Quinone methide

Last updated
Quinone methide
Quinone methide.png
Identifiers
3D model (JSmol)
1922177
ChEBI
PubChem CID
UNII
  • o-:InChI=1S/C7H6O/c1-6-4-2-3-5-7(6)8/h2-5H,1H2
    Key: NSDWWGAIPUNJAX-UHFFFAOYSA-N
  • p-:InChI=1S/C7H6O/c1-6-2-4-7(8)5-3-6/h2-5H,1H2
    Key: OJPNKYLDSDFUPG-UHFFFAOYSA-N
  • o-:C=C1C=CC=CC1=O
  • p-:C=C1C=CC(=O)C=C1
Properties
C7H6O
Molar mass 106.124 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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 a carbon. The carbonyl and methylidene are usually oriented either ortho or para to each other. There are some examples of transient synthetic meta quinone methides.

Contents

Properties

Quinone methides are cross-conjugated rather than aromatic. Nucleophilic addition at the exo-cyclic double bond will result in rearomatisation, making such reactions highly favourable. As a result, quinone methides are excellent, electrophilic Michael acceptors, react quickly with nucleophiles and can be easily reduced. They are able to act as radical scavengers via a similar process, a behaviour exploited by certain polymerisation inhibitors. Quinone methides are more polar than quinones, and therefore more chemically reactive. Simple unhindered quinone methides are short lived reactive intermediates that are not stable enough to be isolated under normal circumstances, they will trimerise in the absence of nucleophiles. [1] Sterically hindered quinone methides can be sufficiently stable to be isolated, with some examples being commercially available.

Preparation

Quinone methides are often prepared by oxidation of the corresponding ortho or para cresol.

Quinone methides can be produced in aqueous solution by photochemical dehydration of o-hydroxybenzyl alcohols (i.e. salicyl alcohol).

Occurrence and applications

Quinones methides are commonly invoked in biochemistry, but are rarely observed as long-lived intermediates.

Biosynthesis of dehydroglycine

Quinone methide itself arises by the degradation of tyrosine, leading ultimately to p-cresol. [2] Various quinone methides are directly involved in the process of lignification (creation of complex lignin polymers) in plants. [3]

Quinone methides have been implicated as the ultimate cytotoxins responsible for the effects of such agents as antitumor drugs, antibiotics, and DNA alkylators. [4] Oxidation to a reactive quinone methide is the mechanistic basis of many phenolic anti-cancer drugs.

Celastrol.png
Pristimerin.png
Proposed sequence of reactions with N-acetyldopamine as substrate resulting in sclerotization (formation of exoskeletons of arthropods. The middle step involving conversion of the ortho quinone to quinone methide, is catalyzed by the enzyme quinone isomerase. < SclerotizationReaction.svg
Proposed sequence of reactions with N-acetyldopamine as substrate resulting in sclerotization (formation of exoskeletons of arthropods. The middle step involving conversion of the ortho quinone to quinone methide, is catalyzed by the enzyme quinone isomerase. <

Celastrol is a triterpenoid quinone methide isolated from Tripterygium wilfordii (Thunder of God vine) and Celastrus regelii that exhibits antioxidant (15 times the potency of α-tocopherol), [6] anti-inflammatory, [7] anticancer, [8] [9] [10] [11] and insecticidal [12] activities.

Pristimerin, the methyl ester of celasterol, is a triterpenoid quinone methide isolated from Maytenus heterophylla that displays antitumor and antiviral [13] activities. Pristimerin has also been found to have a contraceptive effect due to its inhibiting effect on the calcium channel of sperm (CatSper). [14]

Taxodone-to-taxodione.png
Maytenoquinone.png
Maytenoquinone

Taxodone and its oxidized rearrangement product, taxodione, are diterpenoid quinone methides found in Taxodium distichum (bald cypress), Rosmarinus officinalis (rosemary), several Salvia species and other plants, that display anticancer, [15] [16] [17] antibacterial, [18] [19] [20] antioxidant, [21] antifungal, [22] insecticide, [23] and antifeedant [24] activities.

