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== Biosynthesis ==
== Biosynthesis ==
*ah As with other members of the large [[diterpene]] family of natural products, forskolin is derived from [[geranylgeranyl pyrophosphate]] (GGPP). Forskolin, however, contains some unique functional elements, key among them is the presence of a tetrahydopyran derived [[heterocyclic ring]]. This ring is synthesized after the formation of the trans-fused carbon ring systems are formed by a [[carbocation]] mediated [[cyclization]]. The remaining tertiary carbocation is quenched by a molecule of water. After [[deprotonation]], the remaining hydroxyl 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.<ref name="Dewick">{{ cite book | author = Dewick, P. M. | title = Medicinal Natural Products | edition = 3rd | year = 2009 | page = 232 | publisher = Wiley | isbn = 978-0470741689 }}</ref> This forms the core ring system A of forskolin.
*As with other members of the large [[diterpene]] family of natural products, forskolin is derived from [[geranylgeranyl pyrophosphate]] (GGPP). Forskolin, however, contains some unique functional elements, key among them is the presence of a tetrahydopyran derived [[heterocyclic ring]]. This ring is synthesized after the formation of the trans-fused carbon ring systems are formed by a [[carbocation]] mediated [[cyclization]]. The remaining tertiary carbocation is quenched by a molecule of water. After [[deprotonation]], the remaining hydroxyl 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.<ref name="Dewick">{{ cite book | author = Dewick, P. M. | title = Medicinal Natural Products | edition = 3rd | year = 2009 | page = 232 | publisher = Wiley | isbn = 978-0470741689 }}</ref> 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 [[esterification|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.
*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 [[esterification|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.


Revision as of 08:13, 25 October 2013

Forskolin
Names
IUPAC name
(3R,​4aR,​5S,​6S,​6aS,​10S,​10aR,​10bS)-​6,​10,​10b-​trihydroxy-​3,​4a,​7,​7,​10a-​pentamethyl-​1-​oxo-​3-​vinyldodecahydro-​1H-​benzo[f]​chromen-​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 410.50116
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 (also called Coleonol) is a labdane diterpene that is produced by the Indian Coleus plant (Coleus forskohlii). Forskolin is commonly used to raise levels of cyclic AMP (cAMP) in the study and research of cell physiology. Forskolin resensitizes cell receptors by activating the enzyme adenylyl cyclase and increasing the intracellular levels of cAMP. cAMP is an important signal carrier 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. Cyclic AMP acts by activating cAMP-sensitive pathways such as protein kinase A and Epac. Further reading: function of protein kinase A

Biosynthesis

  • As with other members of the large diterpene family of natural products, forskolin is derived from geranylgeranyl pyrophosphate (GGPP). Forskolin, however, contains some unique functional elements, key among them is the presence of a tetrahydopyran derived heterocyclic ring. This ring is synthesized after the formation of the trans-fused carbon ring systems are formed by a carbocation mediated cyclization. The remaining tertiary carbocation is quenched by a molecule of water. After deprotonation, the remaining hydroxyl 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.[2] 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.

Potential medical use

  • Applied with rolipram, forskolin provides a route[further explanation needed] to inhibition of colon cancer cell growth and survival. [3] These two drugs also work together to induce long-term potentiation in neuronal populations. [4]
  • Forskolin is a vasodilator.
  • To date, there have been more than two clinical studies examining the effectiveness of forskolin as a weight loss aid. Only one has been subject to peer-review and published in a medical journal. This clinical study also observed forskolin's role in significantly increasing lean mass, bone mass, and testosterone in the overweight and obese men involved.[5] This research has led to companies marketing forskolin as a bodybuilding supplement.
  • Forskolin may be helpful to control the underlying cause of glaucoma[6] [7][citation needed][8][9]

The sometimes successful use of forskolin to reduce intraocular pressure may be due to its unique ability to stimulate adenylate cyclase activity and increase cAMP which regulates and activates critical enzymes required for the cellular energy required to move fluid out of the eye.

  • Increase skin's natural resistance to burning under UV light (see links below)
  • Stimulate a tanning response when applied topically[citation needed].
  • Reduce urinary tract infections and enhance the ability of antibiotics to kill bacteria that normally survive.[10][11] [citation needed]

Forskolin can also be used to promote nerve repair by increasing cAMP concentrations. Forskolin can activate or upregulate the proliferation of Schwann cells in culture, together with Fibroblast growth factor or Transforming Growth Factor-Beta.

Various experimental studies are underway in using Forskolin as an adjuvant in treatment for diseases such as Parkinsons and/or nerve damage caused by trauma/accident.

References

  1. ^ "Forskolin" (pdf). Sigma Aldrich.
  2. ^ Dewick, P. M. (2009). Medicinal Natural Products (3rd ed.). Wiley. p. 232. ISBN 978-0470741689.
  3. ^ McEwan, D. G.; Brunton, V. G.; Baillie, G. S.; Leslie, N. R.; Houslay, M. D.; Frame, M. C. (2007). "Chemoresistant KM12C Colon Cancer Cells Are Addicted to Low Cyclic AMP Levels in a Phosphodiesterase 4-Regulated Compartment via Effects on Phosphoinositide 3-Kinase" (PDF). Cancer Research. 67 (11): 5248–5257. doi:10.1158/0008-5472.CAN-07-0097. PMID 17545604.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Otmakhov, N.; Khibnik, L.; Otmakhova, N.; Carpenter, S.; Riahi, S.; Asrican, B.; Lisman, J. (2004). "Forskolin-Induced LTP in the CA1 Hippocampal Region Is NMDA Receptor Dependent" (PDF). Journal of Neurophysiology. 91 (1): 1955–1962. doi:10.1152/jn.00941.2003. PMID 14702333.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Godard, M. P.; Johnson, B. A.; Richmond, S. R. (2005). "Body Composition and Hormonal Adaptations Associated with Forskolin Consumption in Overweight and Obese Men". Obesity Research. 13 (8): 1335–1343. PMID 16129715.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Wagh VD, Patil PN, Surana SJ, Wagh KVForskolin: Upcoming antiglaucoma molecule. J Postgrad Med. 2012 Jul;58(3):199-202
  7. ^ English, J. (2000). "Research preview for the new millenium". Vitamin Research News. {{cite journal}}: Unknown parameter |month= ignored (help)
  8. ^ Zeng, S.; Shen, B.; Wen, L.; Hu, B.; Peng, D.; Chen, X.; Zhou, W. (1995). "Experimental studies of the effect of Forskolin on the lowering of intraocular pressure". Yan Ke Xue Bao (Eye Science). 11 (3): 173–176. PMID 8758848.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Head, K. A. (2001). "Natural Therapies for Ocular Disorders, Part Two: Cataracts and Glaucoma" (PDF). Alternative Medicine Review. 6 (2): 141–166. PMID 11302779.
  10. ^ "Herbal treatment Forskolin may help knock out for urinary tract infections once and for all". News Medical. 2007-04-08.
  11. ^ Bishop BL.; et al. (2007). "Cyclic AMP-regulated exocytosis of Escherichia coli from infected bladder epithelial cells". Nat Med. 13 (5): 625–30. doi:10.1038/nm1572. PMID 17417648. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)

Further reading

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