Curcumin

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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 ?)
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 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 Keto–enol tautomer, existing in enolic form in organic solvents and in keto form in water.[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 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 curcumin has been used historically in Ayurvedic medicine,[6] its potential for medicinal properties remains unproven as a therapy when used orally.[3][7][8]

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, cheeses. As a food additive for orange-yellow coloring in prepared foods, its E number is E 100 in the European Union.[9][10] It is also approved by the U.S. FDA to be used as a food coloring in USA.[11]

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 a seven carbon linker and three major functional groups: an α,β-unsaturated β-diketone moiety and an aromatic O-methoxy-phenolic group.[5] The aromatic ring systems, which are phenols, are connected by two α,β-unsaturated carbonyl groups.[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. Because of its hydrophobic nature, curcumin is poorly soluble in water. However, it is easily soluble in organic solvents.[5]

Curcumin is used as a complexometric indicator for boron.[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][7][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]

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.[21]

The intended use of curcumin as a food additive is generally recognized as safe by the U.S. Food and Drug Administration.[22]

Research

In vitro, curcumin exhibits numerous interference properties which may lead to misinterpretation of results.[3][7][23] 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]

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][25] Curcumin has been identified by the U.S. Food and Drug Administration as a "fake cancer 'cure'".[26]

Nevertheless, the research on curcumin did not stop. A set of hybrid compounds based on the structure of curcumin and resveratrol was synthesized and tested on colorectal cancer cells and showed IC50 values ranging from 11.52 ± 2.78 to 29.18 ± 4.36 µM with selectivity indices (SI) higher than 1 compared to the reference drug, 5-fluorouracil (SI = 0.96), the starting compound resveratrol (SI = 0.45) and the equimolar mixture of curcumin plus resveratrol (SI = 0.77) after 48 h of treatment.[27]

Another study showed that curcumin may induce apoptosis by inhibiting the BCAT1 and mTOR pathways in cytarabine‑resistant myeloid leukemia cells.[28]

A review published in 2021 discussed the contribution of curcumin in treatment and mitigation of colorectal cancer as well.[29]

Research fraud

Bharat Aggarwal was a cancer researcher at the University of Texas MD Anderson Cancer Center, who as of April 2018 had 19 papers retracted for research fraud.[30][31] 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".[32][33][34] 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.[33][35] 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.[36]

Alternative medicine

Though there is no evidence for the safety or efficacy of using curcumin as a therapy,[3][7] some alternative medicine practitioners give it intravenously, supposedly as a treatment for numerous diseases.[37][38][39] In 2017, there were two serious cases of adverse events reported from curcumin or turmeric products — one severe allergic reaction and one death[37] — that were caused by administration of a curcumin-polyethylene glycol (PEG40) emulsion product by a naturopath.[39] One treatment caused anaphylaxis leading to death.[37][39]

