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Farnesol
View on Wikipediafrom Wikipedia
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| Names | |
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| Preferred IUPAC name
(2E,6E)-3,7,11-Trimethyldodeca-2,6,10-trien-1-ol | |
| Identifiers | |
3D model (JSmol)
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| ChEBI | |
| ChEMBL | |
| ChemSpider | |
| DrugBank | |
| ECHA InfoCard | 100.022.731 |
| KEGG | |
PubChem CID
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| UNII | |
CompTox Dashboard (EPA)
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| Properties | |
| C15H26O | |
| Molar mass | 222.37 g/mol |
| Appearance | Clear colorless liquid |
| Odor | Floral |
| Density | 0.887 g/cm3 |
| Boiling point | 283 to 284.00 °C (541.40 to 543.20 °F; 556.15 to 557.15 K) at 760 mmHg 111 °C at 0.35 mmHg |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Farnesol is a natural 15-carbon organic compound which is an acyclic sesquiterpene alcohol. Under standard conditions, it is a colorless liquid. It is hydrophobic, and thus insoluble in water, but miscible with oils. As the pyrophosphate ester, farnesol is a precursor to many terpenes and terpenoids.[1] It is a constitutional isomer of Nerolidol.
Uses
[edit]Farnesol is present in many essential oils such as citronella, neroli, cyclamen, lemon grass, tuberose, rose, musk, balsam, and tolu. It is used in perfumery to emphasize the odors of sweet, floral perfumes. It enhances perfume scent by acting as a co-solvent that regulates the volatility of the odorants. It is especially used in lilac and peony perfumes.[2] Farnesol and its ester derivatives are important precursors for a variety of other compounds used as fragrances and vitamins.[1]
Cosmetics
[edit]Farnesol is used as a deodorant in cosmetic products.[3] Farnesol is subject to restrictions on its use in perfumery, because some people may become sensitised to it.[4]
Natural source and synthesis
[edit]In nature
[edit]The pyrophosphate ester of farnesol is the building blocks of possibly all acyclic sesquiterpenoids. These compounds are doubled to form 30-carbon squalene, which is the precursor for steroids in plants, animals, and fungi.[1]
Farnesyl pyrophosphate is produced from the reaction of geranyl pyrophosphate and isopentenyl pyrophosphate. Farnesyl pyrophosphate is the precursor to farnesol and farnesene.
Farnesyl pyrophosphate
Farnesol is used by the fungus Candida albicans as a quorum sensing molecule that inhibits filamentation.[5]
Commercial production
[edit]Obtaining farnesol from natural sources is uneconomical. In industry, farnesol is produced from linalool.[1]
Conversion of geranylacetone to nerolidol, which can be isomerized to farnesol.
History of the name
[edit]Farnesol was named (ca. 1900–1905) after the Farnese acacia tree (Vachellia farnesiana), since the flowers from the tree were the commercial source of the floral essence in which the chemical was identified. This particular acacia species, in turn, is named after Cardinal Odoardo Farnese (1573–1626) of the Italian Farnese family who (from 1550 though the 17th century) maintained some of the first private European botanical gardens in the Farnese Gardens in Rome. The addition of the -ol suffix implies an alcohol.[6] The plant itself was brought to the Farnese gardens from the Caribbean and Central America, where it originates.[7]
See also
[edit]References
[edit]- ^ a b c d Sell, Charles S. (2006). "Terpenoids". Kirk-Othmer Encyclopedia of Chemical Technology. doi:10.1002/0471238961.2005181602120504.a01.pub2. ISBN 0471238961.
- ^ Vom Ende, Marc; Sturm, Wolfgang; Peters, Klaus (2017). "Perfumes". Ullmann's Encyclopedia of Industrial Chemistry. pp. 1–7. doi:10.1002/14356007.a19_171.pub2. ISBN 978-3-527-30673-2.
- ^ Kromidas, L; Perrier, E; Flanagan, J; Rivero, R; Bonnet, I (2006). "Release of antimicrobial actives from microcapsules by the action of axillary bacteria". International Journal of Cosmetic Science. 28 (2): 103–108. doi:10.1111/j.1467-2494.2006.00283.x. PMID 18492144. S2CID 46366332.
