404-86-4 Usage
Uses
Used in Food Industry:
Capsaicin is used as a flavor enhancer for sauces where a pungent note is desired, providing the characteristic heat and spiciness to various dishes.
Used in Pharmaceutical Industry:
Capsaicin is used as a topical analgesic for relieving pain from arthritis, muscle aches, and sprains. It acts as a rubefacient, dilating blood vessels and causing a localized numbing sensation by overwhelming nerves with its heat effect.
Used in Neurobiological Research:
Capsaicin is employed as a tool in neurobiological research, acting as a prototype vanilloid receptor agonist. It is used to study the physiology of pain and the effects as a counterirritant and gastrointestinal stimulant.
Used in Pain Management:
Capsaicin is used in many topical ointments to relieve the pain of peripheral neuropathy, specifically targeting pain in the nerve endings near the surface of the skin.
Used in Multiple Sclerosis Therapy:
Capsaicin is utilized as a K channel blocker in the treatment of multiple sclerosis, potentially providing therapeutic benefits for patients with this condition.
Used in Animal Repellent Industry:
As an animal repellent, capsaicin is used against insects and mites, and has been registered for use in the United States since 1962.
Used in Self-Defense:
Capsaicin is also used in pepper spray, serving as a self-defense tool due to its irritating effects on the eyes and respiratory system.
History
Capsaicin is a naturally occurring substance that is responsible for the burning, pungent sensation associated with the ingestion of hot peppers from the Capsicum genus. The effect elicited by these peppers is at the origin of the name Capsicum, which derives from the Greek kapto, meaning “to bite”.
Hot peppers are a native plant from the American tropics and their use can be traced back to the Aztec and Inca civilizations. The Aztecs named them “chilies” and used them for culinary purposes. After discovery of the New World, chili pods were introduced in Europe and their cultivation expanded to other parts of the globe. Nowadays, hot peppers are found in nearly every country and are an important part of the culinary tradition of many different cultures.
The active component of chili peppers was initially isolated by J. C. Thresh in 1846. The compound was named “capsaicin” and its chemical structure was later determined by E. K. Nelson in 1919. The complete chemical synthesis of 8-methyl-N- vanillyl-6-nonenamide (capsaicin’s IUPAC* name) was reported in 1930 by Spath &Darling. In the 1960’s, Japanese investigators identified additional substances from Capsicum extracts with similar chemical and pharmacological properties that were termed “capsaicinoids”. Currently, this family of chemical analogues includes both natural (homodihydrocapsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin and capsaicin) and synthetic (nonivamide) members.
History
In 1816, Christian Friedrich Bucholz (1770–1818) first carried out the purification
of capsaicin. He obtained incompletely purified capsaicin and named it “capsaicin”
. In 1876, John Clough Thresh (1850–1932) further purified and got pure capsaicin and named it capsaicin. In 1919, Nelson identified the capsaicin structure. In 1930, E.?Spath and S.?F. Darling used chemical synthesis method for the first
time to successfully synthesize capsaicin. In 1961, the Japanese chemists
S.? Kosuge and Y.? Inagaki isolated similar substances from capsicum and named
them capsaicinoids.
More than 14 capsaicin homologues have been found till now, the structures are
similar with capsaicin, and the typical structure is H3CO(HO)-C6H3-CH2-NHCO-R, which is only different from R group. Capsaicin is the highest content in chili
pepper. Capsaicin and dihydrocapsaicin are the most potent active substances in
capsicum. Capsaicin and its analogues have been synthesized in large quantities in
practice and can be used not only in medicine but also in agriculture and industry.
Although there is a long history of pharmacological and chemical studies on
capsaicin, until November 16, 2009, the US Food and Drug Administration (FDA)
approved the first containing high concentration capsaicin prescription Qutenza
(8% capsaicin) patch for the treatment of postherpetic neuralgia. At present, most
countries have capsaicin prescription drugs on market, but clinical indications are
limited in the treatment of pain.
Application in Particular Diseases
In Osteoarthritis:
Capsaicin, an extract of red peppers that causes release and ultimately depletion of substance P from nerve fibers, has been beneficial in providing pain relief in OA when applied topically over affected joints. It may be used alone or in combination with oral analgesics or NSAIDs.
