Chemistry:Curcumin

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Short description: Principal curcuminoid of turmeric
Curcumin
Skeletal formula
Enol form
Skeletal formula
Keto form
Ball-and-stick model
Ball-and-stick model
Names
Pronunciation /ˈkɜːrkjʊmɪn/
Preferred IUPAC name
(1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione
Other names
(1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione
Diferuloylmethane
Curcumin I
C.I. 75300
Natural Yellow 3
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
UNII
Properties
C21H20O6
Molar mass 368.385 g·mol−1
Appearance Bright yellow-orange powder
Melting point 183 °C (361 °F; 456 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Curcumin is a bright yellow chemical produced by plants of the Curcuma longa species. It is the principal curcuminoid of turmeric (Curcuma longa), a member of the ginger family, Zingiberaceae. It is sold as a herbal supplement, cosmetics ingredient, food flavoring, and food coloring.[1]

Chemically, curcumin is a diarylheptanoid, belonging to the group of curcuminoids, which are phenolic pigments responsible for the yellow color of turmeric.[2]

Laboratory and clinical research have not confirmed any medical use for curcumin. It is difficult to study because it is both unstable and poorly bioavailable. It is unlikely to produce useful leads for drug development.[3]

History

Curcumin was named in 1815 when Henri Auguste Vogel and Pierre Joseph Pelletier reported the first isolation of a "yellow coloring-matter" from the rhizomes of turmeric.[4] Later, it was found to be a mixture of resin and turmeric oil. In 1910, Milobedzka and Lampe reported the chemical structure of curcumin to be as diferuloylmethane.[5] Later in 1913, the same group accomplished the synthesis of the compound.

Although used in traditional medicine, the possible therapeutic properties of turmeric or curcumin remain undetermined.[3][6][7]

Uses

Curcumin powder

The most common applications are as an ingredient in dietary supplement, in cosmetics, as flavoring for foods, such as turmeric-flavored beverages in South and Southeast Asia,[1] and as coloring for foods, such as curry powders, mustards, butters, and cheeses. As a food additive for orange-yellow coloring in prepared foods, its E number is E 100 in the European Union.[8][9] It is also approved by the U.S. FDA to be used as a food coloring in US.[10]

Chemistry

A bright red substance in a small glass flask, held by gloved fingers
Curcumin becomes bright red when it interacts electrostatically with a phospholipid film

Curcumin incorporates a seven carbon linker and three major functional groups: an α,β-unsaturated β-diketone moiety and an aromatic O-methoxy-phenolic group.[2][5] The aromatic ring systems, which are phenols, are connected by two α,β-unsaturated carbonyl groups.[2][11] It is a diketone tautomer, existing in enolic form in organic solvents and in keto form in water.[12] The diketones form stable enols and are readily deprotonated to form enolates; the α,β-unsaturated carbonyl group is a good Michael acceptor and undergoes nucleophilic addition.[citation needed] Because of its hydrophobic nature, curcumin is poorly soluble in water[2] but is easily soluble in organic solvents.[5]

Curcumin is used as a complexometric indicator for boron.[2][13] It reacts with boric acid to form a red-colored compound, rosocyanine.

Biosynthesis

The biosynthetic route of curcumin is uncertain. In 1973, Peter J. Roughley and Donald A. Whiting proposed two mechanisms for curcumin biosynthesis. The first mechanism involves a chain extension reaction by cinnamic acid and 5 malonyl-CoA molecules that eventually arylize into a curcuminoid. The second mechanism involves two cinnamate units coupled together by malonyl-CoA. Both use cinnamic acid as their starting point, which is derived from the amino acid phenylalanine.[14]

Plant biosynthesis starting with cinnamic acid is rare compared to the more common p-coumaric acid.[14] Only a few identified compounds, such as anigorufone and pinosylvin, build from cinnamic acid.[15][16]


Curcumin biosynthesis diagram
Biosynthetic pathway of curcumin in Curcuma longa.[14]

Pharmacology

Curcumin displays green fluorescence under UV light

Curcumin, which shows positive results in most drug discovery assays, is regarded as a false lead that medicinal chemists include among "pan-assay interference compounds". This attracts undue experimental attention while failing to advance as viable therapeutic or drug leads,[3][6][17] although some derivatives of curcumin such as EF-24 have seen a significant amount of research.[18]

Factors that limit the bioactivity of curcumin or its analogs include chemical instability, water insolubility, absence of potent and selective target activity, low bioavailability, limited tissue distribution, and extensive metabolism.[3] Very little curcumin escapes the GI tract and most is excreted in feces unchanged.[19] If curcumin enters plasma in reasonable amounts, there is a high risk of toxicity since it is promiscuous, and interacts with several proteins known to increase the risk of adverse effects, including hERG, cytochrome P450s, and glutathione S-transferase.[3]