- ^ "Standards Restricted - IFRA International Fragrance Association". Archived from the original on 2011-12-30. Retrieved 2012-07-19.
- ^ Jacob M. Hornby (2001). "Quorum Sensing in the Dimorphic Fungus Candida albicans Is Mediated by Farnesol". Applied and Environmental Microbiology. 67 (7): 2982–2992. Bibcode:2001ApEnM..67.2982H. doi:10.1128/AEM.67.7.2982-2992.2001. PMC 92970. PMID 11425711.
- ^ "farnesol". Dictionary.com. Retrieved August 27, 2009.
- ^ Fluckiger, F. A. (March 1885). "The Essential Oil Industry in Grasse" (PDF). American Journal of Pharmacy. 57 (3).
Farnesol
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Chemical Characteristics
Molecular Structure
Farnesol is an organic compound classified as an acyclic sesquiterpene alcohol, with the molecular formula C₁₅H₂₆O and a molar mass of 222.37 g/mol.[1] Its preferred IUPAC name is (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol, reflecting its unsaturated structure featuring three double bonds and a primary alcohol group.[8] This nomenclature highlights the 12-carbon main chain (dodeca) extended by methyl substituents, with triene indicating the positions of the double bonds at 2, 6, and 10.[1] The molecular structure of farnesol is built from three isoprene units, each consisting of a five-carbon motif (2-methylbut-2-ene), linked head-to-tail to form a 15-carbon skeleton characteristic of sesquiterpenes.[1] At one terminus, a hydroxyl group (-OH) is attached to carbon 1, making it a primary alcohol, while the chain features branch points with methyl groups at carbons 3, 7, and 11. These branches contribute to the branched, unsaturated nature of the molecule, which lacks any cyclic elements. The overall architecture can be visualized as a linear chain where the isoprene-derived segments create a repeating pattern of double bonds and methyl substitutions, essential for its chemical identity. The double bonds in farnesol adopt predominantly the trans (E) configuration, specifically the (2E,6E)-trans-trans isomer, which is the most common form encountered in natural and synthetic contexts.[9] Farnesol is a constitutional isomer of nerolidol, sharing the same molecular formula but differing in the position of the hydroxyl group and one double bond—nerolidol has the -OH at carbon 3 and a double bond between carbons 1 and 2.[1] This isomerism arises from alternative arrangements of the isoprene units during formation, yet both compounds retain the core sesquiterpene alcohol framework.Physical and Chemical Properties
Farnesol appears as a colorless to pale yellow liquid at room temperature, exhibiting a mild floral odor that contributes to its use in various formulations.[1][10] This physical form is consistent across its common isomers, such as the trans,trans variant, under standard conditions.[1] Key physical properties include a density of 0.886 g/cm³ at 20°C, a boiling point of 283–284°C at 760 mmHg, and a refractive index of approximately 1.49 at 20°C.[1][11] Farnesol demonstrates low water solubility, approximately 0.0065 g/L at 20°C, rendering it hydrophobic due to its nonpolar sesquiterpene structure; it is miscible with organic solvents such as ethanol, ether, and oils.[1][11][10] In terms of stability, farnesol is generally stable under ambient conditions but sensitive to oxidation upon prolonged exposure to air, potentially forming aldehydes or ketones, and to light, which may accelerate degradation; it is recommended to store it in cool, dark conditions to maintain integrity.[1][12][11] It decomposes upon strong heating, releasing acrid smoke and irritating fumes.[1] Chemically, farnesol's primary alcohol functionality enables reactions such as esterification with carboxylic acids or oxoacids to form esters and water.[12] Its three carbon-carbon double bonds allow for hydrogenation to saturated analogs or acid-catalyzed isomerization between cis and trans configurations.[13][14] Additionally, it reacts with strong oxidizing agents to produce oxidized derivatives and is incompatible with alkali metals, nitrides, or strong reducing agents, potentially generating flammable or toxic gases.[1][10][12]Natural Occurrence and Biosynthesis
Sources in Nature