To be effective, capsaicin must be used regularly, and it may take up to 2 weeks to work. It is well tolerated, but some patients experience temporary burning or stinging at the site of application. Patients should be warned not to get the cream in their eyes or mouth and to wash their hands after application.
Application of the cream, gel, or lotion is recommended four times daily, but tapering to twice-daily application may enhance long-term adherence with adequate pain relief.
Indications
Capsaicin (Zostrix) is approved for the relief of pain
following herpes zoster infection (postherpetic neuralgia).
The drug depletes neurons of substance P, an endogenous
neuropeptide that may mediate cutaneous
pain. It is applied to affected skin after open lesions
have healed. Local irritation is common.
Biological Activity
Prototypic vanilloid receptor agonist (pEC 50 values are 7.97 and 7.10 at rat and human VR1 receptors respectively). Excites a subset of primary afferent sensory neurons, with subsequent antinociceptive and anti-inflammatory effects. Reversibly inhibits aggregation of platelets. Also available as part of the Vanilloid TRPV1 Receptor Tocriset? .
Biochem/physiol Actions
Prototype vanilloid receptor agonist. Neurotoxin; activates sensory neurons that give rise to unmyelinated C-fibers, many of which contain substance P. Topical application desensitizes the sensory nerve endings giving a paradoxical antinociceptive effect; systemic administration can be neurotoxic to capsaicin-sensitive cells, especially in newborn animals. Active component of chili peppers.
Pharmacology
Hbgyes, A. (1878) first reported that capsaicin has a strong stimulating effect,
which is the first pharmacological study on capsaicin. And then, a serial of pharmacological effects were discovered. The discovery of capsaicin receptor further
explains the mechanism of capsaicin. The capsaicin receptor, also known as transient voltage receptor cation channel V1 (TRPV1), is a nonselective ligand-gated
cation channel. TRPV1 is widely distributed in the body, mainly in sensory neurons,
and can also be activated by heat and friction damage.
Studies on the analgesic effect of capsaicin were carried out earlier and more
thoroughly. Capsaicin can act on sensory nerve C primary afferent fibers, bind the
end of the neuronal TRPV1 receptor. Capsaicin (1?μM) can result in inward calcium
influx, cell depolarization, neuronal excitation, and glutamate release. The sustained neuron excitement and then failure can result in analgesic and antipruritic
effects.
The mutation of the capsaicin receptor can not only induce obesity but also may
be associated with the occurrence of diabetes. Capsaicin can activate and recruit
brown fat to prevent obesity. Brown fat can produce non-shivering heat in cold
environment and participate in energy consumption. A 10–130?mg daily capsaicin
can significantly increase the body’s energy and fat consumption.
Capsaicin also has a protective effect on the cardiovascular system. Treatment of
capsaicin with rats at a dose of 15?mg/kg can not only promote animal blood circulation and strengthen the cardiovascular function but also reduce the blood pressure
, the serum cholesterol, and triglyceride levels.
The study result of capsaicin on tumor is still controversial. The epidemiology
and basic research have suggested that capsaicin can not only be used as a carcino400
gen but also can prevent cancer. It has been shown that capsaicin can induce cancer
cell apoptosis, and animal experiments have shown that prolonged use of capsaicin
on the skin can induce skin cancer.
Capsaicin is able to scavenge free radicals and inhibit oxidative stress. Capsaicin
can promote gastric secretion, increase appetite, relieve flatulence, improve digestive function, and also prevent gastrointestinal infection and diarrhea. Capsaicin can
improve the performance of sports and anti-fatigue. Capsaicin is capable of thinning
lung mucus, in favor of sputum discharging, enhancing lung tissue perfusion, and
preventing and treating emphysema. Capsaicin is also beneficial on psoriasis, frostbite, cold, etc. In addition, capsaicin is also used for the paralysis of peripheral
nerve function for hypertension treatment.
Capsaicin can be absorbed by the intestine and skin and is able to pass through
the blood-brain barrier.