Safety

As a component of turmeric, curcumin may interact with prescription drugs and dietary supplements.[20] In high amounts, it may be unsafe for women during pregnancy.[20] It may cause side effects, such as nausea, diarrhea, hives, or dizziness.[20] Between 2004 and 2022 there were ten cases of liver injury caused by curcumin herbal and dietary supplements.[21] Curcumin is a contact allergen.[22]

The intended use of curcumin as a food additive is generally recognized as safe by the U.S. Food and Drug Administration.[23]

Medical research

Although curcumin has been assessed in numerous laboratory and clinical studies, it has no medical uses established by well-designed clinical research.[24] According to a 2017 review of more than 120 studies, curcumin has not been successful in any clinical trial, leading the authors to conclude that "curcumin is an unstable, reactive, non-bioavailable compound and, therefore, a highly improbable lead".[3] Curcumin exhibits numerous interference properties which may lead to misinterpretation of results.[3][6][25]

The US government has supported US$150 million in research into curcumin through the National Center for Complementary and Integrative Health, and no support has been found for curcumin as a medical treatment.[3][26]

Research fraud

Bharat Aggarwal was a cancer researcher at the University of Texas MD Anderson Cancer Center, who (As of July 2021 ) had 29 papers retracted for research fraud.[27][28][29] Aggarwal's research had focused on potential anti-cancer properties of herbs and spices, particularly curcumin, and according to a March 2016 article in the Houston Chronicle, "attracted national media interest and laid the groundwork for ongoing clinical trials".[30][31][32] Aggarwal co-founded a company in 2004 called Curry Pharmaceuticals, based in Research Triangle Park, North Carolina, which was seeking to develop drugs based on synthetic analogs of curcumin.[31][33] SignPath Pharma, a company seeking to develop liposomal formulations of curcumin, licensed three patents invented by Aggarwal related to that approach from MD Anderson in 2013.[34]

FDA warnings about dietary supplements

Between 2018 and 2023, the FDA issued 29 warning letters to American manufacturers of dietary supplements for making false claims of anti-disease effects from using products containing curcumin.[35] In each letter, the FDA stated that the supplement product was not an approved new drug because the "product is not generally recognized as safe and effective" for the advertised uses, that "new drugs may not be legally introduced or delivered for introduction into interstate commerce without prior approval from FDA", and that the "FDA approves a new drug on the basis of scientific data and information demonstrating that the drug is safe and effective".[35]

Alternative medicine

Though there is no evidence for the safety or efficacy of using curcumin as a therapy,[3][6] some alternative medicine practitioners give it intravenously, supposedly as a treatment for numerous diseases.[36][37][38] In 2017, two serious cases of adverse events were reported from curcumin or turmeric products—one severe allergic reaction and one death[36]—that were caused by administration of a curcumin-polyethylene glycol (PEG40) emulsion product by a naturopath.[38] One treatment caused anaphylaxis leading to death.[36][38]

Stability

Decontamination of food by ionizing radiation, or food irradiation, is considered a safe and efficient process for elimination of pathogenic bacteria.[39][40] Ionizing radiation treatment can be applied to either raw materials or ready to eat foods, with some countries, like the United States, imposing limitations on its use.[39][41] In 2016, laboratory research established and compared the radiosensitivity of three organic food colorants including curcumin, carmine, and annatto to create data to be used for application whenever food products containing these food colors were to undergo the radiation process.[39] The researchers used spectrophotometry and capillary electrophoresis to establish radiosensitivity of the three organic food colorants. Carmine samples were quite stable against radiation treatment, annatto showed limited stability, and curcumin was found to be stable at high temperatures and in acids, but unstable in alkaline conditions and in the presence of light.[39]

