Crocetin

Last updated
Crocetin [1]
Skeletal formula of crocetin Crocetin.svg
Skeletal formula of crocetin
Ball and stick model of crocetin Crocetin-3D-balls-(rotated).png
Ball and stick model of crocetin
Names
IUPAC name
8,8′-Diapocarotene-8,8′-dioic acid
Systematic IUPAC name
(2E,4E,6E,8E,10E,12E,14E)-2,6,11,15-Tetramethylhexadeca-2,4,6,8,10,12,14-heptaenedioic acid [2]
Other names
8,8'-Diapocarotenedioic acid; [1] Transcrocetinate
Identifiers
3D model (JSmol)
1715455
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.044.265 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 248-708-0
KEGG
MeSH crocetin
PubChem CID
UNII
  • InChI=1S/C20H24O4/c1-15(11-7-13-17(3)19(21)22)9-5-6-10-16(2)12-8-14-18(4)20(23)24/h5-14H,1-4H3,(H,21,22)(H,23,24)/b6-5+,11-7+,12-8+,15-9+,16-10+,17-13+,18-14+ Yes check.svgY
    Key: PANKHBYNKQNAHN-MQQNZMFNSA-N Yes check.svgY
  • InChI=1/C20H24O4/c1-15(11-7-13-17(3)19(21)22)9-5-6-10-16(2)12-8-14-18(4)20(23)24/h5-14H,1-4H3,(H,21,22)(H,23,24)/b6-5+,11-7+,12-8+,15-9+,16-10+,17-13+,18-14+
    Key: PANKHBYNKQNAHN-MQQNZMFNBY
  • CC(C=CC=C(C)C(O)=O)=CC=CC=C(C)C=CC=C(C)C(O)=O
Properties
C20H24O4
Molar mass 328.408 g·mol−1
AppearanceRed crystals
Melting point 285 °C (545 °F; 558 K)
log P 4.312
Acidity (pKa)4.39
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Crocetin is a natural apocarotenoid dicarboxylic acid, a diterpenoid, and a branched-chain dicarboxylic acid. It was the first plant carotenoid to be recognized as early as 1818 while the history of saffron cultivation reaches back more than 3,000 years. The major active ingredient of saffron is the yellow pigment crocin 2 (three other derivatives with different glycosylations are known) containing a gentiobiose (disaccharide) group at each end of the molecule. It is found in the crocus flower together with its glycoside, crocin, and Gardenia jasminoides fruits. It is also known as crocetic acid. [3] [4] It forms brick red crystals with a melting point of 285 °C.

Contents

The chemical structure of crocetin forms the central core of crocin, the compound responsible for the color of saffron. Crocetin is usually extracted commercially from gardenia fruit, due to the high cost of saffron.

A simple and specific HPLC-UV method has been developed to quantify the five major biologically active ingredients of saffron, namely the four crocins and crocetin. [5]

Cell studies

Crocin and crocetin may provide neuroprotection in rats by reducing the production of various neurotoxic molecules, based on an in-vitro cell study. [6]

Physiological effects

A 2009 study involving 14 individuals indicated that oral administration of crocetin may decrease the effects of physical fatigue in healthy men. [7]

A 2010 pilot study investigated the effect of crocetin on sleep. The clinical trial comprised a double-blind, placebo-controlled, crossover trial of 21 healthy adult men with a mild sleep complaint. It concluded that crocetin may (p=0.025) contribute to improving the quality of sleep. [8]

In high concentrations, it has protective effects against retinal damage in vitro and in vivo . [9]

Transcrocetinate sodium

The sodium salt of crocetin, transcrocetinate sodium (INN, also known as trans sodium crocetinate or TSC) is an experimental drug that increases the movement of oxygen from red blood cells into hypoxic (oxygen-starved) tissues. [10] Transcrocetinate sodium belongs to a group of substances known as bipolar trans carotenoid salts, which constitute a subclass of oxygen diffusion-enhancing compounds. [11] Transcrocetinate sodium was one of the first such compounds discovered. [10] [12]

Transcrocetinate sodium Transcrocetinate sodium.svg
Transcrocetinate sodium

Transcrocetinate sodium can be prepared by reacting saffron with sodium hydroxide and extracting the salt of the trans crocetin isomer from the solution. [12] John L. Gainer and colleagues have investigated the effects of transcrocetinate sodium in animal models. [12] [13] They discovered that the drug could reverse the potentially fatal decrease in blood pressure produced by the loss of large volumes of blood in severe hemorrhage, and thereby improve survival. [13]