Anticancer Research
Capsaicin is the major pungent ingredient in red and green chili pepper. It is reportedto induce apoptosis selectively in cancer cells and can suppress the activation ofNF-κB through suppression of NF-κB inhibitor IκBα (Aggarwal and Shishodia 2004). It shows anticancer effects in animal models and suppresses carcinogenesisin colon, skin, lung, tongue, and prostate cancers by altering the metabolism ofcarcinogens. It selectively suppresses the human cancer cell growth of prostate,leukemic, glioma, gastric, and hepatic cancers. It inhibited the tumorigenesis linkedand IL-6-induced activation of STAT-3 and STAT3-regulated gene products likecyclin D1, Bcl-2, Bcl-xL, survivin, and VGEF. It arrests cells in G1 phase andinduces apoptosis (Aggarwal et al. 2008; Clark and Lee 2016).
Clinical Use
In clinical practice, capsaicin is mainly used for topical administration, such as in
the treatment of osteoarthritis and rheumatoid arthritis pain, diabetic nerve pain,
pain after surgery, chemotherapy- or radiotherapy-induced oral pain, psoriasis, etc.
Capsaicin irritates the mucous membrane to cause sneezing, nose bleeding,
coughing, mucus secretion, tears, bronchoconstriction, breathing difficulties, and
other symptoms. The main adverse effects of capsaicin preparations are contact
dermatitis, skin inflammation or blisters, and in severe situation burn-like lesion.
Synthesis
From 3-chloro-2-isopropyltetrahydropyran; biosynthesis from Capsicum frutescens; separation from cis-capsaicin, pelargonic acid vanillamide and dihydrocapsaicin; reaction of capsaicin
Potential Exposure
Botanical animal and insect repellent
used to repel birds, voles, deer, rabbits, squirrels, insects,
and attacking dogs. Capsaicin, which is made from the
Capsicum red chili pepper can be used indoors to protect
carpets and upholstered furniture, and outdoors to protect
fruit and vegetable crops, flowers, ornamental plants,
shrubbery, trees, and lawns. It is also used in pepper sprays
such as MACE, and as an analgesic in creams, lotions and
solid sticks to reduce arthritic, postoperative and neuopathic
pain, such as shingles. Capsaicin is obtained by grinding
dried, ripe Capsicum frutescens L. chili peppers into a fine
powder. The oleoresin is derived by distilling the powder
in a solvent and evaporating the solvent. The resulting
highly concentrated liquid has little odor but has an
extremely pungent taste
Shipping
UN2811 Toxic solids, organic, n.o.s., Hazard
Class: 6.1; Labels: 6.1-Poisonous materials, Technical
Name Required.
Purification Methods
Recrystallise capcaicin from pet ether (b 40-60o), or pet ether/Et2O (9:1). Also purify it by chromatography on neutral Al2O3 (grade V) and elute successively with *C6H6, *C6H6/EtOAc (17:3) then *C6H6/EtOAc (7:3), and distil it at 120o/10-5mm, then repeatedly recrystallise the needles from isopropanol (charcoal). [Crombie et al. J Chem Soc 11025 1955, Bennett & Kirby J Chem Soc(C) 442 1968.] It causes pain and is neurotoxic [Bevan & Szolcsanyi Trends in Pharmacol Sci 11 330 1990, Beilstein 13 IV 2588].
Incompatibilities
Slowly hydrolyzes in water, releasing
ammonia and forming acetate salts.
Waste Disposal
Do not discharge into drains
or sewers. Dispose of waste material as hazardous waste
using a licensed disposal contractor to an approved landfill.
Consult with environmental regulatory agencies for guidance on acceptable disposal practices. Incineration with
effluent gas scrubbing is recommended. In accordance
with 40CFR165, follow recommendations for the disposal
of pesticides and pesticide containers. Noncombustible containers should be crushed and buried under more than
40 cm of soil. Must be disposed properly by following
package label directions or by contacting your local or federal environmental control agency, or by contacting your
regional EPA office
References
1) Gunthorpe et al. (2002) The diversity in the vanilloid (TRPV) receptor family of ion channels; Trends Pharmacol. Sci. 23 183
2) Van Der Stelt and Di Marzo (2004) Endovanilloids. Putative endogenous ligands of transient receptor potential vanilloid 1 channels; Eur. J. Biochem. 271 1827
3) Perkins and Campbell (1992) Capsazepine reversal of the antinociceptive action of capsaicin in vivo; Br. J. Pharmacol. 107 329
4) Kim et al..(2003) Capsaicin exhibits anti-inflammatory property by inhibiting IkB-a degradation in LPS-stimulated peritoneal macrophages; Cell. Signal., 15 299
5) Di Marzo et al. (2001) Hypolocomotor effects in rats of capsaicin and two long chain capsaicin homologues; Eur. J. Pharmacol., 420 123
Check Digit Verification of cas no
The CAS Registry Mumber 404-86-4 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 4,0 and 4 respectively; the second part has 2 digits, 8 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 404-86:
(5*4)+(4*0)+(3*4)+(2*8)+(1*6)=54
54 % 10 = 4
So 404-86-4 is a valid CAS Registry Number.