Farnesol is a sesquiterpene alcohol commonly found in the essential oils of various plants, where it contributes to their characteristic floral and fruity aromas as a volatile compound.[1] Notable plant sources include the essential oils derived from Cymbopogon nardus (citronella), Rosa damascena (rose), Citrus aurantium flowers (neroli), Polianthes tuberosa (tuberose), and Vachellia farnesiana (Farnese acacia), the latter historically serving as an early commercial source that inspired the compound's name.[1][15] In these essential oils, farnesol concentrations are typically low, ranging from 0.1% to 5%, though higher levels up to 2.5% have been reported in select species like cabreuva wood oil.[1][16] In animals, farnesol occurs in trace amounts within human and mammalian tissues, primarily as an intermediate derived from farnesyl pyrophosphate (FPP), a key precursor in the mevalonate biosynthetic pathway.[17] For instance, farnesol and its derivatives, including farnesal and farnesoic acid, have been detected in various mouse tissues such as liver, kidney, and brain, highlighting its endogenous presence in vertebrates.[17] These low-level occurrences underscore farnesol's role in cellular metabolism rather than as a major accumulated compound.[18] Fungal and microbial sources also produce farnesol, particularly certain yeasts where it functions as a signaling molecule. In Candida albicans, farnesol is secreted during growth, accumulating to regulate quorum sensing and morphogenesis.[19] Similarly, Saccharomyces cerevisiae synthesizes farnesol, with production enhanced under alkaline conditions (pH 7.0–8.0), reaching measurable extracellular levels that influence cellular responses.[20] These microbial productions align with farnesol's broader distribution via the mevalonate pathway, as detailed in biosynthetic studies.[21]Biosynthetic Pathways
Farnesol is primarily produced in living organisms through the hydrolysis of farnesyl pyrophosphate (FPP), a key intermediate in isoprenoid biosynthesis, catalyzed by specific phosphatases that cleave the pyrophosphate group. This reaction can be simplified as: In eukaryotes such as animals, fungi, and the cytosolic compartment of plants, FPP is generated via the mevalonate (MVA) pathway. This pathway begins with the condensation of three molecules of acetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), which is reduced by HMG-CoA reductase to mevalonate. Mevalonate undergoes sequential phosphorylation and decarboxylation to yield isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP). These C5 units then condense: DMAPP reacts with IPP to form geranyl pyrophosphate (GPP, C10) via geranyl pyrophosphate synthase, followed by the addition of another IPP molecule to GPP, catalyzed by farnesyl diphosphate synthase (FPPS, EC 2.5.1.21), producing FPP (C15). FPPS is a critical enzyme that ensures the stereospecific formation of the all-trans configuration of FPP, and its activity is tightly regulated, particularly in pathways leading to cholesterol and steroid synthesis where FPP serves as a precursor for squalene production via squalene synthase. In many plants and bacteria, an alternative route known as the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway operates, primarily in plastids of plants and the cytoplasm of bacteria, to generate the same IPP and DMAPP precursors. This pathway starts with the condensation of pyruvate and glyceraldehyde 3-phosphate to form 1-deoxy-D-xylulose 5-phosphate (DXP), which is rearranged and reduced to MEP. Subsequent cyclization, phosphorylation, and reduction steps, involving enzymes such as 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) and (E)-4-hydroxy-3-methylbut-2-enyl pyrophosphate reductase (IspH), yield IPP and DMAPP. From these building blocks, GPP and FPP are assembled identically to the MVA pathway via FPPS, ultimately leading to farnesol through phosphatase-mediated hydrolysis. The MEP pathway complements the MVA pathway in plants, allowing compartmentalized isoprenoid production, while in bacteria, it is the sole route for terpenoid biosynthesis. The regulation of farnesol biosynthesis is interconnected with broader isoprenoid metabolism, where FPP levels influence downstream processes like sterol and steroid production in eukaryotes. For instance, excess FPP can feedback-inhibit early MVA pathway enzymes, such as HMG-CoA reductase, to maintain homeostasis. In organisms relying on the MEP pathway, inhibitors like fosmidomycin target DXR to disrupt IPP/DMAPP supply, indirectly affecting farnesol formation. Specific phosphatases, such as farnesyl diphosphate phosphatase (EC 3.1.7.6) in insects and microbial orthologs like those in Candida albicans, fine-tune farnesol release from FPP, ensuring balanced precursor availability for essential metabolites.Commercial Production