Maytenoquinone, an isomer of taxodione, is a biologically active quinone methide found in Maytenus dispermus . [25]

Kendomycin 2.png

Kendomycin is an antitumor antibacterial quinone methide macrolide first isolated from the bacterium Streptomyces violaceoruber . [26] It has potent activity as an endothelin receptor antagonist and anti-osteoporosis agent. [27]

Elansolid A3 is a quinone methide from the bacterium Chitinophaga sancti that displays antibiotic activity. [28] Antibacterial quinone methides, 20-epi-isoiguesterinol, 6-oxoisoiguesterin, isoiguesterin and isoiguesterinol were found in Salacia madagascariensis . [29] Quinone methides tingenone and netzahualcoyonol were isolated from Salacia petenensis . [30] Nortriterpenoid quinone methide amazoquinone and (7S, 8S)-7-hydroxy-7,8-dihydro-tingenone were isolated from Maytenus amazonica . [31] An antimicrobial quinone methide, 15 alpha-hydroxypristimerin, was isolated from a South American medicinal plant, Maytenus scutioides . [32]

Quinone dimethides

A quinone dimethide (or "xylylene") is a compound with the formula C6H4(=CH2)2. Thus they are related to quinone monomethides (the topic of this article) by replacing the keto group with methylidene. A well studied example is tetracyanoquinodimethane.

Related Research Articles

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

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In chemistry, a nitrene or imene is the nitrogen analogue of a carbene. The nitrogen atom is uncharged and univalent, so it has only 6 electrons in its valence level—two covalent bonded and four non-bonded electrons. It is therefore considered an electrophile due to the unsatisfied octet. A nitrene is a reactive intermediate and is involved in many chemical reactions. The simplest nitrene, HN, is called imidogen, and that term is sometimes used as a synonym for the nitrene class.

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

Caffeic acid is an organic compound that is classified as a hydroxycinnamic acid. This yellow solid consists of both phenolic and acrylic functional groups. It is found in all plants because it is an intermediate in the biosynthesis of lignin, one of the principal components of woody plant biomass and its residues.

Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are broken into two broad subtypes: type I topoisomerases (TopI) and type II topoisomerases (TopII). Topoisomerase plays important roles in cellular reproduction and DNA organization, as they mediate the cleavage of single and double stranded DNA to relax supercoils, untangle catenanes, and condense chromosomes in eukaryotic cells. Topoisomerase inhibitors influence these essential cellular processes. Some topoisomerase inhibitors prevent topoisomerases from performing DNA strand breaks while others, deemed topoisomerase poisons, associate with topoisomerase-DNA complexes and prevent the re-ligation step of the topoisomerase mechanism. These topoisomerase-DNA-inhibitor complexes are cytotoxic agents, as the un-repaired single- and double stranded DNA breaks they cause can lead to apoptosis and cell death. Because of this ability to induce apoptosis, topoisomerase inhibitors have gained interest as therapeutics against infectious and cancerous cells.

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

Ferruginol is a natural phenol with a terpenoid substructure. Specifically, it is a diterpene of the abietane chemical class, meaning it is characterized by three fused six-membered rings and alkyl functional groups. Ferruginol was first identified in 1939 by Brandt and Neubauer as the main component in the resin of the Miro tree and has since been isolated from other conifer species in the families Cupressaceae and Podocarpaceae. As a biomarker, the presence of ferruginol in fossils, mainly resin, is used to describe the density of these conifers in that particular biosphere throughout time.

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

Nargenicin is a 28 carbon macrolide with a fused tricyclic core that has in addition a unique ether bridge. The polyketide antibiotic was isolated from Nocardia argentinensis. Nargenicin is effective towards gram-positive bacteria and been shown to have strong antibacterial activity against Staphylococcus aureus, including strains that are resistant to methicillin. It has also been shown to induce cell differentiation and inhibit cell proliferation in a human myeloid leukemia cell line.

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

Taxodone is a naturally occurring diterpenoid found in Taxodium distichum, Rosmarinus officinalis (rosemary), several salvia species and other plants, along with its oxidized rearrangement product, taxodione. Taxodone and taxodione exhibit anticancer, antibacterial, antioxidant, antifungal, insecticide, and antifeedant activities.

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

Lupeol is a pharmacologically active pentacyclic triterpenoid. It has several potential medicinal properties, like anticancer and anti-inflammatory activity.

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

Abietane is a diterpene that forms the structural basis for a variety of natural chemical compounds such as abietic acid, carnosic acid, and ferruginol which are collectively known as abietanes or abietane diterpenes.

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

Levopimaric acid is an abietane-type of diterpene resin acid. It is a major constituent of pine oleoresin with the chemical formula of C20H30O2. In general, the abietene types of diterpene resin acid have various biological activities, such as antibacterial, cardiovascular and antioxidant. Levopimaric acid accounts for about 18 to 25% of pine oleoresin. The production of oleoresin by conifer species is an important component of the defense response against insect attack and fungal pathogen infection.

