Phorbol

Last updated
Phorbol [1]
Phorbol.svg
Names
Preferred IUPAC name
(1aR,1bS,4aR,7aS,9bS,8R,9R,9aS)-4a,7b,9,9a-Tetrahydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-1,1a,1b,4,4a,7a,7b,8,9,9a-decahydro-5H-cyclopropa[3,4]benzo[1,2-e]azulen-5-one
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.162.035 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C20H28O6/c1-9-5-13-18(24,15(9)22)7-11(8-21)6-12-14-17(3,4)20(14,26)16(23)10(2)19(12,13)25/h5-6,10,12-14,16,21,23-26H,7-8H2,1-4H3/t10-,12+,13-,14-,16-,18-,19-,20-/m1/s1 X mark.svgN
    Key: QGVLYPPODPLXMB-UBTYZVCOSA-N X mark.svgN
  • InChI=1/C20H28O6/c1-9-5-13-18(24,15(9)22)7-11(8-21)6-12-14-17(3,4)20(14,26)16(23)10(2)19(12,13)25/h5-6,10,12-14,16,21,23-26H,7-8H2,1-4H3/t10-,12+,13-,14-,16-,18-,19-,20-/m1/s1
    Key: QGVLYPPODPLXMB-UBTYZVCOBR
  • OCC1=C[C@]([C@@](C(C)4C)([H])[C@]4(O)[C@H](O)[C@H]2C)([H])[C@]2(O)[C@@](C=C(C)C3=O)([H])[C@@]3(O)C1
Properties
C20H28O6
Molar mass 364.438 g·mol−1
Melting point 250 to 251 °C (482 to 484 °F; 523 to 524 K)
Soluble in DMSO (25mg/ml), 100% ethanol (25mg/ml), acetone, ether or dimethyl formamide; almost insoluble in aqueous buffers.
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Phorbol is a natural, plant-derived organic compound. It is a member of the tigliane family of diterpenes. Phorbol was first isolated in 1934 as the hydrolysis product of croton oil, which is derived from the seeds of the purging croton, Croton tiglium . [2] [3] [4] [5] [6] The structure of phorbol was determined in 1967. [7] [8] Various esters of phorbol have important biological properties, the most notable of which is the capacity to act as tumor promoters through activation of protein kinase C. [9] They mimic diacylglycerols, glycerol derivatives in which two hydroxyl groups have reacted with fatty acids to form esters. The most common and potent phorbol ester is 12-O-tetradecanoylphorbol-13-acetate (TPA), also called phorbol-12-myristate-13-acetate (PMA), which is used as a biomedical research tool in contexts such as models of carcinogenesis.

Contents

History and source

Phorbol is a natural product found in many plants, especially those of the Euphorbiaceae and Thymelaeaceae families. [10] [11] Phorbol is the active constituent of the highly toxic New World tropical manchineel or beach apple, Hippomane mancinella. [12] It is very soluble in most polar organic solvents, as well as in water. In the manchineel, this leads to an additional exposure risk during rain, where liquid splashing from an undamaged tree may also be injurious. Contact with the tree or consumption of its fruit can lead to symptoms such as severe pain and swelling. [13] [14] [ non-primary source needed ]

The purging croton, Croton tiglium, is the source of croton oil from which phorbol was initially isolated. Its seeds and oil have been used for hundreds of years in traditional medicine, generally as a purgative, and the seeds were mentioned in Chinese herbal texts 2000 years ago. [15] The purgative effects of the oil are largely attributed to the high percentage of phorbol esters contained in the oil. Phorbol was isolated from C. tiglium seeds in 1934. [2] [3] [4] [5] [6] The structure of the compound was determined in 1967, [7] [8] and a total synthesis was described in 2015. [16]

Mechanism of action

Phorbol derivatives work primarily by interacting with protein kinase C (PKC), although they can interact with other phospholipid membrane receptors. [17] The esters bind to PKC in a similar way to its natural ligand, diacylglycerol, and activate the kinase. [18] Diacylglycerol is degraded quickly by the body, allowing PKC to be reversibly activated. When phorbol esters bind to the receptor, they are not degraded as efficiently by the body, leading to constitutively active PK. [17] PKC is involved in a number of important cell signaling pathways. Thus, phorbol ester exposure can show a wide range of results.