Extraction from Natural Sources
Farnesol is primarily extracted from natural sources through physical separation techniques applied to plant materials rich in essential oils, such as those from citronella grass (Cymbopogon nardus) and rose flowers (Rosa damascena). Historically, early isolations occurred around 1900 from the flowers of Vachellia farnesiana, a shrub whose fragrant blooms provided the compound's namesake, yielding trace amounts of the sesquiterpene alcohol via initial solvent-based methods.[22] These traditional approaches laid the foundation for commercial procurement, though modern extractions emphasize efficiency from higher-yielding plant matrices. Steam distillation remains a cornerstone method for obtaining farnesol-containing essential oils, particularly from citronella leaves and rose petals, where superheated steam volatilizes the compounds, followed by condensation and phase separation to collect the oil layer.[23][24] This hydrodistillation process operates under mild conditions to preserve volatile components, with typical essential oil yields from rose petals ranging from 0.015% to 0.048% by weight of fresh material.[24] Solvent extraction serves as an alternative or complementary technique, employing non-polar solvents like hexane or polar ones like ethanol to dissolve and isolate farnesol from plant tissues, after which the solvent is evaporated and the extract fractionated by distillation or precipitation to concentrate the target compound.[25] These methods target the natural occurrence of farnesol in essential oils, where it constitutes 0.5–1.0% of the total composition in most sources. Despite their efficacy for small-scale production, natural extraction processes suffer from low overall efficiency, with farnesol yields typically limited to trace amounts, often less than 0.01% relative to the input biomass, rendering large-scale isolation uneconomical due to high labor and purification demands. Post-extraction purification is essential to isolate the predominant trans-trans isomer, often involving vacuum distillation to remove lower-boiling impurities under reduced pressure, minimizing thermal degradation, or chromatographic techniques like normal-phase silica gel column chromatography for high-purity separation (up to 99%).[27][28] These steps ensure the final product meets commercial standards for perfumery and other applications, though the inherent low concentration in source materials continues to favor synthetic alternatives for bulk production.Synthetic Methods
Farnesol is primarily produced commercially through a route starting from linalool, involving allylic rearrangement to an ene-type chloride intermediate followed by copper-catalyzed coupling. Linalool is treated with hypochlorous acid to generate the allylic chloride via regioselective chlorination at the allylic position. This chloride then undergoes an SN2'-type cross-coupling reaction with prenylmagnesium chloride in the presence of a copper(I) salt, such as cuprous iodide, yielding farnesol in good yields with high regioselectivity.[29] This method leverages the abundance of linalool from natural sources or synthesis, providing an efficient industrial pathway while allowing control over the double bond geometry. An alternative commercial approach involves the isomerization of nerolidol, a constitutional isomer of farnesol, under acidic conditions to directly afford the target molecule. This simple rearrangement is favored in perfume industry production due to its high yield and the ready availability of nerolidol.[30] The classical chemical synthesis of farnesol proceeds via geranylacetone, prepared industrially from citral and acetone through base-catalyzed aldol condensation. Citral, an α,β-unsaturated aldehyde, condenses with acetone to form the β,γ-unsaturated ketone geranylacetone as a key C13 intermediate in the terpene chain extension.[31] Subsequent chain elongation occurs through a Wittig reaction or, more commonly, the Horner-Wadsworth-Emmons (HWE) olefination using triethyl phosphonoacetate under basic conditions, introducing the terminal isoprenoid unit with E-selectivity. The resulting α,β-unsaturated ester is then reduced, typically with lithium aluminum hydride, to yield farnesol after hydrolysis. This sequence emphasizes stereocontrol to produce the (E,E)-isomer, the predominant natural form, with the HWE step achieving >90% E-geometry due to the stabilized ylide character.