InChI:InChI=1/C18H27NO3/c1-14(2)8-6-4-5-7-9-18(21)19-13-15-10-11-16(20)17(12-15)22-3/h6,8,10-12,14,20H,4-5,7,9,13H2,1-3H3,(H,19,21)/b8-6+
404-86-4Relevant articles and documents
A convenient transformation of 2-alkylidenecycloalkanones into alkyl-substituted bicyclo[ n.1.0]alkan-1-ols: Application to the synthesis of capsaicin
Kananovich, Dzmitry G.,Zubrytski, Dzmitry M.,Kulinkovich, Oleg G.
, p. 1043 - 1046 (2010)
Treatment of 2-alkylidenecycloalkanones with hydrogen iodide in benzene and subsequent reaction of the obtained -iodo ketones with zinc dust in THF in the presence of chlorotrimethylsilane or titanium(IV) chlorotriisopropoxide led to exo- and endo-(n+3)-alkylbicyclo[n.1.0]alkan-1-ols in high yields. Cyclization of the intermediate -iodo ketones under these conditions proceeded in a moderate to good diastereoselectivity, and the resulted bicyclic cyclopropanols were easily separated by column chromatography over silica gel. exo-7- Isopropylbicyclo[4.1.0]heptan-1-ol obtained in this manner was efficiently employed as a key intermediate in the synthesis of capsaicin. Georg Thieme Verlag Stuttgart - New York.
Regioselective hydroxylation and dehydrogenation of capsaicin and dihydrocapsaicin by cultured cells of Phytolacca americana
Hamada, Hiroki,Ono, Tsubasa,Shimoda, Kei
, p. 103 - 107 (2022/03/18)
The biotransformations of capsaicin and dihydrocapsaicin were investigated using cultured plant cells of Phytolacca americana as biocatalysts. Four products, ie 15-hydroxycapsaicin, dihydrocapsaicin, 15-hydroxydihydrocapsaicin, and capsaicin 4-β-glucoside
Aliphatic hydroxylation and epoxidation of capsaicin by cytochrome P450 CYP505X
Migglautsch, Anna K.,Willim, Melissa,Schweda, Bettina,Glieder, Anton,Breinbauer, Rolf,Winkler, Margit
, p. 6199 - 6204 (2018/09/21)
Microbial cytochrome P450 enzymes (CYPs) are able to mimic the metabolism of human CYPs. One challenge is to identify the respective drug metabolites and to compare substrate specificities to those of the human enzymes. In this study, a class VIII self-sufficient CYP from Aspergillus fumigatus (CYP505X) and variants of this enzyme were heterologously expressed in E. coli. The substrate scope of the variants was determined using active pharmaceutical ingredients (APIs) and (hetero)cyclic compounds. Capsaicin – the active compound in chili peppers – was oxidized most efficiently (4.36 μM/min) in a whole cell mediated biotransformation. The products were isolated, purified and their structures elucidated by 1D and 2D NMR. The two major metabolites showed modifications on the lipophilic side chain. Specifically, capsaicin was hydroxylated at position 8 to give (E)-8-hydroxy-N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-6-enamide and epoxidized at the double bond to give N-(4-hydroxy-3-methoxybenzyl)-5-(3-isopropyloxiran-2-yl)-pentanamide.