Crystal structure of phorbol-13-acetate bound to the C1B domain of protein kinase C delta PDB 1ptr EBI.jpg
Crystal structure of phorbol-13-acetate bound to the C1B domain of protein kinase C delta

The main results of phorbol exposure are tumor promotion and inflammatory response. Although phorbol is not a carcinogen itself, it greatly enhances the action of other substances and promotes tumor proliferation. PKC is a key component in biological pathways controlling cell growth and differentiation. When phorbol esters bind to PKC, cell proliferation pathways are activated. This effect greatly promotes tumors when the cells are exposed to even a sub-carcinogenic amount of a substance. [17] PKC is also involved in activation of inflammation pathways such as the NF-κB pathway. Thus, exposure to phorbol products can induce an inflammatory response in tissues. [19] Symptoms can include edema and pain, especially to the skin and mucous membranes. [10] While phorbol itself does not have irritant activity, nearly all phorbol esters are highly irritant, with a wide range of half-maximal inhibitory concentration (IC50) values. [10] The median lethal dose (LD50) of phorbol esters for male mice was found to be about 27 mg/kg, with the mice showing hemorrhage and congestion of pulmonary blood vessels, as well as lesions throughout the body. [18]

Total synthesis

A total synthesis of enantiopure phorbol was developed in 2015. While this synthesis will not replace natural isolation products, it will enable researchers to create phorbol analogs for use in research, especially creating phorbol derivatives that can be evaluated for anti-cancer activity. [16] Previously, the difficulty with synthesizing phorbol had been creating C–C bonds, especially in the six-membered ring at the top of the molecule. This synthesis starts from (+)-3-carene, and uses a series of 19 steps to eventually create (+)-phorbol. [20] [21] [16]

Overview of the complete synthesis of (+)-phorbol starting with (+)-3-carene Phorbol synthesis.png
Overview of the complete synthesis of (+)-phorbol starting with (+)-3-carene

Uses in biomedical research

Because of their mechanism of action, phorbol esters can be used to study tumor proliferation and pain response.[ citation needed ] TPA is most commonly used in the laboratory to induce a cellular response.[ citation needed ] For example, TPA can be used to measure response to pain and test compounds that may mitigate the inflammatory response. [22] TPA and other phorbol esters can also be used to induce tumor formation and to study mechanism of action. [10] TPA, together with ionomycin, can also be used to stimulate T-cell activation, proliferation, and cytokine production, and is used in protocols for intracellular staining of these cytokines.[ citation needed ]

Possible and purported medicinal uses

The phorbol ester tigilanol tiglate reportedly has in vitro anti-cancer, antiviral, and antibacterial activities. [10] The phorbol derivatives in croton oil are used in folk medicine, with purported purgative, counter-irritant, or anthelmintic activities. [23] [ better source needed ]

Related Research Articles

In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins, or a member of this family. PKC enzymes in turn are activated by signals such as increases in the concentration of diacylglycerol (DAG) or calcium ions (Ca2+). Hence PKC enzymes play important roles in several signal transduction cascades.

12-<i>O</i>-Tetradecanoylphorbol-13-acetate Chemical compound

12-O-Tetradecanoylphorbol-13-acetate (TPA), also commonly known as tetradecanoylphorbol acetate, tetradecanoyl phorbol acetate, and phorbol 12-myristate 13-acetate (PMA) is a diester of phorbol. It is a potent tumor promoter often employed in biomedical research to activate the signal transduction enzyme protein kinase C (PKC). The effects of TPA on PKC result from its similarity to one of the natural activators of classic PKC isoforms, diacylglycerol. TPA is a small molecule drug.

<i>Croton</i> (plant) Genus of flowering plants

Croton is an extensive plant genus in the spurge family, Euphorbiaceae. The plants of this genus were described and introduced to Europeans by Georg Eberhard Rumphius. The common names for this genus are rushfoil and croton, but the latter also refers to Codiaeum variegatum. The generic name comes from the Greek κρότος, which means "tick" and refers to the shape of the seeds of certain species.