<i>beta</i>-Araneosene Chemical compound

β-Araneosene is a molecule first isolated in 1975 from the mold Sordaria araneosa by Borschberg. This unprecedented diterpene framework was given the name “araneosene”. In 1976, the skeletal class was renamed to “dolabellane” due to the isolation of several compounds containing this framework found from the sea hare Dolabella californica. Since their initial discovery, there are now more than 150 known dolabellanes, mostly isolated from marine sources.

<span class="mw-page-title-main">Selenenic acid</span> Class of chemical compounds

A selenenic acid is an organoselenium compound and an oxoacid with the general formula RSeOH, where R ≠ H. It is the first member of the family of organoselenium oxoacids, which also include seleninic acids and selenonic acids, which are RSeO2H and RSeO3H, respectively. Selenenic acids derived from selenoenzymes are thought to be responsible for the antioxidant activity of these enzymes. This functional group is sometimes called SeO-selenoperoxol.

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

Celastrol (tripterine) is a chemical compound isolated from the root extracts of Tripterygium wilfordii and Tripterygium regelii. Celastrol is a pentacyclic nortriterpen quinone and belongs to the family of quinone methides. In mice, celastrol is an NR4A1 agonist that alleviates inflammation and induces autophagy. Also in mice, celastrol increase expression of IL1R1, which is the receptor for the cytokine interleukin-1 (IL-1). IL1R1 knock-out mice exposed to celastrol exhibit no leptin-sensitizing or anti-obesity effect.

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

Pomiferin is a prenylated isoflavone that can be found along with osajin in the fruits and female flowers of the osage orange tree.

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

Dihydrotanshinone I (DI) is a naturally occurring compound extracted from Salvia miltiorrhiza Bunge, also known as Chinese sage, red sage root, and the Chinese herbal Dan Shen. It belongs to a class of lipophilic abietane diterpenoids and has been reported to have cytotoxicity to a variety of tumor cells, as well as antiviral effects in vitro. Since they were first discovered, over 40 related compounds and over 50 hydrophilic compounds have been isolated from Dan Shen.

<span class="mw-page-title-main">2-Hydroxyestradiol</span> Chemical compound

2-Hydroxyestradiol (2-OHE2), also known as estra-1,3,5(10)-triene-2,3,17β-triol, is an endogenous steroid, catechol estrogen, and metabolite of estradiol, as well as a positional isomer of estriol.

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

Sugiol is a phenolic abietane derivative of ferruginol and can be used as a biomarker for specific families of conifers. The presence of sugiol can be used to identify the Cupressaceae s.1., podocarpaceae, and Araucaraiaceae families of conifers. The polar terpenoids are among the most resistant molecules to degradation besides n-alkanes and fatty acids, affording them high viability as biomarkers due to their longevity in the sedimentary record. Significant amounts of sugiol has been detected in fossil wood dated to the Eocene and Miocene periods, as well as a sample of Protopodocarpoxylon dated to the middle Jurassic.

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

Chamaecydin is a chemical compound with the molecular formula C30H40O3. It is made up of three six-membered rings and two five-membered rings and has one polar hydroxyl functional group. It is well preserved in the rock record and is only found in a specific family of conifers, the swamp cypress subfamily. The presence and abundance of chamaecydin in the rock record can reveal environmental changes in ancient biomes.