[32] For the HWE step, the reaction can be represented as: followed by reduction: Modern synthetic methods incorporate biocatalysis with engineered enzymes for sustainable production. In metabolically engineered Escherichia coli, the mevalonate pathway is optimized by overexpressing geranyl diphosphate synthase (IspA) to form farnesyl diphosphate (FPP), coupled with phosphatases like PgpB or YbjG to hydrolyze FPP to farnesol, achieving extracellular titers of 1.08 g/L in fed-batch fermentation.[33] Similarly, yeast strains such as Saccharomyces cerevisiae have been modified with sesquiterpene synthases and phosphatase overexpression to co-produce farnesol alongside other terpenoids, reaching yields exceeding 6% of dry cell weight.[34] These biocatalytic routes offer high specificity and reduced waste compared to traditional chemistry. Total synthesis from isoprene units builds the C15 skeleton through sequential assembly of C5 building blocks, often derived from isoprene via halogenation or phosphorylation. Seminal stereoselective approaches, such as those developed by Corey, employ modified Wittig-Schlosser reactions on β-hydroxy phosphonium salts to construct trisubstituted (E)-olefins iteratively, ensuring the (E,E)-configuration of farnesol with high purity (>95% stereoselectivity per step). This method highlights the emphasis on E,E-stereoselectivity across all routes, as the trans,trans-isomer predominates in natural sources and exhibits optimal biological activity, achieved through stabilized ylides or metal-mediated couplings that minimize Z-isomer formation.[35]Uses and Applications
In Perfumery and Cosmetics
Farnesol plays a significant role in perfumery, where it enhances floral notes such as lilac and lily-of-the-valley, imparting a delicate, fresh green-floral character often described as muguet-like.[1][36] It functions as a fixative to prolong the longevity of fragrance compositions and as a co-solvent to regulate the volatility of other odorants, allowing for better harmonization of notes.[37] Typical usage levels in perfume compounds range from 0.5% to 5%, though maximum levels can reach up to 30% in specialized formulations.[37] In cosmetics, farnesol serves as a deodorant agent by inhibiting the growth of odor-causing bacteria, thereby neutralizing body odor without masking it.[38][39] It is commonly incorporated into products like soaps, lotions, aftershaves, and deodorants at concentrations typically between 0.05% and 0.3% to provide effective antimicrobial activity while maintaining a subtle floral scent.[40][41] Regulatory standards from the International Fragrance Association (IFRA) limit farnesol concentrations in finished products due to its potential to cause skin sensitization. For leave-on products such as body lotions and face moisturizers, the maximum acceptable level is 0.29%, while it is lower at 0.097% for baby creams and oils (as of IFRA Standards 49, 2022).[42] Derivatives like farnesyl acetate are also employed in synthetic fragrances, adding volume and freshness to white flower accords with a subtle rosy, berry nuance.[43][44]In Pharmaceuticals and Research
Farnesol serves as a key intermediate in the mevalonate pathway, acting as a precursor for the synthesis of pharmaceuticals such as statins, which inhibit HMG-CoA reductase upstream of farnesyl pyrophosphate production to lower cholesterol levels. It also contributes to the development of nitrogen-containing bisphosphonates, which target farnesyl diphosphate synthase to disrupt prenylation and treat conditions like osteoporosis and bone metastases.[45] In anticancer drug design, farnesol analogs form the basis of farnesyl transferase inhibitors that block the prenylation of Ras proteins, preventing oncogenic signaling in tumors.[46] As an antibiotic adjuvant, farnesol enhances the efficacy of antimicrobial agents against biofilm-associated infections by inhibiting biofilm formation and promoting cell detachment in pathogens such as Candida albicans and Staphylococcus epidermidis.[47] For instance, at concentrations around 3 mM, farnesol reduces C. albicans biofilm biomass by over 50% when applied early in development[48] and synergizes with drugs like colistin to combat resistant Gram-negative bacteria, including Acinetobacter baumannii.[49] This adjuvant role extends to mixed-species biofilms, where farnesol disrupts quorum sensing and membrane integrity without direct bactericidal effects at low doses.