Early investigations of transcrocetinate sodium suggested that it had potential applications in battlefield medicine, specifically in treatment of the many combat casualties with hemorrhagic shock. [10] [13] Additional studies, carried out in animal models, and in clinical trials in humans, indicated that transcrocetinate sodium might prove beneficial in the treatment of a variety of conditions associated with hypoxia and ischemia (a lack of oxygen reaching the tissues, usually due to a disruption in the circulatory system), including cancer, myocardial infarction (heart attack), and stroke. [10] [11] [14] [15] [16]

Transcrocetinate sodium has shown promise of effectiveness in restoring tissue oxygen levels and improving the ability to walk in a clinical trial of patients with peripheral artery disease (PAD) [15] in which reduced delivery of oxygen-rich blood to tissues can cause severe leg pain and impair mobility. The drug has also been under investigation in a clinical trial sponsored by drug developer Diffusion Pharmaceuticals for potential use as a radiosensitizer, increasing the susceptibility of hypoxic cancer cells to radiation therapy, in patients with a form of brain cancer known as glioblastoma. [16] The drug is currently under investigation for its possible use in enhancing the oxygenation status of COVID-19 patients at risk for developing multiple organ failure due to severe respiratory distress. [17]

Mechanism of action

Similar to other oxygen diffusion-enhancing compounds, transcrocetinate sodium appears to improve oxygenation in hypoxic tissues by exerting hydrophobic effects on water molecules in blood plasma and thereby increasing the hydrogen bonding between the water molecules. [18] This in turn causes the overall organization of water molecules in plasma to become more structured, which facilitates the diffusion of oxygen through plasma and promotes the movement of oxygen into tissues. [18] [19] [20]

Trans-crocetin has been found to act as an NMDA receptor antagonist with high affinity, and has been implicated in the psychoactivity of saffron. [21] [22] [23]

