Angelicin is the parent compound in a family of naturally occurring organic compounds known as the angular
furanocoumarin
The furanocoumarins, or furocoumarins, are a class of organic chemical compounds produced by a variety of plants. Most of the plant species found to contain furanocoumarins belong to a handful of plant families. The families Apiaceae and Rutacea ...
s. Structurally, it can be considered as
benzapyra-2-one fused with a furan moiety in the 7,8-position. Angelicin is commonly found in certain
Apiaceae
Apiaceae () or Umbelliferae is a family of mostly aromatic flowering plants named after the type genus ''Apium,'' and commonly known as the celery, carrot, or parsley family, or simply as umbellifers. It is the 16th-largest family of flowering p ...
and
Fabaceae
Fabaceae () or Leguminosae,[International Code of Nomen ...](_blank)
plant species such as ''
Bituminaria bituminosa''. It has a skin permeability coefficient (Log''K
p'') of -2.46.
The maximum absorption is observed at 300 nm. The
1HNMR spectrum is available;
the infrared and mass spectra of angelicin can be found in thi
database The sublimation of angelicin occurs at 120 °C and the pressure of 0.13 Pa. Angelicin is a
coumarin
Coumarin () or 2''H''-chromen-2-one is an aromatic organic chemical compound with formula . Its molecule can be described as a benzene molecule with two adjacent hydrogen atoms replaced by an unsaturated lactone ring , forming a second six-me ...
.
History and etymology
Humans have used plants rich in angelicin for centuries. The earliest known record dates back to 3000 BC when ancient Egyptians applied the oil and sap of local ''
Apiaceae
Apiaceae () or Umbelliferae is a family of mostly aromatic flowering plants named after the type genus ''Apium,'' and commonly known as the celery, carrot, or parsley family, or simply as umbellifers. It is the 16th-largest family of flowering p ...
'' species exposing their skin to sunlight to cure
vitiligo
Vitiligo (, ) is a chronic autoimmune disorder that causes patches of skin to lose pigment or color. The cause of vitiligo is unknown, but it may be related to immune system changes, genetic factors, stress, or sun exposure, and susceptibili ...
. In meantime, tribes in India used ''
Psoralea corylifolia'' which contained
psoralen
Psoralen (also called psoralene) is the parent compound in a family of naturally occurring organic compounds known as the linear furanocoumarins. It is structurally related to coumarin by the addition of a fused furan ring, and may be considered a ...
, the isomer of angelicin. Humans also attempted to harvest the plants as an alternative food source. However, most of them turned out to be unpalatable and toxic such as ''
Angelica archangelica
''Angelica archangelica'', commonly known as angelica, garden angelica, wild celery, and Norwegian angelica, is a biennial plant from the family Apiaceae, a subspecies of which is cultivated for its sweetly scented edible stems and roots. Like ...
'' due to the ability to irritate skin and damage internal organs.

The name "angelicin" stems from the aforementioned plant, ''Angelica''. This Latin name originated in medieval Europe where this plant was also used as a universal treatment to many types of disease not mentioning the
bubonic plague
Bubonic plague is one of three types of Plague (disease), plague caused by the Bacteria, bacterium ''Yersinia pestis''. One to seven days after exposure to the bacteria, flu-like symptoms develop. These symptoms include fever, headaches, and ...
. At this time, people believed that the plant could prevent the soul from being taken over by sorcery, curse and evil spirit (add reference). ''Angelica'' would have appeared in a dream with an angel explaining its applications, hence the name. Ironically, it was later discovered that the plant's oil is toxic when utilized in large quantities particularly when the plant was fresh.
The species of plants where angelicin is found was introduced in Britain in the 19th century. Currently, it can be found in
Canada
Canada is a country in North America. Its Provinces and territories of Canada, ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, making it the world's List of coun ...
and some parts of the
United States
The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...
and
Europe
Europe is a continent located entirely in the Northern Hemisphere and mostly in the Eastern Hemisphere. It is bordered by the Arctic Ocean to the north, the Atlantic Ocean to the west, the Mediterranean Sea to the south, and Asia to the east ...
