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Curcumin

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Not to be confused with Curculin.
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
ECHA InfoCard 100.006.619 Edit this at Wikidata
E number E100 (colours)
UNII
  • InChI=1S/C21H20O6/c1-26-20-11-14(5-9-18(20)24)3-7-16(22)13-17(23)8-4-15-6-10-19(25)21(12-15)27-2/h3-12,24-25H,13H2,1-2H3/b7-3+,8-4+ checkY
    Key: VFLDPWHFBUODDF-FCXRPNKRSA-N checkY
  • InChI=1/C21H20O6/c1-26-20-11-14(5-9-18(20)24)3-7-16(22)13-17(23)8-4-15-6-10-19(25)21(12-15)27-2/h3-12,24-25H,13H2,1-2H3/b7-3+,8-4+
    Key: VFLDPWHFBUODDF-FCXRPNKRBF
  • O=C(\C=C\c1ccc(O)c(OC)c1)CC(=O)\C=C\c2cc(OC)c(O)cc2
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).
☒N verify (what is checkY☒N ?)

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

Chemically, curcumin is a diarylheptanoid, belonging to the group of curcuminoids, which are natural phenols responsible for turmeric's yellow color. It is a tautomeric compound existing in enolic form in organic solvents, and as a keto form in water.[2] Although thoroughly studied in laboratory and clinical studies, curcumin has no confirmed medical uses, and has proved frustrating to scientists because it is unstable, not bioavailable, and unlikely to produce useful leads for drug development.[3]

History

It was first isolated in 1815 when Vogel and Pierre Joseph Pelletier reported the isolation of a "yellow coloring-matter" from the rhizomes of turmeric and named it curcumin.[4] Although curcumin has been used historically in Ayurvedic medicine,[5] its potential for medicinal properties remains unproven as a therapy when used orally.[3][6][7]

Uses

Curcumin powder

The most common applications are as an ingredient in dietary supplement, in cosmetics, and as flavoring for foods, such as turmeric-flavored beverages in the Indian Subcontinent and Southeast Asia.[1] As a food additive for gold-orange coloring in turmeric and prepared foods, its E number is E100.[8]

Annual sales of curcumin have increased since 2012.[1] The largest market is in North America, where sales exceeded US$20 million in 2014.[1]

Chemistry

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

Curcumin incorporates several functional groups whose structure was first identified in 1910.[9] The aromatic ring systems, which are phenols, are connected by two α,β-unsaturated carbonyl groups. 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.

Curcumin is used as a complexometric indicator for boron.[10] It reacts with boric acid to form a red-colored compound, rosocyanine.

Biosynthesis

The biosynthetic route of curcumin is uncertain. In 1973, Roughly and 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 arylized 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.[11]

Plant biosyntheses starting with cinnamic acid is rare compared to the more common p-coumaric acid.[11] Only a few identified compounds, such as anigorufone and pinosylvin, build from cinnamic acid.[12][13]


Curcumin biosynthesis diagram
Biosynthetic pathway of curcumin in Curcuma longa.[11]

Pharmacology

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" attracting undue experimental attention while failing to advance as viable therapeutic or drug leads.[3][6][14] In vitro, curcumin inhibits certain epigenetic enzymes (the histone deacetylases: HDAC1, HDAC3, HDAC8), transcriptional co-activator proteins (the p300 histone acetyltransferase)[15][16][17] and the arachidonate 5-lipoxygenase enzyme.[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, extensive metabolism, and potential for toxicity.[3]

Safety

Two preliminary clinical studies in cancer patients consuming high doses of curcumin (up to 8 grams per day for 3–4 months) showed no toxicity, though some subjects reported mild nausea or diarrhea.[19]

Research

In vitro, curcumin exhibits numerous interference properties which may lead to misinterpretation of results.[3][6][20] Although curcumin has been assessed in numerous laboratory and clinical studies, it has no medical uses established by well-designed clinical research.[21] According to a 2017 review of over 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]

Cancer studies using curcumin conducted by Bharat Aggarwal, formerly a researcher at the MD Anderson Cancer Center, were deemed fraudulent and subsequently retracted by the publisher.[22]

Adverse reaction to intravenous injection

Despite concerns about safety or efficacy and the absence of reliable clinical research,[3][6] some alternative medicine practitioners give turmeric intravenously, supposedly as a treatment for numerous diseases.[23] In 2017 there were two serious cases of adverse events reported – one severe allergic reaction and one death – that were caused by injection of a curcumin emulsion product administered by a naturopath.[24][25]

The US government has supported $150 million in research into curcumin through the National Center for Complementary and Integrative Health.