References

  1. ↑ 1.0 1.1 "The State of the Curcumin Market" (in en-US). December 28, 2015. http://www.naturalproductsinsider.com/articles/2015/12/the-state-of-the-curcumin-market.aspx. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 CID 969516 from PubChem
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 "The Essential Medicinal Chemistry of Curcumin". Journal of Medicinal Chemistry 60 (5): 1620–1637. March 2017. doi:10.1021/acs.jmedchem.6b00975. PMID 28074653. 
    See also: "Curcumin May (Not) Defy Science". ACS Medicinal Chemistry Letters 8 (5): 467–470. May 2017. doi:10.1021/acsmedchemlett.7b00139. PMID 28523093. 
  4. ↑ Vogel, A; Pelletier, J (July 1815). "Examen chimique de la racine de Curcuma" (in fr). Journal de Pharmacie et des Sciences Accessoires 1: 289–300. Template:Gallica. https://books.google.com/books?id=dqU8AAAAcAAJ&pg=PA289. 
  5. ↑ 5.0 5.1 5.2 Farooqui, Tahira; Farooqui, Akhlaq A. (2019). "Curcumin: Historical Background, Chemistry, Pharmacological Action, and Potential Therapeutic Value". Curcumin for Neurological and Psychiatric Disorders. pp. 23–44. doi:10.1016/B978-0-12-815461-8.00002-5. ISBN 978-0-12-815461-8. 
  6. ↑ 6.0 6.1 6.2 6.3 "Deceptive curcumin offers cautionary tale for chemists". Nature 541 (7636): 144–145. January 2017. doi:10.1038/541144a. PMID 28079090. Bibcode: 2017Natur.541..144B. 
  7. ↑ "Turmeric". US National Center for Complementary and Integrative Health, National Institutes of Health. April 2020. https://nccih.nih.gov/health/turmeric/ataglance.htm. 
  8. ↑ European Commission. "Food Additives". https://webgate.ec.europa.eu/foods_system/main/index.cfm?event=substance.view&identifier=5. 
  9. ↑ "Curcumin, E 100, page 9". Specifications for food additives listed in Annexes II and III to Regulation (EC) No 1333/2008 of the European Parliament. March 9, 2012. https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:2012R0231:20121129:EN:PDF. 
  10. ↑ "CFR – Code of Federal Regulations Title 21". https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=73.600. 
  11. ↑ "Zur Kenntnis des Curcumins" (in de). Berichte der Deutschen Chemischen Gesellschaft 43 (2): 2163–2170. 1910. doi:10.1002/cber.191004302168. https://zenodo.org/record/1426403. 
  12. ↑ "The effect of the water on the curcumin tautomerism: a quantitative approach". Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 132: 815–820. November 2014. doi:10.1016/j.saa.2014.05.096. PMID 24973669. Bibcode: 2014AcSpA.132..815M. http://eprints.ugd.edu.mk/10453/1/The%20effect%20of%20the%20water%20on%20the%20curcumin%20tautomerism.pdf. 
  13. ↑ "EPA Methods – PDF – EPA Method 2123 – CAS Analytical Genprice Lab". https://caslab.com/EPA-Methods/PDF/EPA-Method-2123.pdf. 
  14. ↑ 14.0 14.1 14.2 "The biosynthetic pathway of curcuminoid in turmeric (Curcuma longa) as revealed by 13C-labeled precursors". Bioscience, Biotechnology, and Biochemistry 72 (7): 1789–1798. July 2008. doi:10.1271/bbb.80075. PMID 18603793. 
  15. ↑ "Variability of phenylpropanoid precursors in the biosynthesis of phenylphenalenones in Anigozanthos preissii". Phytochemistry 53 (3): 331–337. February 2000. doi:10.1016/S0031-9422(99)00544-0. PMID 10703053. 
  16. ↑ "Stilbene Synthase from Seedlings of Pinus sylvestris: Purification and Induction in Response to Fungal Infection". Molecular Plant-Microbe Interactions 3 (6): 444–449. 1990. doi:10.1094/MPMI-3-444. http://www.apsnet.org/publications/mpmi/backissues/Documents/1990Articles/Microbe03_444.pdf. 
  17. ↑ "Can Invalid Bioactives Undermine Natural Product-Based Drug Discovery?". Journal of Medicinal Chemistry 59 (5): 1671–1690. March 2016. doi:10.1021/acs.jmedchem.5b01009. PMID 26505758. 
  18. ↑ He, Yonghan; Li, Wen; Hu, Guangrong; Sun, Hui; Kong, Qingpeng (11 December 2018). "Bioactivities of EF24, a Novel Curcumin Analog: A Review". Frontiers in Oncology 8: 614. doi:10.3389/fonc.2018.00614. PMID 30619754. 
  19. ↑ "Curcumin uptake and metabolism". BioFactors 39 (1): 14–20. 2013. doi:10.1002/biof.1042. PMID 22996406. 
  20. ↑ 20.0 20.1 20.2 "Turmeric". Drugs.com. December 6, 2017. https://www.drugs.com/mtm/turmeric.html. 
  21. ↑ Halegoua-DeMarzio, Dina; Navarro, Victor; Ahmad, Jawad; Avula, Bharathi; Barnhart, Huiman; Barritt, A. Sidney; Bonkovsky, Herbert L.; Fontana, Robert J. et al. (2023). "Liver Injury Associated with Turmeric—A Growing Problem: Ten Cases from the Drug-Induced Liver Injury Network [DILIN"]. The American Journal of Medicine (Elsevier BV) 136 (2): 200–206. doi:10.1016/j.amjmed.2022.09.026. ISSN 0002-9343. PMID 36252717. 
