Quinone methide explained

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.

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 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),[5] anti-inflammatory,[6] anticancer,[7] [8] [9] [10] and insecticidal [11] activities.

Pristimerin, the methyl ester of celasterol, is a triterpenoid quinone methide isolated from Maytenus heterophylla that displays antitumor and antiviral [12] activities. Pristimerin has also been found to have a contraceptive effect due to its inhibiting effect on the calcium channel of sperm (CatSper).[13]

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,[14] [15] [16] antibacterial,[17] [18] [19] antioxidant,[20] antifungal,[21] insecticide,[22] and antifeedant [23] activities.

Maytenoquinone, an isomer of taxodione, is a biologically active quinone methide found in Maytenus dispermus.[24]

Kendomycin is an antitumor antibacterial quinone methide macrolide first isolated from the bacterium Streptomyces violaceoruber.[25] It has potent activity as an endothelin receptor antagonist and anti-osteoporosis agent.[26]

Elansolid A3 is a quinone methide from the bacterium Chitinophaga sancti that displays antibiotic activity.[27] Antibacterial quinone methides, 20-epi-isoiguesterinol, 6-oxoisoiguesterin, isoiguesterin and isoiguesterinol were found in Salacia madagascariensis.[28] Quinone methides tingenone and netzahualcoyonol were isolated from Salacia petenensis.[29] Nortriterpenoid quinone methide amazoquinone and (7S, 8S)-7-hydroxy-7,8-dihydro-tingenone were isolated from Maytenus amazonica.[30] An antimicrobial quinone methide, 15 alpha-hydroxypristimerin, was isolated from a South American medicinal plant, Maytenus scutioides.[31]

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.

