Forskolin

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Forskolin
Forskolin.svg
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 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
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 Yes check.svgY
    Key: OHCQJHSOBUTRHG-KGGHGJDLSA-N Yes check.svgY
  • 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).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

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.

Contents

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

Mechanism of action

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

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

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

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

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

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

Related Research Articles

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Adenylate cyclase is an enzyme with systematic name ATP diphosphate-lyase . It catalyzes the following reaction:

<span class="mw-page-title-main">Cyclic adenosine monophosphate</span> Cellular second messenger

Cyclic adenosine monophosphate is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transduction in many different organisms, conveying the cAMP-dependent pathway.

<span class="mw-page-title-main">Cyclic nucleotide</span> Cyclic nucleic acid

A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, and a single phosphate group. As can be seen in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) images, the 'cyclic' portion consists of two bonds between the phosphate group and the 3' and 5' hydroxyl groups of the sugar, very often a ribose.

<span class="mw-page-title-main">Guanylate cyclase</span> Lyase enzyme that synthesizes cGMP from GTP

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G<sub>s</sub> alpha subunit Mammalian protein found in Homo sapiens

The Gs alpha subunit is a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. Gsα is a GTPase that functions as a cellular signaling protein. Gsα is the founding member of one of the four families of heterotrimeric G proteins, defined by the alpha subunits they contain: the Gαs family, Gαi/Gαo family, Gαq family, and Gα12/Gα13 family. The Gs-family has only two members: the other member is Golf, named for its predominant expression in the olfactory system. In humans, Gsα is encoded by the GNAS complex locus, while Golfα is encoded by the GNAL gene.

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<span class="mw-page-title-main">ADCY5</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 5 is an enzyme that in humans is encoded by the ADCY5 gene.

<span class="mw-page-title-main">ADCY1</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 1 is an enzyme that in humans is encoded by the ADCY1 gene.

<span class="mw-page-title-main">ADCY2</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">ADCY7</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 7 is an enzyme that in humans is encoded by the ADCY7 gene.

<span class="mw-page-title-main">ADCY9</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 9 is an enzyme that in humans is encoded by the ADCY9 gene.

<span class="mw-page-title-main">ADCY8</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 8 is an enzyme that in humans is encoded by the ADCY8 gene.

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<span class="mw-page-title-main">Ribose</span> Group of simple sugar and carbohydrate compounds

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References

  1. ↑ "Forskolin" (PDF). Sigma Aldrich.
  2. 1 2 3 "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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