[50] In research, farnesol is employed as a probe to study protein prenylation, where it replenishes farnesyl pools to reverse inhibition-induced effects like apoptosis in models treated with statins or bisphosphonates.[51] It induces apoptosis in cancer cell lines by mechanisms including competitive inhibition of diacylglycerol binding to protein kinase C and activation of caspase pathways, independent of its effects on cholesterol synthesis.[52] These properties make it valuable for investigating cellular processes like cell cycle arrest and geranylgeranylation in cardiovascular and proliferative diseases.[53] Farnesol has shown potential in neurodegenerative therapy by promoting the farnesylation of the PARIS protein (ZNF746), which represses PGC-1α and contributes to mitochondrial dysfunction in Parkinson's disease models; supplementation with farnesol reduces PARIS accumulation and neurotoxicity in dopaminergic neurons.[54] In cancer research, it disrupts Ras signaling by modulating membrane localization and downstream pathways like ERK1/2, inhibiting tumor growth in skin and pancreatic models at doses that suppress proliferation without excessive toxicity.[55] Derivatives such as farnesylthiosalicylic acid (Salirasib) further exemplify this by competing with farnesylated Ras for chaperone binding, enhancing anti-tumor effects.[56] Preclinical studies also indicate farnesol's potential in autoimmune conditions, such as reducing inflammation and disease severity in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis, possibly by modulating gut microbiome and brain transcriptomics.[57][58] Farnesol is additionally used as a flavoring agent in food products, where it imparts subtle floral notes and is recognized as generally recognized as safe (GRAS) by the U.S. Food and Drug Administration (FDA) and evaluated as safe by the Joint FAO/WHO Expert Committee on Food Additives (JECFA).[59][60] In pest control, it functions as an insect attractant, serving as a precursor to juvenile hormones and pheromones that influence reproductive behaviors, and as a repellent in formulations against aphids and other pests.[1][61] As of November 2025, farnesol is not approved as a standalone pharmaceutical but is incorporated into experimental formulations for topical antifungal treatments and adjuvant therapies in preclinical and early-phase trials, including lipid nanoparticle systems to improve antibiotic delivery against resistant infections.[62] Ongoing investigations focus on its role in combination regimens for cancer and neurodegeneration, with no large-scale human trials reported for direct systemic use.[63]Biological Roles
In Microorganisms
In microorganisms, farnesol serves as a key quorum-sensing molecule, particularly in the fungal pathogen Candida albicans, where it accumulates at high cell densities to inhibit hyphal formation and biofilm development, thereby regulating morphogenesis and community behavior. [64] This inhibition occurs through interference with the cAMP-protein kinase A signaling pathway, preventing the transition from yeast to hyphal forms essential for virulence and tissue invasion. [65] Farnesol exhibits antimicrobial effects against various fungi by disrupting cell membranes, leading to leakage of intracellular contents and inhibition of growth. [66] This membrane perturbation enhances the efficacy of antifungal agents, reducing drug resistance in species like Candida albicans by downregulating efflux pumps and altering ergosterol composition in the plasma membrane. [67] Additionally, farnesol induces apoptosis-like programmed cell death in yeast under stress conditions, activating metacaspases and reactive oxygen species accumulation to eliminate damaged cells and control population dynamics. [68] In Candida albicans, this process involves phosphatidylserine externalization and DNA fragmentation, mimicking metazoan apoptosis to maintain cellular homeostasis. [69] These biological effects are concentration-dependent, with farnesol effectively inducing morphological changes and inhibitory responses in yeast at thresholds of 10–50 μM, corresponding to natural accumulation levels during stationary phase growth. [48] At lower concentrations, it promotes adaptive responses, while higher levels trigger cytotoxicity. [70]In Plants and Animals
