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Forskolin

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Forskolin
Names
IUPAC name
(13R)-1α,6β,9α-Trihydroxy-11-oxo-8α,13-epoxylabd-14-en-7β-yl acetate
Systematic IUPAC name
(3R,4aR,5S,6S,6aS,10S,10aR,10bS)-3-Ethenyl-6,10,10b-trihydroxy-3,4a,7,7,10a-pentamethyl-1-oxododecahydro-1H-naphtho[2,1-b]pyran-5-yl acetate
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.060.354 Edit this at Wikidata
UNII
  • InChI=1S/C22H34O7/c1-8-19(5)11-14(25)22(27)20(6)13(24)9-10-18(3,4)16(20)15(26)17(28-12(2)23)21(22,7)29-19/h8,13,15-17,24,26-27H,1,9-11H2,2-7H3/t13-,15-,16-,17-,19-,20-,21+,22-/m0/s1 checkY
    Key: OHCQJHSOBUTRHG-KGGHGJDLSA-N checkY
  • InChI=1/C22H34O7/c1-8-19(5)11-14(25)22(27)20(6)13(24)9-10-18(3,4)16(20)15(26)17(28-12(2)23)21(22,7)29-19/h8,13,15-17,24,26-27H,1,9-11H2,2-7H3/t13-,15-,16-,17-,19-,20-,21+,22-/m0/s1
    Key: OHCQJHSOBUTRHG-KGGHGJDLBB
  • CC(=O)O[C@H]1[C@H]([C@@H]2[C@]([C@H](CCC2(C)C)O)([C@@]3([C@@]1(O[C@@](CC3=O)(C)C=C)C)O)C)O
Properties
C22H34O7
Molar mass 410.507 g·mol−1
Solubility Soluble in organic solvents such as ethanol, chloroform and DMSO[1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Forskolin (coleonol) is a labdane diterpene produced by the plant Coleus barbatus (blue spur flower). Other names include pashanabhedi, Indian coleus, makandi, HL-362, mao hou qiao rui hua.[2] As with other members of the large diterpene class of plant metabolites, forskolin is derived from geranylgeranyl pyrophosphate (GGPP). Forskolin contains some unique functional elements, including the presence of a tetrahydropyran-derived heterocyclic ring.

Forskolin is commonly used in laboratory research to increase levels of cyclic AMP by stimulation of adenylate cyclase.[2]

Mechanism of action

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Forskolin is used in biochemistry experiments to raise levels of cyclic AMP (cAMP) in studies of cell physiology.[2][3] Forskolin activates the enzyme adenylyl cyclase and increases intracellular levels of cAMP. cAMP is an important second messenger necessary for the proper biological response of cells to hormones and other extracellular signals. It is required for cell communication in the hypothalamus-pituitary gland axis, and for the feedback control of hormones via induction of corticotropin-releasing factor gene transcription.[4] Cyclic AMP acts by activating cAMP-sensitive pathways such as protein kinase A and EPAC1.

Chemistry

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It is defined as a category 4 chemical with acute dermal toxicity based on 2012 OSHA Hazard Communication Standard (29 CFR 1910.1200).[5]

Derivatives

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Its derivatives include colforsin daropate, NKH477,[6] and FSK88,[7] which may be more potent than forskolin at raising cAMP. These derivatives may have pharmaceutical utility against bronchoconstriction and heart failure.[8][9]

Chemical synthesis

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A total chemical synthesis has been reported. The key step of this chemical synthesis is photocyclization of a synthetic intermediate in presence of oxygen and methylene blue, followed by a singlet oxygen Diels-Alder reaction.[10]

Biosynthesis

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The heterocyclic ring is synthesized after the formation of the trans-fused carbon ring systems formed by a carbocation mediated cyclization. The remaining tertiary carbocation is quenched by a molecule of water. After deprotonation, the remaining hydroxy group is free to form the heterocyclic ring. This cyclization can occur either by attack of the alcohol oxygen onto the allylic carbocation formed by loss of diphosphate, or by an analogous SN2'-like displacement of the diphosphate.[11] This forms the core ring system A of forskolin.

