Chemistry:Celastrol

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Celastrol
Celastrol.svg
Names
IUPAC name
3-Hydroxy-9β,13α-dimethyl-2-oxo-24,25,26-trinoroleana-1(10),3,5,7-tetraen-29-oic acid
Systematic IUPAC name
(2R,4aS,6aS,12bR,14aS,14bR)-10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydropicene-2-carboxylic acid
Other names
Tripterine
Identifiers
3D model (JSmol)
ChemSpider
UNII
Properties
C29H38O4
Molar mass 450.619 g·mol−1
Appearance Crystalline solid
Melting point 213 °C (415 °F; 486 K)[1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references
Tracking categories (test):

Celastrol (tripterine) is a chemical compound isolated from the root extracts of Tripterygium wilfordii (Thunder god vine) and Tripterygium regelii (Regel's threewingnut). Celastrol is a pentacyclic nortriterpen quinone and belongs to the family of quinone methides. In mice, celastrol is an NR4A1 agonist that alleviates inflammation and induces autophagy.[2] Also in mice, celastrol increase expression of IL1R1, which is the receptor for the cytokine interleukin-1 (IL-1). IL1R1 knock-out mice exposed to celastrol exhibit no leptin-sensitizing or anti-obesity effect.[3]

In in vitro and in vivo animal experiments, celastrol exhibits antibacterial,[4] antioxidant,[5] anti-inflammatory,[6][7] anticancer,[8][9][10][11][12] and insecticidal [13] activities. It has been shown to have obesity-controlling effects in mice by inhibiting negative regulators of leptin.[14][15][16] Celastrol has also shown to possess (by inhibition of NF-κB in the hypothalamus[17]) anti-diabetic effects on diabetic nephropathy and improve whole-body insulin resistance.[18]

Celastrol inhibits IKK-NF-κB signaling via multiple molecular targets: direct inhibition of IKKα and β kinases, inactivation of CDC37 and p23, which are HSP90 chaperone proteins, inhibition of proteasome function and activation of HSF1, which triggers the heat shock response. The available evidence indicates that celastrol bonds covalently to the thiol groups of cysteine residues in its molecular targets.[19]

Celastrol also has demonstrated in vitro inhibitory effects against the carbapenemase of CRE Klebsiella pneumoniae, in combination with thymol, a monoterpene.[20]

References

  1. ↑ "SARS-CoV 3CLpro inhibitory effects of quinone-methide triterpenes from Tripterygium regelii". Bioorganic & Medicinal Chemistry Letters 20 (6): 1873–6. March 2010. doi:10.1016/j.bmcl.2010.01.152. PMID 20167482. 
  2. ↑ "The Orphan Nuclear Receptor 4A1: A Potential New Therapeutic Target for Metabolic Diseases". J Diabetes Res 2018: 9363461. 2018. doi:10.1155/2018/9363461. PMID 30013988. 
  3. ↑ "IL1R1 is required for celastrol's leptin-sensitization and antiobesity effects". Nature Medicine 25 (4): 575–582. April 2019. doi:10.1038/s41591-019-0358-x. PMID 30833749. 
  4. ↑ "Antimicrobial Activity and Mode of Action of Celastrol, a Nortriterpen Quinone Isolated from Natural Sources". Foods 10 (3): 591. March 2021. doi:10.3390/foods10030591. PMID 33799720. 
  5. ↑ "Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer's disease". Progress in Neuro-Psychopharmacology & Biological Psychiatry 25 (7): 1341–57. October 2001. doi:10.1016/S0278-5846(01)00192-0. PMID 11513350. 
  6. ↑ "Suppression of inflammatory responses by celastrol, a quinone methide triterpenoid isolated from Celastrus regelii". European Journal of Clinical Investigation 39 (9): 819–27. September 2009. doi:10.1111/j.1365-2362.2009.02186.x. PMID 19549173. 
  7. ↑ "Celastrus-derived celastrol suppresses autoimmune arthritis by modulating antigen-induced cellular and humoral effector responses". The Journal of Biological Chemistry 286 (17): 15138–46. April 2011. doi:10.1074/jbc.M111.226365. PMID 21402700. 
  8. ↑ "Celastrol-induced degradation of FANCD2 sensitizes pediatric high-grade gliomas to the DNA-crosslinking agent carboplatin". EBioMedicine 50: 81–92. November 2019. doi:10.1016/j.ebiom.2019.10.062. PMID 31735550. 
  9. ↑ "Enhancement of radiation sensitivity in lung cancer cells by celastrol is mediated by inhibition of Hsp90". International Journal of Molecular Medicine 27 (3): 441–6. March 2011. doi:10.3892/ijmm.2011.601. PMID 21249311. 
  10. ↑ "Identification of a potent natural triterpenoid inhibitor of proteosome chymotrypsin-like activity and NF-kappaB with antimyeloma activity in vitro and in vivo". Blood 113 (17): 4027–37. April 2009. doi:10.1182/blood-2008-09-179796. PMID 19096011. 
  11. ↑ "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". The Journal of Pharmacology and Experimental Therapeutics 334 (2): 489–99. August 2010. doi:10.1124/jpet.110.165654. PMID 20472666. 
  12. ↑ "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". Molecular Pharmacology 76 (4): 734–44. October 2009. doi:10.1124/mol.109.056259. PMID 19574249. 
  13. ↑ "Insecticidal activity of Maytenus species (Celastraceae) nortriterpene quinone methides against codling moth, Cydia pomonella (L.) (Lepidoptera: tortricidae)". Journal of Agricultural and Food Chemistry 48 (1): 88–92. January 2000. doi:10.1021/jf990008w. PMID 10637057. 
  14. ↑ Kyriakou E, Schmidt S, Dodd GT, et al. Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus. J Med Chem. 2018;61(24):11144-11157. doi:10.1021/acs.jmedchem.8b01224
  15. ↑ "Celastrol-Induced Weight Loss Is Driven by Hypophagia and Independent From UCP1". Diabetes 67 (11): 2456–2465. November 2018. doi:10.2337/db18-0146. PMID 30158241. 
  16. ↑ "Treatment of obesity with celastrol". Cell 161 (5): 999–1011. May 2015. doi:10.1016/j.cell.2015.05.011. PMID 26000480. 
  17. ↑ "Inhibition of NF-κB activation through targeting IκB kinase by celastrol, a quinone methide triterpenoid". Biochemical Pharmacology 72 (10): 1311–1321. 2006. doi:10.1016/j.bcp.2006.08.014. PMID 16984800. 
  18. ↑ "Celastrol, an NF-κB inhibitor, improves insulin resistance and attenuates renal injury in db/db mice". PLOS ONE 8 (4): e62068. 2013. doi:10.1371/journal.pone.0062068. PMID 23637966. Bibcode: 2013PLoSO...862068K. 
  19. ↑ "Celastrol: Molecular targets of Thunder God Vine". Biochem Biophys Res Commun 394 (3): 439–42. April 2010. doi:10.1016/j.bbrc.2010.03.050. PMID 20226165. 
  20. ↑ "In vitro activity of celastrol in combination with thymol against carbapenem-resistant Klebsiella pneumoniae isolates". The Journal of Antibiotics 75: 679–690. 27 September 2022. doi:10.1038/s41429-022-00566-y. 



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