Forskolin

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

Contents

Mechanism of action

Forskolin is commonly used in biochemistry to raise levels of cyclic AMP (cAMP) in the study and research 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

Derivatives

Its derivatives include colforsin daropate, NKH477, [5] and FSK88, [6] which may be more potent than forskolin at raising cAMP. These derivatives may have pharmaceutical utility against bronchoconstriction and heart failure. [7] [8]

Chemical Synthesis

A total chemical synthesis has been reported. The key step of this chemial synthesis is photocyclization of a synthetic intermediate in presence of oxygen and methylene blue, followed by a singlet oxygen Diels-Alder reaction. [9]

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. [10] 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.

Fat loss

In animals, forskolin, or extracts of Coleus barbatus containing forskolin, reduce food intake, body weight, and fat mass. In humans, forskolin reduces body fat mass while increasing lean body mass. [11] [12] In mice, extracts of Coleus forskohlii exhibited dose-dependent liver toxicity although purified forskolin did not exhibit liver toxicity. [13]

Other

Forskolin has been used in traditional medicine for treating heart failure. [2]

See also

Related Research Articles

<span class="mw-page-title-main">Adenylyl cyclase</span> Enzyme with key regulatory roles in most cells

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

Guanylate cyclase is a lyase enzyme that converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) and pyrophosphate:

<span class="mw-page-title-main">Alfred G. Gilman</span> American pharmacologist

Alfred Goodman Gilman was an American pharmacologist and biochemist. He and Martin Rodbell shared the 1994 Nobel Prize in Physiology or Medicine "for their discovery of G-proteins and the role of these proteins in signal transduction in cells."

<span class="mw-page-title-main">ADCY6</span> Protein-coding gene in humans

Adenylyl cyclase type 6 is an enzyme that in humans is encoded by the ADCY6 gene.

<span class="mw-page-title-main">ADCY3</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 3 is an enzyme that in humans is encoded by the ADCY3 gene.

<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

Adenylyl cyclase type 2 is an enzyme typically expressed in the brain of humans, that is encoded by the ADCY2 gene. It belongs to the adenylyl cyclase class-3 or guanylyl cyclase family because it contains two guanylate cyclase domains. ADCY2 is one of ten different mammalian isoforms of adenylyl cyclases. ADCY2 can be found on chromosome 5 and the "MIR2113-POU3F2" region of chromosome 6, with a length of 1091 amino-acids. An essential cofactor for ADCY2 is magnesium; two ions bind per subunit.

<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.

<span class="mw-page-title-main">ADCY4</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase type 4 is an enzyme that in humans is encoded by the ADCY4 gene.

In the field of molecular biology, the cAMP-dependent pathway, also known as the adenylyl cyclase pathway, is a G protein-coupled receptor-triggered signaling cascade used in cell communication.

<span class="mw-page-title-main">Colforsin daropate</span> Chemical compound

Colforsin daropate is a carboxylic ester derived from the condensation of forskolin (colforsin) with N,N-dimethyl-β-alanine.

<span class="mw-page-title-main">Bithionol</span> Chemical compound

Bithionol is an antibacterial, anthelmintic, and algaecide. It is used to treat Anoplocephala perfoliata (tapeworms) in horses and Fasciola hepatica.

<span class="mw-page-title-main">ADCY10</span> Protein-coding gene in the species Homo sapiens

Adenylyl cyclase 10 also known as ADCY10 is an enzyme that, in humans, is encoded by the ADCY10 gene.

<span class="mw-page-title-main">Terpene synthase C terminal domain</span> Protein domain

In molecular biology, this protein domain belongs to the terpene synthase family (TPS). Its role is to synthesize terpenes, which are part of primary metabolism, such as sterols and carotene, and also part of the secondary metabolism. This entry will focus on the C terminal domain of the TPS protein.

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

Ribose is a simple sugar and carbohydrate with molecular formula C5H10O5 and the linear-form composition H−(C=O)−(CHOH)4−H. The naturally-occurring form, d-ribose, is a component of the ribonucleotides from which RNA is built, and so this compound is necessary for coding, decoding, regulation and expression of genes. It has a structural analog, deoxyribose, which is a similarly essential component of DNA. l-ribose is an unnatural sugar that was first prepared by Emil Fischer and Oscar Piloty in 1891. It was not until 1909 that Phoebus Levene and Walter Jacobs recognised that d-ribose was a natural product, the enantiomer of Fischer and Piloty's product, and an essential component of nucleic acids. Fischer chose the name "ribose" as it is a partial rearrangement of the name of another sugar, arabinose, of which ribose is an epimer at the 2' carbon; both names also relate to gum arabic, from which arabinose was first isolated and from which they prepared l-ribose.

References

  1. ↑ "Forskolin" (PDF). Sigma Aldrich.
  2. 1 2 3 4 "Forskolin". Drugs.com. 2018. Retrieved 23 March 2018.
  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. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ "The First Total Synthesis of (±)-Forskolin". Synfacts. 18 (5): 0563. May 2022. doi: 10.1055/s-0041-1738000 . S2CID   248315371.
  10. ↑ Dewick, P. M. (2009). Medicinal Natural Products (3rd ed.). Wiley. p. 232. ISBN   978-0470741689.
  11. ↑ 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.
  12. ↑ Majeed, Muhammed; Majeed, Shaheen; Nagabhushanam, Kalyanam; Gnanamani, Muthuraman; Mundkur, Lakshmi (February 2021). "Lesser Investigated Natural Ingredients for the Management of Obesity". Nutrients. 13 (2): 510. doi: 10.3390/nu13020510 . PMC   7913945 . PMID   33557185.
  13. ↑ Jakopin, Žiga (January 2019). "Risks associated with fat burners: A toxicological perspective". Food and Chemical Toxicology. 123: 205–224. doi:10.1016/j.fct.2018.10.051. PMID   30401639. S2CID   53228872.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.