lightest and abundance of the chemical elements, most abundant chemical element in the universe, constituting about 75% of all baryon, normal matter ...

adjacent to this reactive

chromophore A chromophore is the part of a molecule responsible for its color. The word is derived . The color that is seen by our eyes is that of the light not Absorption (electromagnetic radiation), absorbed by the reflecting object within a certain wavele ...

. Kupchan demonstrated that taxodone aromatizes to a

catechol Catechol ( or ), also known as pyrocatechol or 1,2-dihydroxybenzene, is an organic compound with the molecular formula . It is the ''ortho'' isomer of the three isomeric benzenediols. This colorless compound occurs naturally in trace amounts. It ...

ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...

upon exposure to mild

acid An acid is a molecule or ion capable of either donating a proton (i.e. Hydron, hydrogen cation, H+), known as a Brønsted–Lowry acid–base theory, Brønsted–Lowry acid, or forming a covalent bond with an electron pair, known as a Lewis ...

. Air

oxidation Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

of this

affords taxodione.

Synthesis

Taxodone rearranges easily in the presence of mild

acids An acid is a molecule or ion capable of either donating a proton (i.e. hydrogen cation, H+), known as a Brønsted–Lowry acid, or forming a covalent bond with an electron pair, known as a Lewis acid. The first category of acids are the ...

and reacts readily with

nucleophiles In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...

. Although taxodone shows higher

and

activity than taxodione it eluded creation in the laboratory for over 25 years because of its inherent instability. During this time several different groups reported syntheses of the more stable taxodione. In 1993 taxodone was synthesized for the first time in a 16 step sequence utilizing a unique phenol benzylic epoxide electron reorganization in the final step. As taxodone readily decomposes into taxodione this synthesis of taxodone also constitutes a formal synthesis of taxodione as well. Since the synthesis of taxodone there have been additional syntheses of taxodione and analogs.

References

External links

The First Total Synthesis of (±)-Taxodone
*{{cite journal , author1=Sanchez, Anthony J. , author2=Konopelski, Joseph P. , title = Phenol Benzylic Epoxide to Quinone Methide Electron Reorganization: The Synthesis of (±)-Taxodone, journal = J. Org. Chem. , year = 1994, volume = 59, pages = 5445–5452, issue = 18 , doi = 10.1021/jo00097a057
Taxodone, Pubchem entryQuinone methides, Steven Edward RokitBiological and toxicological consequences of quinone methide formationRecent Advances in the Chemistry of Terpenoid Tumor Inhibitors
Quinone methides Tertiary alcohols Diterpenes Phenanthrenes Enols Secondary alcohols Diols Isopropyl compounds Hydroxyketones