Croton oil is an oil prepared from the seeds of Croton tiglium, a tree belonging to the order Euphorbiales and family Euphorbiaceae, and native or cultivated in India and the Malay Archipelago. Small doses taken internally cause diarrhea. Externally, the oil can cause irritation and swelling. Croton oil is used in Phenol-croton oil chemical peels for its caustic exfoliating effects it has on the skin. Used in conjunction with phenol solutions, it results in an intense reaction that leads to initial skin sloughing. Since croton oil is very irritating and painful, it is used in laboratory animals to study how pain works, pain-relieving and anti-inflammatory drugs, and immunology.

<span class="mw-page-title-main">Phorbol esters</span> Group of chemical compounds

Phorbol esters are a class of chemical compounds found in a variety of plants, particularly in the families Euphorbiaceae and Thymelaeaceae. Chemically, they are ester derivatives of the tetracyclic diterpenoid phorbol.

<span class="mw-page-title-main">C1 domain</span>

C1 domain binds an important secondary messenger diacylglycerol (DAG), as well as the analogous phorbol esters. Phorbol esters can directly stimulate protein kinase C, PKC.

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

Protein kinase C delta type is an enzyme that in humans is encoded by the PRKCD gene.

<span class="mw-page-title-main">PRKCB1</span> Protein-coding gene in the species Homo sapiens

Protein kinase C beta type is an enzyme that in humans is encoded by the PRKCB gene.

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

Protein kinase C gamma type is an enzyme that in humans is encoded by the PRKCG gene.

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

Protein kinase C theta (PKC-θ) is an enzyme that in humans is encoded by the PRKCQ gene. PKC-θ, a member of serine/threonine kinases, is mainly expressed in hematopoietic cells with high levels in platelets and T lymphocytes, where plays a role in signal transduction. Different subpopulations of T cells vary in their requirements of PKC-θ, therefore PKC-θ is considered as a potential target for inhibitors in the context of immunotherapy.

<span class="mw-page-title-main">GPRC5A</span> Protein-coding gene in the species Homo sapiens

Retinoic acid-induced protein 3 is a protein that in humans is encoded by the GPRC5A gene. This gene and its encoded mRNA was first identified as a phorbol ester-induced gene, and named Phorbol Ester Induced Gen 1 (PEIG-1); two years later it was rediscovered as a retinoic acid-inducible gene, and named Retinoic Acid-Inducible Gene 1 (RAIG1). Its encoded protein was later named Retinoic acid-induced protein 3.

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

Protein kinase C iota type is an enzyme that in humans is encoded by the PRKCI gene.

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

Protein kinase C eta type is an enzyme that in humans is encoded by the PRKCH gene.

<span class="mw-page-title-main">PRKD3</span> Protein-coding gene in the species Homo sapiens

Serine/threonine-protein kinase D3 (PKD3) or PKC-nu is an enzyme that in humans is encoded by the PRKD3 gene.

<span class="mw-page-title-main">Chimerin 2</span> Protein-coding gene in the species Homo sapiens

Chimerin 2 (beta-chimaerin) is a protein that in humans is encoded by the CHN2 gene.

<span class="mw-page-title-main">Phorbol 12,13-dibutyrate</span> Chemical compound

Phorbol 12,13-dibutyrate (PDBu) is a phorbol ester which is one of the constituents of croton oil. As an activator of protein kinase C, it is a weak tumor promoter compared to 12-O-tetradecanoylphorbol-13-acetate.

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

Tigilanol tiglate, sold under the brand name Stelfonta is a medication used to treat dogs with non-metastatic, skin-based (cutaneous) mast cell tumors (MCTs). The FDA is also approving Stelfonta to treat non-metastatic MCTs located under the dog's skin (subcutaneous), in particular areas of a dog's leg. Stelfonta is injected directly into the MCT. Stelfonta works by activating a protein that spreads throughout the treated tumor, which disintegrates tumor cells.

<span class="mw-page-title-main">Diglyceride</span> Type of fat derived from glycerol and two fatty acids

A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. Diglycerides are natural components of food fats, though minor in comparison to triglycerides. DAGs can act as surfactants and are commonly used as emulsifiers in processed foods. DAG-enriched oil has been investigated extensively as a fat substitute due to its ability to suppress the accumulation of body fat; with total annual sales of approximately USD 200 million in Japan since its introduction in the late 1990s till 2009.