. Because of the toxicity of certain plant parts and the ability of plant to proliferate, it is included in the list of
invasive species
An invasive species is an introduced species that harms its new environment. Invasive species adversely affect habitats and bioregions, causing ecological, environmental, and/or economic damage. The term can also be used for native spec ...
.
The leaves of ''Angelica archangelica,'' which are rich in angelicin, are used to extract the compound. There were multiple studies on the toxicity of angelicin one of which showed that the compound elicits
chromosomal damage in hamster cells exposed to 320-380 nm UV light. The chromosomal aberrations were shown to be also induced in humans.
Nowadays, it is debated whether ''Angelica'' should be considered toxic. However, it is certain that the toxicity is dependent on the dose of angelicin administered and is solely the matter of experts when it comes to its application.
Biological synthesis

The biosynthesis of angelicin can be described as a variation in the biological synthesis of furanocoumarins. It begins from the capture of organic carbon by photosynthesis and the formation of carbohydrates. Subsequently, the carbohydrates become the substrates of the
shikimic acid pathway where they are converted to phenylalanine and tyrosine. Enzymes such as ammonialyases, methylases and hydroxylases then transform these amino acids to cinnamic acid derivatives which undergo
''o''-hydroxylation yielding coumarins. The coumarins can undergo further reactions such as
prenylation
Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar to ...
and oxidation to give multiple furanocoumarins one of which is angelicin.

Here, the biosynthesis of angelicin is described in more detail starting at L-phenylalanine as a precursor. The phenylalanine undergoes a non-oxidative deamination by
phenylalanine ammonia-lyase
The enzyme phenylalanine ammonia lyase (EC 4.3.1.24) catalysis, catalyzes the conversion of L-phenylalanine to ammonia and cinnamic acid, ''trans''-cinnamic acid.:
:L-phenylalanine = ''trans''-cinnamate + NH3
Phenylalanine ammonia lyase (PAL) i ...
(PAL) to ''trans''-
cinnamic acid
Cinnamic acid is an organic compound with the formula phenyl, C6H5-CH=CH-Carboxylic acid, COOH. It is a white crystalline compound that is slightly soluble in water, and freely soluble in many organic solvents. Classified as an unsaturated carboxy ...
. Afterwards, the ''trans''-cinnamic acid is hydroxylated at the ''para'' position by
''trans''-cinnamate 4-monooxygenase (C4H) which utilizes NADPH, H
+ and O
2. The product,
''p''-coumaric acid, is then converted to
umbelliferone
Umbelliferone, also known as 7-hydroxycoumarin, hydrangine, skimmetine, and ''beta''-umbelliferone, is a natural product of the coumarin family.
It absorbs ultraviolet light strongly at several wavelengths. There are some indications that this c ...
, the important intermediate of biosynthesis pathway.

4-Coumaric acid 2-hydroxylase (C2’H) hydroxylates the ''p''-coumaric acid at the ''ortho'' position. Notably, this reaction uses alpha-ketoglutarate which is reduced to succinate both of which are involved in the
Krebs cycle
The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of biochemical reactions that release the energy stored in nutrients through acetyl-CoA oxidation. The e ...
. The newly formed ''trans''-dihydrocinnamic acid undergoes a photochemical isomerization to a ''cis'' isomer which spontaneously
lactonizes to yield umbeliferone.

Subsequently, umbelliferone 6-
prenyltransferase (PT) couples umbelliferone with prenyl diphosphate to give osthenol and pyrophosphate. Osthenol is oxidized to (+)-columbianetin by (+)-columbianetin synthase (CS), a putative
plant cytochrome P450, although the details of this reaction are not clear. The biosynthesis is terminated with the oxidation of (+)-columbianetin yielding angelicin by
angelicin synthase (AS) which is also considered as the enzyme of cytochrome P450 family.