References

  1. ↑ Cavitt, S. B.; R., H. Sarrafizadeh; Gardner, P. D. (April 1962). "The Structure of o-Quinone Methide Trimer". The Journal of Organic Chemistry. 27 (4): 1211–1216. doi:10.1021/jo01051a021.
  2. ↑ Stich, T. A.; Myers, W. K.; Britt, R. D., "Paramagnetic intermediates generated by radical S-adenosylmethionine (SAM) enzymes", Acc. Chem. Res. 2014, 47, 2235-2243.
  3. ↑ Quinone Methides in Lignification
  4. ↑ Wang P, Song Y, Zhang L, He H, Zhou X (2005). "Quinone methide derivatives: important intermediates to DNA alkylating and DNA cross-linking actions". Curr Med Chem . 12 (24): 2893–2913. doi:10.2174/092986705774454724. PMID   16305478.
  5. ↑ Andersen, Svend Olav (2010). "Insect Cuticular Sclerotization: A Review". Insect Biochemistry and Molecular Biology. 40 (3): 166–178. doi:10.1016/j.ibmb.2009.10.007. PMID   19932179.
  6. ↑ Allison AC, Cacabelos R, Lombardi VR, Alvarez XA, Vigo C (2001). "Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer's disease". Prog Neuropsychopharmacol Biol Psychiatry . 25 (7): 1341–1357. doi:10.1016/S0278-5846(01)00192-0. PMID   11513350. S2CID   21569585.
  7. ↑ Kim DH, Shin EK, Kim YH, Lee BW, Jun JG, Park JH, Kim JK (2009). "Suppression of inflammatory responses by celastrol, a quinone methide triterpenoid isolated from Celastrus regelii". Eur J Clin Invest . 39 (9): 819–827. doi:10.1111/j.1365-2362.2009.02186.x. PMID   19549173. S2CID   205291261.
  8. ↑ Lee JH, Choi KJ, Seo WD, Jang SY, Kim M, Lee BW, Kim JY, Kang S, Park KH, Lee YS, Bae S (2011). "Enhancement of radiation sensitivity in lung cancer cells by celastrol is mediated by inhibition of Hsp90". Int J Mol Med . 27 (3): 441–446. doi: 10.3892/ijmm.2011.601 . PMID   21249311.
  9. ↑ Tiedemann; et al. (2009). "Identification of a potent natural triterpenoid inhibitor of proteosome chymotrypsin-like activity and NF-kappaB with antimyeloma activity in vitro and in vivo". Blood . 113 (17): 4027–37. doi:10.1182/blood-2008-09-179796. PMC   3952546 . PMID   19096011.
  10. ↑ Zhu H, Liu XW, Cai TY, Cao J, Tu CX, Lu W, He QJ, Yang B (2010). "Celastrol acts as a potent antimetastatic agent targeting beta1 integrin and inhibiting cell-extracellular matrix adhesion, in part via the p38 mitogen-activated protein kinase pathway". J Pharmacol Exp Ther . 334 (2): 489–499. doi:10.1124/jpet.110.165654. PMID   20472666. S2CID   25854329.
  11. ↑ Byun; et al. (2009). "Reactive oxygen species-dependent activation of Bax and Poly(ADP)-ribose) polymerase-1 is required for mitochondrial cell death induced by triterpenoid Pristimerin in human cervical cancer cells". Mol. Pharmacol. 76 (4): 734–44. doi:10.1124/mol.109.056259. PMID   19574249. S2CID   6541041.
  12. ↑ Avilla J, Teixidò A, Velázquez C, Alvarenga N, Ferro E, Canela R (2000). "Insecticidal activity of Maytenus species (Celastraceae) nortriterpene quinone methides against codling moth, Cydia pomonella (L.) (Lepidoptera: tortricidae)". Journal of Agricultural and Food Chemistry . 48 (1): 88–92. doi:10.1021/jf990008w. PMID   10637057.
  13. ↑ Murayama T, Eizuru Y, Yamada R, Sadanari H, Matsubara K, Rukung G, Tolo FM, Mungai GM, Kofi-Tsekpo M (2007). "Anticytomegalovirus activity of pristimerin, a triterpenoid quinone methide isolated from Maytenus heterophylla (Eckl. & Zeyh.)". Antivir Chem Chemother . 18 (3): 133–139. doi:10.1177/095632020701800303. PMID   17626597. S2CID   22381089.
  14. ↑ Nadja Mannowetza; Melissa R. Millera; Polina V. Lishko (2017). "Regulation of the sperm calcium channel CatSper by endogenous steroids and plant triterpenoids". Proceedings of the National Academy of Sciences of the United States of America . 114 (22): 5743–5748. Bibcode:2017PNAS..114.5743M. doi: 10.1073/pnas.1700367114 . PMC   5465908 . PMID   28507119.
  15. ↑ Kupchan, S. M.; Karim, A; Marcks, C. (1968). "Tumor inhibitors. XXXIV. Taxodione and taxodone, two novel diterpenoid quinone methide tumor inhibitors from Taxodium distichum". J Am Chem Soc . 90 (21): 5923–4. doi:10.1021/ja01023a061. PMID   5679178.