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

Mezerein is a toxic diterpene ester found in the sap of Daphne mezereum and related plants. Plants of the genera Euphorbiaceae and Thymelaeaceae possess a wide variety of different phorbol esters, which share the capacity of mimicking diacylglycerol (DAG) and thus activating different isoforms of protein kinase C. Mezerein was first isolated in 1975. It has antileukemic properties in mice, but it is also defined as a weak promoter of skin cancers in the same species. All parts of the plants contain an acrid and irritant sap that contains mezerein, thought to be the principal poison. The sap is especially prevalent in the bark and berries.

Karen L. Leach is an American biochemist with extensive drug discovery experience in large pharmaceutical research laboratories. Her expertise in molecular pharmacology, signal transduction and protein kinases, has been used to establish mechanisms of toxicity for therapeutics such as the novel antibiotic linezolid (Zyvox).

References

  1. ↑ Merck Index , 11th Edition, 7306
  2. 1 2 Flaschenträger B; v. Wolffersdorff R (1934). "Über den Giftstoff des Crotonöles. 1. Die Säuren des Crotonöles". Helvetica Chimica Acta. 17 (1): 1444–1452. doi:10.1002/hlca.193401701179.
  3. 1 2 Flaschenträger B, Wigner G (1942). "Über den Giftstoff des Crotonöles. V. Die Gewinnung von Crotonharz, Dünnem Öl und Phorbol aus dem Crotonöl durch Alkoholyse". Helvetica Chimica Acta. 25 (3): 569–581. doi:10.1002/hlca.19420250315.
  4. 1 2 Kauffmann T, Neumann H, Lenhardt K (1959). "Zur Konstitution des Phorbols, I. Über die reduzierende Gruppe des Phorbols". Chemische Berichte. 92 (8): 1715–1726. doi:10.1002/cber.19590920802.
  5. 1 2 Kauffmann T, Eisinger A, Jasching W, Lenhardt K (1959). "Zur Konstitution des Phorbols, I. Über die reduzierende Gruppe des Phorbols". Chemische Berichte. 92 (8): 1727–1738. doi:10.1002/cber.19590920803.
  6. 1 2 Tseng SS, van Duuren BL, Solomon JJ (1977). "Synthesis of 4aα-Phorbol 9-Myristate 9a-Acetate and Related Esters". J. Org. Chem. 42 (33): 3645–3649. doi:10.1021/jo00443a002. PMID   915585.
  7. 1 2 Hecker E; Bartsch H; Bresch H; Gschwendt M; Härle B; Kreibich G; Kubinyi H; Schairer HU; v. Szczepanski C; Thielmann HW (1967). "Structure and Stereochemistry of the Tetracyclic Diterpene Phorbol from Croton tiglium L". Tetrahedron Letters. 8 (33): 3165–3170. doi:10.1016/S0040-4039(01)89890-7.
  8. 1 2 Pettersen RC, Ferguson G, Crombie L, Games ML, Pointer DJ (1967). "The Structure and Stereochemistry of Phorbol, Diterpene Parent of Co-carcinogens of Croton Oil". Chem. Commun. 1967 (14): 716–717. doi:10.1039/C19670000716.
  9. ↑ Blumberg PM (1988). "Protein Kinase C as the Receptor for the Phorbol Ester Tumor Promoters: Sixth Rhoads Memorial Award Lecture" (PDF). Cancer Res. 48 (1): 1–8. PMID   3275491.
  10. 1 2 3 4 5 Wang, Xiao-Yang; Liu, Li-Ping; Qin, Guo-Wei; Kang, Ting-Guo (2015). "Tigliane Diterpenoids from the Euphorbiaceae and Thymelaeaceae Families". Chemical Reviews. 115 (9): 2975–3011. doi:10.1021/cr200397n. PMID   25906056.
  11. ↑ Beutler, John A.; Alvarado, Ada Belinda; McCloud, Thomas G. (1989). "Distribution of phorbol ester bioactivity in the euphorbiaceae". Phytotherapy Research. 3 (5): 188–192. doi:10.1002/ptr.2650030507. S2CID   85408071.