It is noteworthy that the biosynthesis of angelicin diverges at the umbelliferone as it is also converted to psoralen, the isomer of angelicin. In fact, psoralen, from which the family of linear furanocoumarins descends, is by far much more abundant in plants than angelicin. As a result, most herbivorous insects are resistant to psoralen. Now, it is increasingly recognized that plants devised the pathway leading to angelicin as an alternative defense mechanism. For example, angelicin enhances the toxicity of psoralen by acting as an inhibitor of the detoxifying cytochrome P450 in insects. Moreover, the comparison of the protein sequences of
psoralen synthase
In enzymology, a psoralen synthase () is an enzyme that catalyzes the chemical reaction
:(+)-marmesin + NADPH + H+ + O2 \rightleftharpoons psoralen + NADP+ + acetone + 2 H2O
The 4 substrates of this enzyme are (+)-marmesin, NADPH, H+, and O2 ...
and angelicin synthase shows a 70%
identity
Identity may refer to:
* Identity document
* Identity (philosophy)
* Identity (social science)
* Identity (mathematics)
Arts and entertainment Film and television
* ''Identity'' (1987 film), an Iranian film
* ''Identity'' (2003 film), an ...
overall and 40% identity in the substrate recognition sites.
This implies that the biosynthesis of angelicin is a relatively recently evolved trait.
Chemical synthesis

Iodination of commercially available
umbelliferone
Umbelliferone, also known as 7-hydroxycoumarin, hydrangine, skimmetine, and ''beta''-umbelliferone, is a natural product of the coumarin family.
It absorbs ultraviolet light strongly at several wavelengths. There are some indications that this c ...
(7-hydroxycoumarin) yields 7-hydroxy-8-iodocoumarin.
Acetoxy group can be introduced into hydroxyl of 7-hydroxy-8-iodocoumarin, which is used to create
vaginol or vaginidiol with an isopropyl
Grignard reagent
Grignard reagents or Grignard compounds are chemical compounds with the general formula , where X is a halogen and R is an organic group, normally an alkyl or aryl. Two typical examples are methylmagnesium chloride and phenylmagnesium bromi ...
and commercially available epoxy aldehydes. Subsequent acid-catalysed fragmentation of vaginol with
dichloromethane
Dichloromethane (DCM, methylene chloride, or methylene bichloride) is an organochlorine compound with the formula . This colorless, volatile liquid with a chloroform-like, sweet odor is widely used as a solvent. Although it is not miscible with ...
in
trifluoroacetic acid
Trifluoroacetic acid (TFA) is a synthetic organofluorine compound with the chemical formula CF3CO2H. It belongs to the subclass of per- and polyfluoroalkyl substances (PFASs) known as ultrashort-chain perfluoroalkyl acids (PFAAs). TFA is not ...
yields angelicin.
The compound can be isolated from natural sources, albeit this affords a low yield due to the prevalence of other furanocoumarins. The popular technique is air drying the aerial parts and ground roots of plant followed by ''n''-hexane extraction and column chromatography over silica gel.
Medical use
Angelicin derivatives are used to treat
psoriasis
Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...
and
cancer
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
. One way of treating these diseases is by photochemotherapy (
PUVA
PUVA (psoralen and UVA) is an ultraviolet light therapy treatment for skin diseases: vitiligo, eczema, psoriasis, graft-versus-host disease, mycosis fungoides, large plaque parapsoriasis, and cutaneous T-cell lymphoma, using the sensitizing e ...
) which combines UV irradiation with
photosensitizing chemical.
In most cases the 4,5’-dimethylangelicin is applied owing to its firm binding and specificity to DNA. Also, it was shown that it is actively inhibits the synthesis of nucleic acids in tumor cells thereby decreasing their growth.