In plants, farnesol serves as a volatile compound involved in signaling for defense mechanisms against herbivores and pathogens, contributing to the emission of herbivore-induced plant volatiles that attract natural enemies or deter attackers.[71] As a sesquiterpene alcohol derived from the hydrolysis of farnesyl pyrophosphate (FPP), it acts as a precursor in the biosynthesis of various sesquiterpenes found in essential oils, which enhance plant resilience through antimicrobial and repellent properties.[72][73] In insects, farnesol acts as a precursor to juvenile hormones, which regulate development, reproduction, and metamorphosis, and functions as a pheromone influencing reproductive behaviors and flagellar motility.[3] In other animals, including vertebrates, farnesol functions as an intermediate in the mevalonate pathway, where two molecules of FPP are condensed to form squalene, a key step in cholesterol biosynthesis essential for membrane integrity and hormone production.[74] It modulates calcium homeostasis by inhibiting voltage-gated Ca²⁺ channels, potentially protecting against Ca²⁺-induced cell death.[3] Additionally, farnesol-derived FPP is crucial for the farnesylation of proteins, such as the small GTPases Ras and Rho, which regulates cellular signaling, proliferation, and cytoskeletal dynamics.[75][76] In humans, endogenous farnesol is present at detectable levels in tissues like the skin, where it influences keratinocyte differentiation, and the liver, where it undergoes glucuronidation as part of its metabolism.[77][78] It exhibits neuroprotective effects, particularly in Parkinson's disease models, by promoting the farnesylation of parkin-interacting substrate (PARIS, or ZNF746), which inhibits its repressive activity on PGC-1α and thereby prevents neurodegeneration.[79] As of 2024, research also highlights farnesol's antioxidant and anti-inflammatory properties, contributing to neuroprotection in broader neurodegenerative diseases.[7] Metabolically, farnesol is primarily converted to farnesyl pyrophosphate through phosphorylation, enabling its role in protein prenylation and integration into broader isoprenoid pathways.[80] The physiological roles of farnesol reflect its evolutionary conservation, as the mevalonate pathway—responsible for its production—is ubiquitously present across eukaryotic kingdoms, originating early in evolution to support essential lipid modifications and signaling.[3][80]History and Nomenclature
Discovery
Farnesol was first isolated from the flowers of Vachellia farnesiana, known as the Farnese acacia, during the early 20th century.[80] The compound was extracted via distillation of the acacia flowers and identified as a sesquiterpene alcohol, with the initial description appearing in scientific literature ca. 1900–1905.[81] The structure, first proposed in 1898, was confirmed in the 1920s through degradation and synthesis by chemist Leopold Ruzicka, advancing understanding of sesquiterpenes in natural product chemistry.[82]Etymology
The name "farnesol" derives from Vachellia farnesiana (formerly Acacia farnesiana), known as the Farnese acacia, the plant from which the compound was first extracted in the early 20th century.[15] The specific epithet farnesiana honors the prominent Italian Farnese family, particularly Cardinal Odoardo Farnese (1573–1626), whose botanical gardens in Rome featured the first documented European cultivation of the plant around 1611, as described by Tobias Aldini in 1625.[83] This connection reflects the family's patronage of botany under Cardinal Alessandro Farnese, linking the term to historical horticultural importations from the Americas.[84] The term "farnesol" itself was coined between 1900 and 1905, borrowing from German "farnesol" and appending the suffix "-ol" to denote its nature as an alcohol, in reference to its isolation from V. farnesiana flower extracts used in perfumery.[84] Its earliest recorded use appears in 1904 in the Journal of the Chemical Society.[81] Linguistically, it stems from the New Latin farnesiana, a Latinized form of the family name "Farnese" (from Latin Farnesianus), emphasizing the botanical origin over a purely systematic chemical descriptor.[85] To distinguish isomers, terms like "trans,trans-farnesol" or "(E,E)-farnesol" specify the configuration of the molecule's double bonds, reflecting its sesquiterpenoid structure.[1] In the mid-20th century, the International Union of Pure and Applied Chemistry (IUPAC) adopted the systematic name (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol for the predominant all-trans isomer, standardizing nomenclature for precision in scientific literature and avoiding ambiguity in terpenoid chemistry.[1]References
- https://pubchem.ncbi.nlm.nih.gov/compound/Farnesol