  12. ↑ Adolf, W; Hecker, E (1984). "On the active principles of the spurge family. X. Skin irritants, cocarcingoens, and cryptic carcinogens from the latex of the manchineel tree". J Nat Prod. 47 (3): 482–496. doi:10.1021/np50033a015. PMID   6481361.
  13. ↑ Strickland, Nicola H (August 12, 2000). "Eating a manchineel "beach apple"". BMJ. 321 (7258): 428. doi:10.1136/bmj.321.7258.428. PMC   1127797 . PMID   10938053.
  14. ↑ Blue, Lauren M; Sailing, Christopher; DeNapoles, Christopher; Fondots, Jordan; Johnson, Edward S (2011). "Manchineel Dermatitis in North American Students in the Caribbean". Journal of Travel Medicine. 18 (6): 422–424. doi: 10.1111/j.1708-8305.2011.00568.x . PMID   22017721.
  15. ↑ Zhang, Xiao-Long; Wang, Lun; Li, Fu; Yu, Kai; Wang, Ming-Kui (2013). "Cytotoxic Phorbol Esters of Croton tiglium". Journal of Natural Products. 13 (5): 858–864. doi:10.1021/np300832n. PMID   23701597.
  16. 1 2 3 Kawamura, Shuhei; Chu, Hang; Felding, Jakob; Baran, Phil S. (2016). "Nineteen-step total synthesis of (+)-phorbol". Nature. 532 (7597): 90–3. Bibcode:2016Natur.532...90K. doi:10.1038/nature17153. PMC   4833603 . PMID   27007853..
  17. 1 2 3 Goel, Gunjan; Makkar, Harinder P.S.; Francis, George; Becker, Klaus (July 2007). "Phorbol Esters: Structure, Biological Activity, and Toxicity in Animals". International Journal of Toxicology. 26 (4): 279–288. CiteSeerX   10.1.1.320.6537 . doi:10.1080/10915810701464641. PMID   17661218. S2CID   11550625 . Retrieved 27 October 2023.
  18. 1 2 Li, Cai-Yan; Devappa, Rakshit K; Liu, Jian-Xin; Lv, Jian-Min; Makkar, HPS; Becker, K (February 2010). "Toxicity of Jatropha curcas phorbol esters in mice". Food and Chemical Toxicology. 48 (2): 620–625. doi:10.1016/j.fct.2009.11.042. PMID   19944127.
  19. ↑ Moscat, Jorge; Diaz-Meco, María T; Rennert, Paul (January 2003). "NF-κB activation by protein kinase C isoforms and B-cell function". EMBO Reports. 4 (1): 31–36. doi:10.1038/sj.embor.embor704. PMC   1315804 . PMID   12524517.
  20. ↑ Wender, Paul A.; Kogen, Hiroshi; Lee, Hee Yoon; Munger, John D.; Wilhelm, Robert S.; Williams, Peter D. (1989). "Studies on tumor promoters. 8. The synthesis of phorbol". Journal of the American Chemical Society. 111 (24): 8957. doi:10.1021/ja00206a050.
  21. ↑ Wender, Paul A.; Rice, Kenneth D.; Schnute, Mark E. (1997). "The First Formal Asymmetric Synthesis of Phorbol". Journal of the American Chemical Society. 119 (33): 7897. doi:10.1021/ja9706256.
  22. ↑ Medeiros, Rodrigo; Otuki, Michel F; Avellar, Maria Christina W; Calixto, João (March 2007). "Mechanisms underlying the inhibitory actions of the pentacyclic triterpene α-amyrin in the mouse skin inflammation induced by phorbol ester 12-O-tetradecanoylphorbol-13-acetate". European Journal of Pharmacology. 22 (2–3): 227–235. doi:10.1016/j.ejphar.2006.12.005.
  23. ↑ Pal, Prince Kumar; Nandi, Manmath Kumar; Singh, Narendra Kumar (Jan–Mar 2014). "Detoxification of Croton tiglium L. seeds by Ayurvedic process of Śodhana". Ancient Science of Life. 33 (3): 157–161. doi: 10.4103/0257-7941.144619 . PMC   4264303 . PMID   25538350.

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