External links

Notes and References

  1. Cavitt . S. B. . R. . H. Sarrafizadeh . Gardner . P. D. . The Structure of o-Quinone Methide Trimer . The Journal of Organic Chemistry . April 1962 . 27 . 4 . 1211–1216 . 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. http://www.ars.usda.gov/research/publications/publications.htm?seq_no_115=229334 Quinone Methides in Lignification
  4. Wang P, Song Y, Zhang L, He H, Zhou X . Quinone methide derivatives: important intermediates to DNA alkylating and DNA cross-linking actions . . 2005 . 12 . 24 . 2893–2913 . 16305478 . 10.2174/092986705774454724.
  5. Allison AC, Cacabelos R, Lombardi VR, Alvarez XA, Vigo C . Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer's disease.. . 2001 . 25 . 7 . 1341–1357 . 10.1016/S0278-5846(01)00192-0 . 11513350. 21569585.
  6. Kim DH, Shin EK, Kim YH, Lee BW, Jun JG, Park JH, Kim JK . Suppression of inflammatory responses by celastrol, a quinone methide triterpenoid isolated from Celastrus regelii . . 2009 . 39 . 9 . 819–827 . 10.1111/j.1365-2362.2009.02186.x . 19549173. 205291261 .
  7. Lee JH, Choi KJ, Seo WD, Jang SY, Kim M, Lee BW, Kim JY, Kang S, Park KH, Lee YS, Bae S . Enhancement of radiation sensitivity in lung cancer cells by celastrol is mediated by inhibition of Hsp90.. Int J Mol Med. 2011 . 27 . 3 . 441–446 . 21249311 . 10.3892/ijmm.2011.601. free.
  8. Tiedemann. Identification of a potent natural triterpenoid inhibitor of proteosome chymotrypsin-like activity and NF-kappaB with antimyeloma activity in vitro and in vivo. . . 2009 . 113 . 4027–37 . 10.1182/blood-2008-09-179796 . 19096011 . 17. etal . 3952546.
  9. Zhu H, Liu XW, Cai TY, Cao J, Tu CX, Lu W, He QJ, Yang B . 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 . . 2010 . 334 . 2 . 489–499 . 20472666 . 10.1124/jpet.110.165654. 25854329.
  10. Byun. 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. . . 2009 . 76 . 734–44 . 10.1124/mol.109.056259 . 19574249 . 4. 6541041 . etal.
  11. Avilla J, Teixidò A, Velázquez C, Alvarenga N, Ferro E, Canela R . Insecticidal activity of Maytenus species (Celastraceae) nortriterpene quinone methides against codling moth, Cydia pomonella (L.) (Lepidoptera: tortricidae).. . 2000 . 48 . 1 . 88–92 . 10.1021/jf990008w . 10637057.
  12. Murayama T, Eizuru Y, Yamada R, Sadanari H, Matsubara K, Rukung G, Tolo FM, Mungai GM, Kofi-Tsekpo M . Anticytomegalovirus activity of pristimerin, a triterpenoid quinone methide isolated from Maytenus heterophylla (Eckl. & Zeyh.).. . 2007 . 18 . 3 . 133–139. 17626597 . 10.1177/095632020701800303. 22381089.
  13. Nadja Mannowetza . Melissa R. Millera . Polina V. Lishko . Regulation of the sperm calcium channel CatSper by endogenous steroids and plant triterpenoids. . 2017 . 114. 22. 5743–5748. 10.1073/pnas.1700367114 . 28507119. 5465908. 2017PNAS..114.5743M. free.
  14. Kupchan, S. M. . Karim, A . Marcks, C. . Tumor inhibitors. XXXIV. Taxodione and taxodone, two novel diterpenoid quinone methide tumor inhibitors from Taxodium distichum. . 1968. 90 . 5923–4 . 21 . 10.1021/ja01023a061 . 5679178.
  15. Zaghloul AM, Gohar AA, Naiem ZA, Abdel Bar FM . Taxodione, a DNA-binding compound from Taxodium distichum L. (Rich.). . . 2008. 63 . 5–6. 355–360 . 10.1515/znc-2008-5-608. 18669020 . 23956301. free .
  16. Ayhan Ulubelen, Gülaçti Topçu, Hee-Byung Chai and John M. Pezzuto . Cytotoxic Activity of Diterpenoids Isolated from Salvia hypargeia . . 1999. 37 . 2 . 148–151 . 10.1076/phbi.37.2.148.6082.
  17. Vivek K. Bajpai . Sun Chul Kan . amp . Antibacterial abietane-type diterpenoid, taxodone from Metasequoia glyptostroboides Miki ex Hu. . 2010. 35. 533–538. 4 . 10.1007/s12038-010-0061-z . 21289435. 25656295.
  18. Vivek K. Bajpai . Minkyun Na . Sun Chul Kang . The role of bioactive substances in controlling foodborne pathogens derived from Metasequoia glyptostroboides Miki ex Hu. . 2010. 48. 7 . 1945–1949 . 10.1016/j.fct.2010.04.041 . 20435080.
  19. Tada M, Kurabe J, Yoshida T, Ohkanda T, Matsumoto Y . Syntheses and antibacterial activities of diterpene catechol derivatives with abietane, totarane and podocarpane skeletons against methicillin-resistant Staphylococcus aureus and Propionibacterium acnes . . 2010. 58 . 6 . 818–824 . 10.1248/cpb.58.818. free . 20522992.
  20. Ufuk Kolak . Ahmed Kabouche . Mehmet Öztürk . Zahia Kabouche . Gülaçtl Topçu . Ayhan Ulubelen . Ayhan Ulubelen . Antioxidant diterpenoids from the roots of Salvia barrelieri. . 2009. 20. 320–327. 4 . 10.1002/pca.1130 . 19402189. 2009PChAn..20..320K .
  21. Norihisa Kusumoto . Tatsuya Ashitani . Tetsuya Murayama . Koichi Ogiyama . Koetsu Takahashi . Antifungal Abietane-Type Diterpenes from the Cones of Taxodium distichum Rich. . 2010. 36. 1381–1386. 12 . 10.1007/s10886-010-9875-2. 21072573 . 11861719.
  22. Norihisa Kusumoto . Tatsuya Ashitani . Yuichi Hayasaka . Tetsuya Murayama . Koichi Ogiyama . Koetsu Takahashi . Antitermitic Activities of Abietane-type Diterpenes from Taxodium distichum Cones. . 2009. 35. 635–642. 6 . 10.1007/s10886-009-9646-0. 19475449 . 42622420.
  23. M. C. Ballesta-Acosta1, M. J. Pascual-Villalobos and B. Rodríguez . Short communication. The antifeedant activity of natural plant products towards the larvae of Spodoptera littoralis . . 2008. 6 . 1 . 85–91 . 10.5424/sjar/2008061-304. free.
  24. J. D. Martín. New diterpenoids extractives of Maytenus dispermus. . 1973. 29. 17. 2553–2559. 10.1016/0040-4020(73)80172-3.
  25. H B Bode . A Zeeck . amp . J Chem Soc Perkin Trans 1 . 2000 . 323 . 3 . 10.1039/a908387a . Structure and biosynthesis of kendomycin, a carbocyclic ansa-compound from Streptomyces . 323–328.
  26. https://web.archive.org/web/20060829132137/http://www.chem.wisc.edu/~burke/Kendo.htm Burke Research Group
  27. Jansen R, Gerth K, Steinmetz H, Reinecke S, Kessler W, Kirschning A, Müller R . Elansolid A3, a Unique p-Quinone Methide Antibiotic from Chitinophaga sancti.. . 2011 . 21626585 . 10.1002/chem.201100457 . 17 . 28 . 7739–44.
  28. Thiem DA, Sneden AT, Khan SI, Tekwani BL . Bisnortriterpenes from Salacia madagascariensis.. . 2005 . 68 . 2 . 251–254 . 10.1021/np0497088. 15730255.
  29. Setzer WN, Holland MT, Bozeman CA, Rozmus GF, Setzer MC, Moriarity DM, Reeb S, Vogler B, Bates RB, Haber WA . Isolation and frontier molecular orbital investigation of bioactive quinone-methide triterpenoids from the bark of Salacia petenensis.. . 2001 . 67 . 1 . 65–69 . 11270725 . 10.1055/s-2001-10879.
  30. Chávez H, Estévez-Braun A, Ravelo AG, González AG . New phenolic and quinone-methide triterpenes from Maytenus amazonica.. . 1999 . 62 . 3 . 434–436 . 10096852 . 10.1021/np980412+.
  31. González AG, Alvarenga NL, Bazzocchi IL, Ravelo AG, Moujir L . A new bioactive norquinone-methide triterpene from Maytenus scutioides.. . 1998 . 64 . 8 . 767–771 . 10075545 . 10.1055/s-2006-957581. 11522064.

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