References

  1. ^ a b c d Majeed, Shaheen (28 December 2015). "The State of the Curcumin Market". Natural Products Insider.
  2. ^ Manolova, Yana; Deneva, Vera; Antonov, Liudmil; Drakalska, Elena; Momekova, Denitsa; Lambov, Nikolay (2014). "The effect of the water on the curcumin tautomerism: A quantitative approach". Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 132: 815–820. doi:10.1016/j.saa.2014.05.096. {{cite journal}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  3. ^ a b c d e f g Nelson, K. M.; Dahlin, J. L.; Bisson, J.; Graham, J.; Pauli, G. F.; Walters, M. A. (2017). "The Essential Medicinal Chemistry of Curcumin: Miniperspective". Journal of Medicinal Chemistry. 60 (5): 1620–1637. doi:10.1021/acs.jmedchem.6b00975. PMC 5346970. PMID 28074653.
  4. ^ Vogel, H.; Pelletier, J. (1815). "Curcumin –biological and medicinal properties". Journal de Pharmacie. I: 289.
  5. ^ Wilken, Reason; Veena, Mysore S.; Wang, Marilene B.; Srivatsan, Eri S. (2011). "Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma". Molecular Cancer. 10: 12. doi:10.1186/1476-4598-10-12. ISSN 1476-4598. PMC 3055228. PMID 21299897.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  6. ^ a b c d Baker, Monya (9 January 2017). "Deceptive curcumin offers cautionary tale for chemists". Nature. 541 (7636): 144–145. doi:10.1038/541144a. PMID 28079090.
  7. ^ "Turmeric". US National Center for Complementary and Integrative Health, National Institutes of Health. 31 May 2016. Retrieved 15 June 2016.
  8. ^ European Commission. "Food Additives". Retrieved 2014-02-15.
  9. ^ Miłobȩdzka, J.; van Kostanecki, S.; Lampe, V. (1910). "Zur Kenntnis des Curcumins". Berichte der deutschen chemischen Gesellschaft. 43 (2): 2163–2170. doi:10.1002/cber.191004302168.
  10. ^ "EPA Method 212.3: Boron (Colorimetric, Curcumin)" (PDF).
  11. ^ a b c Kita, Tomoko; Imai, Shinsuke; Sawada, Hiroshi; Kumagai, Hidehiko; Seto, Haruo (2008). "The Biosynthetic Pathway of Curcuminoid in Turmeric (Curcuma longa) as Revealed by 13C-Labeled Precursors". Bioscience, Biotechnology, and Biochemistry. 72 (7): 1789–1798. doi:10.1271/bbb.80075.
  12. ^ Schmitt, Bettina; Hölscher, Dirk; Schneider, Bernd (2000). "Variability of phenylpropanoid precursors in the biosynthesis of phenylphenalenones in Anigozanthos preissii". Phytochemistry. 53 (3): 331–337. doi:10.1016/S0031-9422(99)00544-0. PMID 10703053.
  13. ^ Gehlert, R.; Schoeppner, A.; Kindl, H. (1990). "Stilbene Synthase from Seedlings of Pinus sylvestris: Purification and Induction in Response to Fungal Infection" (pdf). Molecular Plant-Microbe Interactions. 3 (6): 444–449. doi:10.1094/MPMI-3-444.
  14. ^ Bisson, Jonathan; McAlpine, James B.; Friesen, J. Brent; Chen, Shao-Nong; Graham, James; Pauli, Guido F. (2016-03-10). "Can Invalid Bioactives Undermine Natural Product-Based Drug Discovery?". Journal of Medicinal Chemistry. 59 (5): 1671–1690. doi:10.1021/acs.jmedchem.5b01009. ISSN 0022-2623. PMC 4791574. PMID 26505758.
  15. ^ Reuter, S.; Gupta, S. C.; Park, B.; Goel, A.; Aggarwal, B. B. (May 2011). "Epigenetic changes induced by curcumin and other natural compounds". Genes & Nutrition. 6 (2): 93–108. doi:10.1007/s12263-011-0222-1. PMC 3092901. PMID 21516481.
  16. ^ Vahid, F.; Zand, H.; Nosrat-Mirshekarlou, E.; Najafi, R.; Hekmatdoost, A. (May 2015). "The role dietary of bioactive compounds on the regulation of histone acetylases and deacetylases: a review". Gene. 562 (1): 8–15. doi:10.1016/j.gene.2015.02.045. PMID 25701602.
  17. ^ "Curcumin". IUPHAR. IUPHAR/BPS Guide to PHARMACOLOGY. Retrieved 22 May 2015.
  18. ^ Bishayee, K.; Khuda-Bukhsh, A. R. (September 2013). "5-lipoxygenase antagonist therapy: a new approach towards targeted cancer chemotherapy". Acta Biochimica et Biophysica Sinica. 45 (9). Shanghai: 709–719. doi:10.1093/abbs/gmt064. PMID 23752617.
  19. ^ Hsu, C. H.; Cheng, A. L. (2007). "Clinical studies with curcumin". Advances in Experimental Medicine and Biology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY. 595: 471–480. doi:10.1007/978-0-387-46401-5_21. ISBN 978-0-387-46400-8. PMID 17569225.
  20. ^ Lowe, Derek (12 January 2017). "Curcumin Will Waste Your Time". In the Pipeline.
  21. ^ "Curcumin". Micronutrient Information Center; Phytochemicals. Linus Pauling Institute, Oregon State University, Corvallis. 2016. Retrieved 18 June 2016.
  22. ^ Ackerman, T. (29 February 2012). "M.D. Anderson professor under fraud probe". Houston Chronicle. Retrieved 8 March 2016.
  23. ^ Hermes, Britt Marie (27 March 2017). "Naturopathic Doctors Look Bad After California Woman Dies From Turmeric Injection". Forbes. Retrieved 12 May 2017.
  24. ^ "FDA investigates two serious adverse events associated with ImprimisRx's compounded curcumin emulsion product for injection". Food and Drug Administration. 4 August 2017.
  25. ^ Hermes, Britt Marie (April 10, 2017). "Confirmed: Licensed Naturopathic Doctor Gave Lethal 'Turmeric' Injection". Forbes. Retrieved December 9, 2017.
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