See also

References

  1. 1 2 Merck Index, 11th Edition, 2592
  2. ↑ CID 5281232 from PubChem
  3. ↑ Umigai N, Murakami K, Ulit MV, et al. (May 2011). "The pharmacokinetic profile of crocetin in healthy adult human volunteers after a single oral administration". Phytomedicine. 18 (7): 575–8. doi:10.1016/j.phymed.2010.10.019. PMID   21112749.
  4. ↑ Ichi, T; Higashimura, Y; Katayama, T; Koda, T; Shimizu, T; Tada, M (1995). "Analysis of Crocetin Derivatives from Gardenia". Nippon Shokuhin Kagaku Kogaku Kaishi. 42 (10): 776–783. doi: 10.3136/nskkk.42.776 . S2CID   87600533.
  5. ↑ Li, Na; Lin, Ge; Kwan, Yiu-Wa; Min, Zhi-Da (July 1999). "Simultaneous quantification of five major biologically active ingredients of saffron by high-performance liquid chromatography". Journal of Chromatography A. 849 (2): 349–355. doi:10.1016/S0021-9673(99)00600-7. PMID   10457433.
  6. ↑ Nam KN, Park YM, Jung HJ, Lee JY, Min BD, Park SU, Jung WS, Cho KH, Park JH, Kang I, Hong JW, Lee EH (2010). "Anti-inflammatory effects of crocin and crocetin in rat brain microglial cells". European Journal of Pharmacology . 648 (1–3): 110–6. doi:10.1016/j.ejphar.2010.09.003. PMID   20854811.
  7. ↑ Mizuma H, Tanaka M, Nozaki S, Mizuno K, Tahara T, Ataka S, Sugino T, Shirai T, Kajimoto Y, Kuratsune H, Kajimoto O, Watanabe Y (March 2009). "Daily oral administration of crocetin attenuates physical fatigue in human subjects". Nutrition Research. 29 (3): 145–50. doi:10.1016/j.nutres.2009.02.003. PMID   19358927.
  8. ↑ Kuratsune H, Umigai N, Takeno R, Kajimoto Y, Nakano T (September 2010). "Effect of crocetin from Gardenia jasminoides Ellis on sleep: a pilot study". Phytomedicine. 17 (11): 840–3. doi:10.1016/j.phymed.2010.03.025. PMID   20537515.
  9. ↑ Yamauchi, M; Tsuruma, K; Imai, S; Nakanishi, T; Umigai, N; Shimazawa, M; Hara, H (2011). "Crocetin prevents retinal degeneration induced by oxidative and endoplasmic reticulum stresses via inhibition of caspase activity". European Journal of Pharmacology. 650 (1): 110–9. doi:10.1016/j.ejphar.2010.09.081. PMID   20951131.
  10. 1 2 3 4 Gainer, J (2008). "Trans-sodium crocetinate for treating hypoxia/ischemia". Expert Opinion on Investigational Drugs. 17 (6): 917–924. doi:10.1517/13543784.17.6.917. PMID   18491992. S2CID   71663644.
  11. 1 2 USpatent 8,206,751,Gainer J,"New Class of Therapeutics that Enhance Small Molecule Diffusion",issued 2009-04-30
  12. 1 2 3 USpatent 6,060,511,Gainer J,"Trans-sodium crocetinate, methods of making and methods of use thereof",issued 2000-05-09
  13. 1 2 3 Giassi L; et al. (2001). "Trans-Sodium Crocetinate Restores Blood Pressure, Heart Rate, and Plasma Lactate after Hemorrhagic Shock". Journal of Trauma-Injury Infection & Critical Care. 51 (5): 932–938. doi:10.1097/00005373-200111000-00018. PMID   11706343.
  14. ↑ Lapchak P (2010). "Efficacy and safety profile of the carotenoid trans sodium crocetinate administered to rabbits following multiple infarct ischemic strokes: A combination therapy study with tissue plasminogen activator". Brain Research. 1309: 136–145. doi:10.1016/j.brainres.2009.10.067. PMID   19891959. S2CID   25369069.
  15. 1 2 Mohler E; et al. (2010). "Evaluation of trans sodium crocetinate on safety and exercise performance in patients with peripheral artery disease and intermittent claudication". Vascular Medicine. 16 (5): 346–352. doi:10.1177/1358863X11422742. PMC   4182020 . PMID   22003000.
  16. 1 2 "Safety and Efficacy Study of Trans Sodium Crocetinate (TSC) With Concomitant Radiation Therapy and Temozolomide in Newly Diagnosed Glioblastoma (GBM)". ClinicalTrials.gov. November 2011. Retrieved 18 September 2012.
  17. ↑ "Diffusion Pharmaceuticals Announces FDA Accelerated Review of TSC Clinical Development Plan to Treat COVID-19 Patients with ARDS". Diffusion Pharmaceuticals. May 5, 2020. Retrieved May 25, 2020.
  18. 1 2 Stennett a; et al. (2006). "Trans sodium crocetinate and diffusion enhancement". The Journal of Physical Chemistry B. 110 (37): 18078–18080. doi:10.1021/jp064308+. PMID   16970413.
  19. ↑ Laidig, K.E.; J.L. Gainer; V. Daggett (1998). "Altering Diffusivity in Biological Solutions through Modification of Solution Structure and Dynamics". Journal of the American Chemical Society. 120 (36): 9394–9395. doi:10.1021/ja981656j.
  20. ↑ Manabe H; et al. (2010). "Protection against focal ischemic injury to the brain by trans-sodium crocetinate". Journal of Neurosurgery. 113 (4): 802–809. doi:10.3171/2009.10.JNS09562. PMC   3380430 . PMID   19961314.
  21. ↑ Berger F, Hensel A, Nieber K (2011). "Saffron extract and trans-crocetin inhibit glutamatergic synaptic transmission in rat cortical brain slices". Neuroscience. 180: 238–47. doi:10.1016/j.neuroscience.2011.02.037. PMID   21352900. S2CID   23525322.
  22. ↑ Lautenschläger M, Lechtenberg M, Sendker J, Hensel A (2014). "Effective isolation protocol for secondary metabolites from saffron: semi-preparative scale preparation of crocin-1 and trans-crocetin". Fitoterapia. 92: 290–5. doi:10.1016/j.fitote.2013.11.014. PMID   24321578.
  23. ↑ Lautenschläger M, Sendker J, Hüwel S, Galla HJ, Brandt S, Düfer M, Riehemann K, Hensel A (2015). "Intestinal formation of trans-crocetin from saffron extract (Crocus sativus L.) and in vitro permeation through intestinal and blood brain barrier". Phytomedicine. 22 (1): 36–44. doi:10.1016/j.phymed.2014.10.009. PMID   25636868.
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