  16. ↑ Zaghloul AM, Gohar AA, Naiem ZA, Abdel Bar FM (2008). "Taxodione, a DNA-binding compound from Taxodium distichum L. (Rich.)". Z Naturforsch C . 63 (5–6): 355–360. doi: 10.1515/znc-2008-5-608 . PMID   18669020. S2CID   23956301.
  17. ↑ Ayhan Ulubelen, Gülaçti Topçu, Hee-Byung Chai and John M. Pezzuto (1999). "Cytotoxic Activity of Diterpenoids Isolated from Salvia hypargeia". Pharmaceutical Biology . 37 (2): 148–151. doi:10.1076/phbi.37.2.148.6082.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ↑ Vivek K. Bajpai & Sun Chul Kan (2010). "Antibacterial abietane-type diterpenoid, taxodone from Metasequoia glyptostroboides Miki ex Hu". Journal of Biosciences . 35 (4): 533–538. doi:10.1007/s12038-010-0061-z. PMID   21289435. S2CID   25656295.
  19. ↑ Vivek K. Bajpai; Minkyun Na; Sun Chul Kang (2010). "The role of bioactive substances in controlling foodborne pathogens derived from Metasequoia glyptostroboides Miki ex Hu". Food and Chemical Toxicology . 48 (7): 1945–1949. doi:10.1016/j.fct.2010.04.041. PMID   20435080.
  20. ↑ Tada M, Kurabe J, Yoshida T, Ohkanda T, Matsumoto Y (2010). "Syntheses and antibacterial activities of diterpene catechol derivatives with abietane, totarane and podocarpane skeletons against methicillin-resistant Staphylococcus aureus and Propionibacterium acnes". Chem Pharm Bull . 58 (6): 818–824. doi: 10.1248/cpb.58.818 . PMID   20522992.
  21. ↑ Ufuk Kolak; Ahmed Kabouche; Mehmet Öztürk; Zahia Kabouche; Gülaçtl Topçu; Ayhan Ulubelen (2009). "Antioxidant diterpenoids from the roots of Salvia barrelieri". Phytochemical Analysis . 20 (4): 320–327. doi:10.1002/pca.1130. PMID   19402189.
  22. ↑ Norihisa Kusumoto; Tatsuya Ashitani; Tetsuya Murayama; Koichi Ogiyama; Koetsu Takahashi (2010). "Antifungal Abietane-Type Diterpenes from the Cones of Taxodium distichum Rich". Journal of Chemical Ecology . 36 (12): 1381–1386. doi:10.1007/s10886-010-9875-2. PMID   21072573. S2CID   11861719.
  23. ↑ Norihisa Kusumoto; Tatsuya Ashitani; Yuichi Hayasaka; Tetsuya Murayama; Koichi Ogiyama; Koetsu Takahashi (2009). "Antitermitic Activities of Abietane-type Diterpenes from Taxodium distichum Cones". Journal of Chemical Ecology . 35 (6): 635–642. doi:10.1007/s10886-009-9646-0. PMID   19475449. S2CID   42622420.
  24. ↑ M. C. Ballesta-Acosta1, M. J. Pascual-Villalobos and B. Rodríguez (2008). "Short communication. The antifeedant activity of natural plant products towards the larvae of Spodoptera littoralis". Spanish Journal of Agricultural Research . 6 (1): 85–91. doi: 10.5424/sjar/2008061-304 .
  25. ↑ J. D. Martín (1973). "New diterpenoids extractives of Maytenus dispermus". Tetrahedron . 29 (17): 2553–2559. doi:10.1016/0040-4020(73)80172-3.
  26. ↑ H B Bode & A Zeeck (2000). "Structure and biosynthesis of kendomycin, a carbocyclic ansa-compound from Streptomyces". J Chem Soc Perkin Trans 1. 323 (3): 323–328. doi:10.1039/a908387a.
  27. ↑ Burke Research Group University of Wisconsin
  28. ↑ Jansen R, Gerth K, Steinmetz H, Reinecke S, Kessler W, Kirschning A, Müller R (2011). "Elansolid A3, a Unique p-Quinone Methide Antibiotic from Chitinophaga sancti". Chem. Eur. J. 17 (28): 7739–44. doi:10.1002/chem.201100457. PMID   21626585.
  29. ↑ Thiem DA, Sneden AT, Khan SI, Tekwani BL (2005). "Bisnortriterpenes from Salacia madagascariensis". J Nat Prod . 68 (2): 251–254. doi:10.1021/np0497088. PMID   15730255.
  30. ↑ Setzer WN, Holland MT, Bozeman CA, Rozmus GF, Setzer MC, Moriarity DM, Reeb S, Vogler B, Bates RB, Haber WA (2001). "Isolation and frontier molecular orbital investigation of bioactive quinone-methide triterpenoids from the bark of Salacia petenensis". Planta Med . 67 (1): 65–69. doi:10.1055/s-2001-10879. PMID   11270725.
  31. ↑ Chávez H, Estévez-Braun A, Ravelo AG, González AG (1999). "New phenolic and quinone-methide triterpenes from Maytenus amazonica". J Nat Prod . 62 (3): 434–436. doi:10.1021/np980412+. PMID   10096852.
  32. ↑ González AG, Alvarenga NL, Bazzocchi IL, Ravelo AG, Moujir L (1998). "A new bioactive norquinone-methide triterpene from Maytenus scutioides". Planta Med . 64 (8): 767–771. doi:10.1055/s-2006-957581. PMID   10075545. S2CID   11522064.
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