  22. ↑ "Curcumin: A Contact Allergen". J Clin Aesthet Dermatol 8 (11): 43–48. November 2015. PMID 26705440. 
  23. ↑ "GRAS Notice (GRN) No. 822". GRAS Notice Inventory. https://www.fda.gov/media/132575/download. 
  24. ↑ "Curcumin". Micronutrient Information Center; Phytochemicals. Linus Pauling Institute, Oregon State University, Corvallis. 2016. http://lpi.oregonstate.edu/mic/dietary-factors/phytochemicals/curcumin. 
  25. ↑ Lowe, Derek (12 January 2017). "Curcumin Will Waste Your Time". Science Blogs. https://www.science.org/content/blog-post/curcumin-waste-your-time. 
  26. ↑ "Everybody Needs To Stop With This Turmeric Molecule". Forbes. January 19, 2017. https://www.forbes.com/sites/samlemonick/2017/01/19/everybody-needs-to-quit-it-with-this-turmeric-molecule/#39ccce9079ff. 
  27. ↑ "The Retraction Watch Leaderboard". 16 June 2015. https://retractionwatch.com/the-retraction-watch-leaderboard/. 
  28. ↑ "M.D. Anderson professor under fraud probe". Houston Chronicle. February 29, 2012. http://www.chron.com/news/houston-texas/article/M-D-Anderson-professor-under-fraud-probe-3360037.php. 
  29. ↑ "Caught Our Notice: Researcher who once threatened to sue Retraction Watch now up to 19 retractions". Retraction Watch. April 10, 2018. https://retractionwatch.com/2018/04/10/caught-our-notice-researcher-who-once-threatened-to-sue-retraction-watch-now-up-to-19-retractions/#more-63985. 
  30. ↑ "M.D. Anderson scientist, accused of manipulating data, retires". Houston Chronicle. March 2, 2016. https://www.houstonchronicle.com/news/houston-texas/houston/article/M-D-Anderson-scientist-accused-of-falsifying-6865704.php. 
  31. ↑ 31.0 31.1 "Spice Healer". Scientific American 296 (2): 66–69. February 2007. doi:10.1038/scientificamerican0207-66. PMID 17367023. Bibcode: 2007SciAm.296b..66S. 
  32. ↑ "In cancer fight, a spice brings hope to the table". Houston Chronicle. July 11, 2005. http://www.chron.com/news/houston-texas/article/In-cancer-fight-a-spice-brings-hope-to-the-table-1913487.php. 
  33. ↑ "From exotic spice to modern drug?". Cell 130 (5): 765–768. September 2007. doi:10.1016/j.cell.2007.08.024. PMID 17803897. 
  34. ↑ "Biotech startup raises $1M for lung cancer treatment using component of tumeric". Med City News. March 26, 2013. https://medcitynews.com/2013/03/biotech-startup-raises-1m-for-lung-cancer-treatment-using-component-of-tumeric/?trendmd_shared=0. 
  35. ↑ 35.0 35.1 "Warning Letters: Curcumin (search term)". US Food and Drug Administration. 23 April 2023. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters. 
  36. ↑ 36.0 36.1 36.2 "FDA investigates two serious adverse events associated with ImprimisRx's compounded curcumin emulsion product for injection". Food and Drug Administration. August 4, 2017. https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm570192.htm. 
  37. ↑ "Naturopathic Doctors Look Bad After California Woman Dies From Turmeric Injection". Forbes. March 27, 2017. https://www.forbes.com/sites/brittmariehermes/2017/03/27/naturopathic-doctors-look-bad-after-california-woman-dies-from-turmeric-injection/. 
  38. ↑ 38.0 38.1 38.2 "Confirmed: Licensed Naturopathic Doctor Gave Lethal 'Turmeric' Injection". Forbes. April 10, 2017. https://www.forbes.com/sites/brittmariehermes/2017/04/10/confirmed-licensed-naturopathic-doctor-gave-lethal-turmeric-injection/#3f73874d6326. 
  39. ↑ 39.0 39.1 39.2 39.3 Cosentino, Helio M.; Takinami, Patricia Y.I.; del Mastro, Nelida L. (2016). "Comparison of the ionizing radiation effects on cochineal, annatto and turmeric natural dyes" (in en). Radiation Physics and Chemistry 124: 208–211. doi:10.1016/j.radphyschem.2015.09.016. Bibcode: 2016RaPC..124..208C. https://linkinghub.elsevier.com/retrieve/pii/S0969806X1530058X. 
  40. ↑ Farkas, József; Mohácsi-Farkas, Csilla (2011). "History and future of food irradiation" (in en). Trends in Food Science & Technology 22 (2–3): 121–126. doi:10.1016/j.tifs.2010.04.002. https://linkinghub.elsevier.com/retrieve/pii/S0924224410001044. 
  41. ↑ "Code of Federal Regulations: Title 21, Section 179.26". U.S. Food and Drug Administration. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-179/subpart-B/section-179.26. 



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