In PUVA, angelicin is less popular than psoralen, although both furanocoumarins are photosensitizing and used in couple with long-wave UV irradiation. Angelicin and psoralen are used in other skin disorders such as vitiligo and
mycosis
Fungal infection, also known as mycosis, is a disease caused by fungi. Different types are traditionally divided according to the part of the body affected: superficial, subcutaneous, and systemic. Superficial fungal infections include common ...
. DNA photobinding is the most studied aspect of the photobiology and photochemistry of angelicin. According to the mechanism, long-range UV light triggers angelicin to bind to the pyrimidine bases of DNA in the same manner as psoralen. In this way, the inhibition of DNA replication via the formation of
photoadducts can occur. This might be the basis for the desired therapeutic effect as in the case of psoralen derivatives.
However, extreme care should be taken while using PUVA due to the side effects it may bring. Therefore, this type of treatment is sometimes used as a last resort and often corticosteroids are used instead.
One of the main adverse effects of PUVA is
phototoxicity
Phototoxicity, also called photoirritation, is a chemically induced skin irritation, requiring light, that does not involve the immune system. It is a type of photosensitivity.
The skin response resembles an exaggerated sunburn. The involved chem ...
which can be tackled by heteroanalogues of angelicin. For example, recently researchers have shown that if furan ring is replaced by 1-substituted
pyrazole
Pyrazole is an organic compound with the chemical formula, formula . It is a heterocycle characterized as an azole with a 5-membered ring of three carbon atoms and two adjacent nitrogen atoms, which are in Arene substitution pattern, ortho-substi ...
or
thiophene
Thiophene is a heterocyclic compound with the formula C4H4S. Consisting of a planar five-membered ring, it is aromatic as indicated by its extensive substitution reactions. It is a colorless liquid with a benzene-like odor. In most of its reacti ...
ring, the new angelicin heteroanalogues show virtually no phototoxicity.
Interaction with biomolecules

It was shown that angelicin exhibits a multifaceted effect on various biomolecules which stem from the compound's structure and
photoreactivity. For example, the planar structure allows angelicin to
intercalate between the DNA bases. When exposed to ultraviolet light, it undergoes a C
4-photo
cycloaddition
In organic chemistry, a cycloaddition is a chemical reaction in which "two or more Unsaturated hydrocarbon, unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of th ...
reaction with thymine and cytosine forming a monoadduct. The double bonds of angelicin involved in this reaction are the 3,4 and 4’,5’.
However, the rest of the angelicin's aromatic system cannot react with the pyrimidine of complementary strand owing to the unfavorable alignment of reactive double bonds. Lipids are also susceptible to the photoinduced reactions with angelicin which can be either aerobic or anaerobic. The aerobic reactions cause lipid peroxidation whereas the anaerobic pathway leads to the conjugation of angelicin with unsaturated fatty acid chains such as
linolenic acid
Linolenic acid is a type of naturally-occurring fatty acid. It can refer to either of two octadecatrienoic acids (i.e. with an 18-carbon chain and three double bonds, which are found in the '' cis'' configuration), or a mixture of the two. Lino ...
in a manner similar to the formation of pyrimidine adducts.

Proteins were demonstrated to interact with angelicin in a non-covalent fashion. For instance, there is a measurable affinity of angelicin towards human serum albumin (19.10 × 10
4 mol
−1L
−1) which has one non-covalent binding site per angelicin molecule. The ultraviolet light (365 nm) facilitates its covalent binding to proteins which is enhanced in the presence of oxygen. At this wavelength, angelicin can also modify certain amino acids.
Toxicity
According to the
MSDS of Sigma-Aldrich, the
LD50 of angelicin is 322 mg/kg which shows acute toxicity if orally administered to rats. The possible consequences are alteration in
circadian rhythm
A circadian rhythm (), or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism (i.e., Endogeny (biology), endogenous) and responds to the env ...
and
righting reflex
The righting reflex, also known as the labyrinthine righting reflex, or the Cervico-collic reflex; is a reflex that corrects the orientation of the body when it is taken out of its normal upright position. It is initiated by the vestibular system, ...