Total synthesis of capsaicin analogues from lignin-derived compounds by combined heterogeneous metal, organocatalytic and enzymatic cascades in one pot
Anderson, Mattias,Afewerki, Samson,Berglund, Per,Cordova, Armando
supporting information, p. 2113 - 2118 (2014/07/07)
The total synthesis of capsaicin analogues was performed in one pot, starting from compounds that can be derived from lignin. Heterogeneous palladium nanoparticles were used to oxidise alcohols to aldehydes, which were further converted to amines by an enzyme cascade system, including an amine transaminase. It was shown that the palladium catalyst and the enzyme cascade system could be successfully combined in the same pot for conversion of alcohols to amines without any purification of intermediates. The intermediate vanillylamine, prepared with the enzyme cascade system, could be further converted to capsaicin analogues without any purification using either fatty acids and a lipase, or Schotten-Baumann conditions, in the same pot. An aldol compound (a simple lignin model) could also be used as starting material for the synthesis of capsaicin analogues. Using L-alanine as organocatalyst, vanillin could be obtained by a retro-aldol reaction. This could be combined with the enzyme cascade system to convert the aldol compound to vanillylamine in a one-step one-pot reaction.
[8-[Bis(carboxymethyl)aminomethyl]-6-bromo-7-hydroxycoumarin-4-yl]methyl Moieties as photoremovable protecting groups for compounds with COOH, NH 2, OH, and C-O functions
Hagen, Volker,Kilic, Funda,Schaal, Janina,Dekowski, Brigitte,Schmidt, Reinhard,Kotzur, Nico
scheme or table, p. 2790 - 2797 (2010/08/03)
We introduce a variant of coumarin-based photoactivatable protecting groups and use it exemplarily for caging of a carboxylic acid, an amine, a phenol, and a carbonyl compound. The caged compounds are efficiently photolyzed at long-wavelength UV/vis irradiation. Compared to the corresponding (6-bromo-7-hydroxycoumarin-4-yl)methyl (Bhc) derivatives, the novel coumarin-type caged compounds are distinguished by (i) dramatically increased solubilities in aqueous buffers, (ii) lower pKa values of the C7 hydroxyl of the coumarin chromophore, thus permitting efficient photorelease at lower pH, and (iii) higher photolysis quantum yields in the case of photoprotected carbonyl compounds. The primary step of the photocleavages occurs with rate constants of about 109 s-1.
Compounds and compositions for treating infection
-
, (2009/04/24)
Compounds from 14 Kenyan plants, including from the root of Dovyalis abyssinica and Clutia robusta have been characterized and isolated, and their uses are disclosed.
Drug delivery by an enzyme-mediated cyclization of a lipid prodrug with unique bilayer-formation properties
Linderoth, Lars,Peters, Gnther H.,Madsen, Robert,Andresen, Thomas L.
supporting information; experimental part, p. 1823 - 1826 (2009/09/07)
Special delivery: Liposomal drug-delivery systems in which prodrugs are activated specifically by disease-associated enzymes have great potential for the treatment of severe diseases, such as cancer. A new type of phospholipid-based prodrug has the ability to form stable small unilamellar vesicles (see picture). Activation of the prodrug vesicles by the enzyme sPLA2 initiates a cyclization reaction, which leads to the release of the drug.
Kavalactone compositions and methods of use
-
, (2008/06/13)
This invention relates to kavalactone-containing compositions, and more particularly to compositions having compounds derived from kavalactones and from capsaicinoids. The compositions are useful in modulating pain, and thus can be used to mediate, or eliminate, sensations of pain, thereby providing pain relief and reduction.
Formulations for the treatment of gastro-oesophageal reflux
-
, (2008/06/13)
Formulations for the treatment of gastro-oesophageal reflux diseases include a carrier vehicle and an active gastro-protective agent. The carrier vehicle is either capable of forming a floating barrier layer on contact with gastric acid or of forming a bioadhesive film before any contact with gastric acid, so as to protect gastric mucosa from irritation by the gastric acid. A preferred active ingredient is capsaicin. The carrier vehicle preferably contains alginate or cross-linked polyacrylic acid.
Method for industrial purification of capsaicin
-
, (2008/06/13)
The invention provides a method for industrial purification of Capsaicin in high purity from capsinoids (Capsaicin and analogues), more specifically, a method for industrial purification of Capsaicin which comprises contacting capsinoids containing Capsaicin in a hydrophilic solvent with a silver compound in an aqueous solution to form a Capsaicin-silver complex which is soluble in water, and recovering highly pure Capsaicin from the Capsaicin-silver complex without chromatography.