The remaining modifications of the core ring system A can putatively be understood as a series of oxidation reactions to form a poly-ol B which is then further oxidized and esterified to form the ketone and acetate ester moieties seen in forskolin. However, because the biosynthetic gene cluster has not been described, this putative synthesis could be incorrect in the sequence of oxidation/esterification events, which could occur in almost any order.

Weight loss

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Although forskolin has been used in preliminary weight loss research, the low quality of the studies and inconclusive results prevented any determination of effects.[12]

See also

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References

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  1. ^ "Forskolin" (PDF). Sigma Aldrich.
  2. ^ a b c "Forskolin". Drugs.com. 20 November 2023. Retrieved 28 November 2024.
  3. ^ Alasbahi, RH; Melzig, MF (January 2012). "Forskolin and derivatives as tools for studying the role of cAMP". Die Pharmazie. 67 (1): 5–13. doi:10.1691/ph.2012.1642. PMID 22393824.
  4. ^ Kageyama, K; Tamasawa, N; Suda, T (July 2011). "Signal transduction in the hypothalamic corticotropin-releasing factor system and its clinical implications". Stress. 14 (4): 357–67. doi:10.3109/10253890.2010.536279. PMID 21438777. S2CID 9631868.
  5. ^ "Targetmol Forskolin SDS". 27 September 2024. Retrieved 27 September 2024.
  6. ^ Morinobu S, Fujimaki K, Okuyama N, Takahashi M, Duman RS (May 1999). "Stimulation of adenylyl cyclase and induction of brain-derived neurotrophic factor and TrkB mRNA by NKH477, a novel and potent forskolin derivative". Journal of Neurochemistry. 72 (5): 2198–205. doi:10.1046/j.1471-4159.1999.0722198.x. PMID 10217303.
  7. ^ Li Z, Wang J (November 2006). "A forskolin derivative, FSK88, induces apoptosis in human gastric cancer BGC823 cells through caspase activation involving regulation of Bcl-2 family gene expression, dissipation of mitochondrial membrane potential and cytochrome c release". Cell Biology International. 30 (11): 940–6. doi:10.1016/j.cellbi.2006.06.015. PMID 16889987. S2CID 7288869.
  8. ^ Wajima Z, Yoshikawa T, Ogura A, Imanaga K, Shiga T, Inoue T, Ogawa R (April 2002). "Intravenous colforsin daropate, a water-soluble forskolin derivative, prevents thiamylal-fentanyl-induced bronchoconstriction in humans". Critical Care Medicine. 30 (4): 820–6. doi:10.1097/00003246-200204000-00017. PMID 11940752. S2CID 22244620.
  9. ^ Sanbe A, Takeo S (July 1995). "Effects of NKH477, a water-soluble forskolin derivative, on cardiac function in rats with chronic heart failure after myocardial infarction". The Journal of Pharmacology and Experimental Therapeutics. 274 (1): 120–6. PMID 7616388.
  10. ^ "The First Total Synthesis of (±)-Forskolin". Synfacts. 18 (5): 0563. May 2022. doi:10.1055/s-0041-1738000. S2CID 248315371.
  11. ^ Dewick, P. M. (2009). Medicinal Natural Products (3rd ed.). Wiley. p. 232. ISBN 978-0470741689.
  12. ^ Barrea, Luigi; Altieri, Barbara; Polese, Barbara; De Conno, Barbara; Muscogiuri, Giovanna; Colao, Annamaria; Savastano, Silvia (April 2019). "Nutritionist and obesity: brief overview on efficacy, safety, and drug interactions of the main weight-loss dietary supplements". International Journal of Obesity Supplements. 9 (1): 32–49. doi:10.1038/s41367-019-0007-3. PMC 6683127. PMID 31391923.
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