,
ataxia
Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...
and
analgesia
Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professionals ...
.
Angelicin demonstrates phototoxic and
photomutagenic effects when in contact with skin. It enhances the sensitivity of skin to UV light
[E. Gorgus, C. Lohr, N. Raquet, S. Guth, and D. Schrenk. ]
Limettin and furocoumarins in beverages containing citrus juices or extracts
'. Food and Chemical Toxicology, 48(1):93–98, 2010. leading to severe skin damage such as
erythema
Erythema (, ) is redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries. It occurs with any skin injury, infection, or inflammation. Examples of erythema not associated with pathology inc ...
and
blister
A blister is a small pocket of body fluid (lymph, serum, plasma, blood, or pus) within the upper layers of the skin, usually caused by forceful rubbing (friction), burning, freezing, chemical exposure or infection. Most blisters are filled ...
s.
[B. V. Davidov A. Ya. Potapenko, V. L. Sukhorukov. ]
A comparison between skin-photosensitizing activities of 8-methoxypsoralen and angelicin
'' Experientia 40, pages 264–265, 1982.[Christiane Lohr, Nicole Raquet, and Dieter Schrenk]
''Application of the concept of relative photomutagenic potencies to selected furocoumarins in V79 cells''
Toxicology in Vitro, 24(2):558–566, 2010. Upon irradiation with UV light of longer wavelength, angelicin forms DNA monoadducts which can cause skin cancer.
In contrast, the isomer of angelicin, psoralen, was reported to be five to ten times more active than angelicin and
cross-link DNA . This impedes DNA replication more prominently due to the inability for the two strands of DNA helix to separate.
Both psoralen and angelicin can be used in cancer therapeutics to suppress DNA replication in tumor cells and induce
apoptosis
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
– as mentioned in medical use – but they should be handled with care as they can cause
photodermatitis
Photodermatitis, sometimes referred to as sun poisoning or photoallergy, is a form of allergic contact dermatitis in which the allergen must be activated by light to sensitize the allergic response, and to cause a rash or other systemic effects ...
in healthy cells as a side effect.
In mammalian cell cultures, angelicin showed
mutagen
In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer in ...
ic and
cytotoxic
Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are toxic metals, toxic chemicals, microbe neurotoxins, radiation particles and even specific neurotransmitters when the system is out of balance. Also some types of dr ...
effects while playing a role of strong inhibitor of drug metabolism.
The inhibition is due to the fact that angelicin decreases the activity and expression of
CYP1A1 which is regulated by
aryl hydrocarbon receptor
The aryl hydrocarbon receptor (also known as AhR, AHR, ahr, ahR, AH receptor, or as the dioxin receptor) is a protein that in humans is encoded by the AHR gene. The aryl hydrocarbon receptor is a transcription factor that regulates gene express ...
s (AhR). There are three hypotheses proposed to explain the phenomenon:
# Angelicin attenuates the
catalytic activity performed by CYP1A1 regardless the presence of UV light.
# Angelicin triggers the
gene expression
Gene expression is the process (including its Regulation of gene expression, regulation) by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, ...
of CYP1A1 by activation of AhR when no UV light is available.
# Angelicin leads to CYP1A1 gene expression without the involvement of AhR.
The phototoxic properties of angelicin were deployed by its use as a natural pesticide and disinfectant. Note that it is difficult to readily determine whether only angelicin poses the highest risk of phototoxicity and photomutagenicity as in plants angelicin always occurs in a mixture with angelicin derivatives, psoralen and other furanocoumarins. Moreover, the furanocoumarin composition of most plant species is not definitely known as well as the toxic properties of some furanocoumarins.
References
{{coumarin
Furanocoumarins