References

  1. ^ a b Majeed S (28 December 2015). "The State of the Curcumin Market". Natural Products Insider.
  2. ^ Manolova Y, Deneva V, Antonov L, Drakalska E, Momekova D, Lambov N (November 2014). "The effect of the water on the curcumin tautomerism: a quantitative approach" (PDF). Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 132: 815–20. Bibcode:2014AcSpA.132..815M. doi:10.1016/j.saa.2014.05.096. PMID 24973669.
  3. ^ a b c d e f g h i Nelson KM, Dahlin JL, Bisson J, Graham J, Pauli GF, Walters MA (March 2017). "The Essential Medicinal Chemistry of Curcumin". Journal of Medicinal Chemistry. 60 (5): 1620–1637. doi:10.1021/acs.jmedchem.6b00975. PMC 5346970. PMID 28074653.
    See also: Nelson KM, Dahlin JL, Bisson J, Graham J, Pauli GF, Walters MA (May 2017). "Curcumin May (Not) Defy Science". ACS Medicinal Chemistry Letters. 8 (5): 467–470. doi:10.1021/acsmedchemlett.7b00139. PMC 5430405. PMID 28523093.
  4. ^ Vogel H, Pelletier J (1815). "Curcumin –biological and medicinal properties". Journal de Pharmacie. 1: 289.
  5. ^ a b c Farooqui T, Farooqui AA (2019). "Curcumin: Historical Background, Chemistry, Pharmacological Action, and Potential Therapeutic Value". Curcumin for Neurological and Psychiatric Disorders: 23–44. doi:10.1016/B978-0-12-815461-8.00002-5.
  6. ^ Wilken R, Veena MS, Wang MB, Srivatsan ES (February 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. PMC 3055228. PMID 21299897.
  7. ^ a b c d Baker M (January 2017). "Deceptive curcumin offers cautionary tale for chemists". Nature. 541 (7636): 144–145. Bibcode:2017Natur.541..144B. doi:10.1038/541144a. PMID 28079090.
  8. ^ "Turmeric". US National Center for Complementary and Integrative Health, National Institutes of Health. May 31, 2016. Retrieved June 15, 2016.
  9. ^ European Commission. "Food Additives". Retrieved February 15, 2014.
  10. ^ "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. Retrieved July 24, 2019.
  11. ^ "CFR - Code of Federal Regulations Title 21". www.accessdata.fda.gov.
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  13. ^ "EPA Method 212.3: Boron (Colorimetric, Curcumin)" (PDF).
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  15. ^ Schmitt B, Hölscher D, Schneider B (February 2000). "Variability of phenylpropanoid precursors in the biosynthesis of phenylphenalenones in Anigozanthos preissii". Phytochemistry. 53 (3): 331–7. doi:10.1016/S0031-9422(99)00544-0. PMID 10703053.
  16. ^ 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.
  17. ^ Bisson J, McAlpine JB, Friesen JB, Chen SN, Graham J, Pauli GF (March 2016). "Can Invalid Bioactives Undermine Natural Product-Based Drug Discovery?". Journal of Medicinal Chemistry. 59 (5): 1671–90. doi:10.1021/acs.jmedchem.5b01009. PMC 4791574. PMID 26505758.
  18. ^ He Y, Li W, Hu G, Sun H, Kong Q. Bioactivities of EF24, a Novel Curcumin Analog: A Review. Front Oncol. 2018 Dec 11;8:614. doi:10.3389/fonc.2018.00614 PMID 30619754
  19. ^ Metzler M, Pfeiffer E, Schulz SI, Dempe JS (2013). "Curcumin uptake and metabolism". BioFactors. 39 (1): 14–20. doi:10.1002/biof.1042. PMID 22996406. S2CID 8763463.
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  22. ^ "GRAS Notice (GRN) No. 822". U.S. Food & Drug Administration. GRAS Notice Inventory.
  23. ^ Lowe D (January 12, 2017). "Curcumin Will Waste Your Time". In the Pipeline. Archived from the original on April 6, 2019. Retrieved June 19, 2017.
  24. ^ "Curcumin". Micronutrient Information Center; Phytochemicals. Linus Pauling Institute, Oregon State University, Corvallis. 2016. Retrieved June 18, 2016.
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  26. ^ "187 Fake Cancer 'Cures' Consumers Should Avoid". U.S. Food and Drug Administration. Archived from the original on May 2, 2017. Retrieved May 20, 2020.
  27. ^ Hernández C, Moreno G, Herrera-R A, Cardona-G W (May 2021). "New Hybrids Based on Curcumin and Resveratrol: Synthesis, Cytotoxicity and Antiproliferative Activity against Colorectal Cancer Cells". Molecules. 26 (9): 2661. doi:10.3390/molecules26092661. PMC 8124228. PMID 34062841.
  28. ^ Tseng YH, Yang RC, Chiou SS, Shieh TM, Shih YH, Lin PC (August 2021). "Curcumin induces apoptosis by inhibiting BCAT1 expression and mTOR signaling in cytarabine‑resistant myeloid leukemia cells". Molecular Medicine Reports. 24 (2): 565. doi:10.3892/mmr.2021.12204. PMID 34109436.
  29. ^ Karthika C, Hari B, Mano V, Radhakrishnan A, Janani SK, Akter R, et al. (June 2021). "Curcumin as a great contributor for the treatment and mitigation of colorectal cancer". Experimental Gerontology. 152: 111438. doi:10.1016/j.exger.2021.111438. PMID 34098006.
  30. ^ Ackerman T (February 29, 2012). "M.D. Anderson professor under fraud probe". Houston Chronicle. Retrieved March 8, 2016.
  31. ^ "Caught Our Notice: Researcher who once threatened to sue Retraction Watch now up to 19 retractions". Retraction Watch. April 10, 2018.
  32. ^ Ackerman T (March 2, 2016). "M.D. Anderson scientist, accused of manipulating data, retires". Houston Chronicle.
  33. ^ a b Stix G (February 2007). "Spice Healer". Scientific American. 296 (2): 66–9. Bibcode:2007SciAm.296b..66S. doi:10.1038/scientificamerican0207-66. PMID 17367023.
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  35. ^ Singh S (September 2007). "From exotic spice to modern drug?". Cell. 130 (5): 765–8. doi:10.1016/j.cell.2007.08.024. PMID 17803897. S2CID 16044143.
  36. ^ Baum S (March 26, 2013). "Biotech startup raises $1M for lung cancer treatment using component of tumeric". Med City News.
  37. ^ a b c "FDA investigates two serious adverse events associated with ImprimisRx's compounded curcumin emulsion product for injection". Food and Drug Administration. August 4, 2017.
  38. ^ Hermes BM (March 27, 2017). "Naturopathic Doctors Look Bad After California Woman Dies From Turmeric Injection". Forbes. Retrieved May 12, 2017.
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External links