Guggulsterone

Last updated
Guggulsterone
Guggulsterone E.png
E-Guggulsterone
Guggulsterone Z.png
Z-Guggulsterone
Names
IUPAC name
(8R,9S,10R,13S,14S)-17-Ethylidene-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15-decahydrocyclopenta[a]phenanthrene-3,16-dione
Other names
Pregna-4,17-diene-3,16-dione
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.118.937 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • (E):InChI=1S/C21H28O2/c1-4-16-19(23)12-18-15-6-5-13-11-14(22)7-9-20(13,2)17(15)8-10-21(16,18)3/h4,11,15,17-18H,5-10,12H2,1-3H3/b16-4-/t15-,17+,18+,20+,21-/m1/s1
    Key: WDXRGPWQVHZTQJ-AUKWTSKRSA-N
  • (Z):InChI=1S/C21H28O2/c1-4-16-19(23)12-18-15-6-5-13-11-14(22)7-9-20(13,2)17(15)8-10-21(16,18)3/h4,11,15,17-18H,5-10,12H2,1-3H3/b16-4+/t15-,17+,18+,20+,21-/m1/s1
    Key: WDXRGPWQVHZTQJ-OSJVMJFVSA-N
  • (E):O=C1C[C@@]2([H])[C@]3([H])CCC4=CC(CC[C@]4(C)[C@@]3([H])CC[C@]2(C)/C1=C\C)=O
  • (Z):O=C1C[C@@]2([H])[C@]3([H])CCC4=CC(CC[C@]4(C)[C@@]3([H])CC[C@]2(C)/C1=C/C)=O
Properties
C21H28O2
Molar mass 312.453 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Guggulsterone is a phytosteroid found in the resin of the guggul plant, Commiphora mukul. Guggulsterone can exist as either of two stereoisomers, E-guggulsterone and Z-guggulsterone. In humans, it acts as an antagonist of the farnesoid X receptor, which was once believed to result in decreased cholesterol synthesis in the liver. Several studies have been published that indicate no overall reduction in total cholesterol occurs using various dosages of guggulsterone, and levels of low-density lipoprotein ("bad cholesterol") increased in many people. [1] [2] Nevertheless, guggulsterone is an ingredient in many nutritional supplements. Guggulsterone was also found to have interactions with the viral ADP ribose phosphatase enzyme of SARS-CoV-2 and has been proposed as a potential candidate for the development of therapeutics for the treatment of COVID-19. [3]

Guggulsterone is a broad-spectrum ligand of steroid hormone receptors, and is known to possess the following activities: [4] [5] [6] [7]

Guggulsterone has been found in animal research to be orally active; it has an absolute bioavailability of 42.9% after oral administration in rats, with a half-life of around 10 hours in this species, indicating a good pharmacokinetic profile. [8]

Synthesis

Guggulsterone can be synthesized from 16-DPA, progesterone or DHEA. A synthesis of guggulsterone from 16-DPA is described. [9] [10] Note that for the first step in the patent LiAlH4 is used in THF. However, just NaBH4 in EtOH would work for this step although the acetoxy ester would not be expected to get reduced if using this reagent.

Guggulsterone synthesis.svg

The reduction of 16-DPA [979-02-2] with sodium borohydride leads to 5,16-pregnadiene-3b-20 diol, PC22295555 (2). Acetylation is accompanied by some kind of a bond reorganization to give PC58830759, PC90955911 or PC90960662 (3). Saponification of both the acetyl groups gives PC90795454 (4). Oppenauer oxidation concludes the synthesis (5).

References

  1. ↑ Szapary, PO; Wolfe, ML; Bloedon, LT; Cucchiara, AJ; Dermarderosian, AH; Cirigliano, MD; Rader, DJ (2003). "Guggulipid Ineffective for Lowering Cholesterol". JAMA. 290 (6): 765–772. doi:10.1001/jama.290.6.765. PMID   12915429.
  2. ↑ Sahni, S; Hepfinger, CA; Sauer, KA (2005). "Guggulipid Use in Hyperlipidemia". Am J Health-Syst Pharm. 62 (16): 1690–1692. doi:10.2146/ajhp040580. PMID   16085931.
  3. ↑ Kciuk M, Mujwar S, Rani I, Munjal K, Gielecińska A, Kontek R, Shah K (2022). "Computational Bioprospecting Guggulsterone against ADP Ribose Phosphatase of SARS-CoV-2". Molecules. 27 (23) 8287: 8287. doi: 10.3390/molecules27238287 . PMC   9739500 . PMID   36500379.
  4. ↑ Burris, T. P. (2004). "The Hypolipidemic Natural Product Guggulsterone Is a Promiscuous Steroid Receptor Ligand". Molecular Pharmacology. 67 (3): 948–954. doi:10.1124/mol.104.007054. ISSN   0026-895X. PMID   15602004. S2CID   309272.
  5. ↑ Brobst, D. E. (2004). "Guggulsterone Activates Multiple Nuclear Receptors and Induces CYP3A Gene Expression through the Pregnane X Receptor". Journal of Pharmacology and Experimental Therapeutics. 310 (2): 528–535. doi:10.1124/jpet.103.064329. ISSN   0022-3565. PMID   15075359. S2CID   7093631.
  6. ↑ Hugo Kubinyi; Gerhard Müller (6 March 2006). Chemogenomics in Drug Discovery: A Medicinal Chemistry Perspective. John Wiley & Sons. pp. 394–. ISBN   978-3-527-60402-9.
  7. ↑ Roger Blumenthal; JoAnne Foody; Nathan D. Wong (25 February 2011). Preventive Cardiology: A Companion to Braunwald's Heart Disease. Elsevier Health Sciences. pp. 1563–. ISBN   978-1-4377-3785-1.
  8. ↑ Verma, N.; Singh, S.K.; Gupta, R.C. (1999). "Pharmacokinetics of Guggulsterone after Intravenous and Oral Administration in Rats". Pharmacy and Pharmacology Communications. 5 (5): 349–354. doi:10.1211/146080899128734956 (inactive 5 July 2025). ISSN   1460-8081.{{cite journal}}: CS1 maint: DOI inactive as of July 2025 (link)
  9. ↑ Heonjoong Kang, Jungyeob Ham, Jungwook Chin, WO2004094450 (2004 to Seoul Nat Univ Ind Foundation). Location in patent: Page 28; 56-57.
  10. ↑ Yusuf Khawja Windsor Villa 2Nd Floor Hamied, EP0447706 (1991 to Cipla Limited).
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