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Molecular Nutrition & Food Research
Pharmacological and nutritional effects of natural coumarins and their
structure-activity relationships
Jing-Jing Zhu, Jian-Guo Jiang*
College of Food and Bioengineering, South China University of Technology, Guangzhou, 510640,
China
*Author for correspondence (e-mail: jgjiang@scut.edu.cn; phone +86-20-87113849; fax:
+86-20-87113843)
Abstract
Coumarins are fused benzene and pyrone ring systems with a wide spectrum of bioactivities including
anti-tumor, anti-inflammation, antiviral and antibacterial effects. In this paper, the current
development of coumarins-based drugs is introduced, and their structure-activity relationship is
discussed by reviewing the relevant literatures published in the past twenty years. Coumarin
molecules can be customized by the target site to prevent systemic side effects by virtue of structural
modification. The ortho-phenolic hydroxyl on the benzene ring had remarkable antioxidant and
anti-tumor activities. Coumarins with aryl groups at the C-4 position have good activities in anti-HIV,
anti-tumor, anti-inflammation and analgesia. C-3 phenylcoumarins have strong anti-HIV and
antioxidant effects. Tetracycline pyranocoumarins can significantly inhibit the HIV, osthol structural
analogues have antimicrobial activity. Praeruptorin C and its derivatives play an important role in
lowering blood pressure and dilating coronary arteries, and khellactone derivatives have significant
Received: 24-Dec-2017; Revised: 27-Apr-2018; Accepted: 27-Apr-2018
This article has been accepted for publication and undergone full peer review but has not been through
the copyediting, typesetting, pagination and proofreading process, which may lead to differences
between this version and the Version of Record. Please cite this article as doi:
10.1002/mnfr.201701073.
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inhibitory effects on AIDS, cancer and cardiovascular diseases. It is concluded that the specific site on
the core structure of coumarin exhibits one or more activities due to the electronic or steric effects of
the substituents. This review is designed to be conducive to rational design and development of more
active and less toxic agents with a coumarin scaffold.
Key words: Coumarins / Bioactivity / Structure / Pharmacology / Effect
Abbreviations: ADR, adriamycin; ALT, alanine aminotransferase; AST, aspartic transaminase;
AKP, alkaline phosphatase; BHT, butylated hydroxytoluene; CDK, cyclin-dependent kinase; CKI,
cyclin-dependent kinase inhibitor; COX-2, cyclooxygenase-2; Con-A, concanavalin A; DHMC,
4-methyl-7,8-dihydroxycoumarin; DR5, death receptor 5; EC50, half maximal effective
concentration; ERK, extracellular regulated protein kinase; GSH, glutathione; GST, glutathione
transferase; GPX, glutathione peroxidase; Hsp90, heat shock protein 90; IN,
integrase; IC50, half
maximal inhibitory concentration; IL-6, interleukin-6; IFN-γ, interferon γ; JNK, Jun N-terminal
kinase; 5-LOX, 5-lipoxygenase; MAPK, mitogen activated protein kinase; MBC, minimal
bactericidal concentration; MDR, multidrug; MDA, methane dicarboxylic aldehyde; MIC, minimum
inhibitory concentration; NSCLC, non-small cell lung carcinoma cell; NO, nitric oxide; NOS, nitric
oxide synthase; ο-DHC, the coumarins of the ortho-diphenol hydroxyl group; RT, reverse
transcriptase; PR, protease; PGE2, prostaglandin E2; PGD2, prostaglandin D2; QSAR, quantitative
structure–activity relationship; ROS, reactive oxygen species; SOD, superoxide dismutase; TERT,
human telomerase reverse transcriptase; TI, therapeutic index; TNF-α, tumor necrosis factor-α; VCR,
vincristine; Vpr, viral protein R.
1 Introduction
2
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The coumarin class of organic compounds consists of a 1, 2-benzopyrone ring system as a basic
parent scaffold.[1] It is a general designation of a large class of phenolic substances found in plants and
made of a fused benzene and α-pyrone ring.[2] Coumarins, initially found in tonka bean (Dipteryx
odorata Wild),[3, 4] are distributed over nearly 30 families and 150 species. A few important ones are
Rutaceae, Umbelliferae, Clusiaceae, Caprifoliaceae, Oleaceae, and Apiaceae.[5] Some plants like
Fructus cnidii, Fructus psoraleae, Angelicae pubescentis, Radix Angelicae dahuricae, Radix
Peucedani, Cortex fraxini are rich in coumarins.[6]
Coumarins are subdivided into simple coumarins, furanocoumarins, pyranocoumarins and other
coumarins based on the differences of substituent locations and characteristics in the chemical
structures. Coumarins are characterized by low molecular weight, easy synthesis and high
bioavailability, as well as a variety of pharmacological activities. Recently, they have become
important lead compounds in drug research development.[7] The toxicity of coumarins and their
derivatives is low, and their target organ toxicity is species-specific and non-genotoxic, which is
associated with the metabolism and detoxification abilities of different species.[8]
Coumarins exhibit a wide range of pharmacological activities including anti-HIV, anti-tumor,
antihypertensive, antihyperlipidemic, anti-inflammatory analgesic etc.[9] The relationships between
their pharmacological effects and chemical structures are the basis of drug design. Therefore, it has
become a priority for drug research and development to study more plant coumarin ingredients, find
effective lead compounds, improve the extraction processes, synthesize and screen highly efficient
coumarins with low toxicities.[10] This review focuses on the pharmacological properties and
structure-function relationships of various coumarins, many of which are derived from plants known
or thought to have medicinal properties, in order to find more targeted and efficient coumarin lead
compounds and provide ideas for structural transformation and optimization.
2 Structure and classification
3
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2.1 Simple coumarins
1, 2-benzopyrone is the basic parent nucleus of coumarins (Fig. 1). Generally speaking, the ones
where only the benzene ring is replaced by other groups such as hydroxyl, methoxyl, methylenedioxy
and isopentenyl, without forming furan rings or pyran rings between C-7 hydroxyl groups and C-6 or
C-8 positions, are called simple coumarins. For example, the esculetin from Cortex Fraxini and the
aurapten from Narirutin belong to simple coumarins.[11] The isopentenyl groups can also be directly
connected to the C-5, C-6 or C-8 positions in addition to the oxygen atom in benzene ring. However,
the C-6 or C-8 positions at the benzene ring are easier to be alkylated because of the higher
electronegativity from the aspect of biosynthetic pathway. Thus, the C-6 or C-8 positions are more
often to be substituted by isobutenyl.[12]
2.2 Furanocoumarins
Furanocoumarins are formed by the substitution of furyl at the 6,7 or 7,8 position of the simple
coumarin. As the formation of furan ring is between 7-hydroxyl and 6-isopentenyl, the body of the
furan ring, benzene ring and α-pyrone ring is in a straight line, which is known as linear
furanocoumarin (Fig. 2). The imperatorin in Radix Angelicae dahuricae and psoralen in Fructus
psoraleae belong to linear furanocoumarins. When the furan ring is generated at the 7-hydroxyl and
8-isopentenyl, the structure of the furan ring, benzene ring and α-pyrone ring is in a polyline, which is
called as angular furanocoumarin (Fig. 3).[13] The isobergapten from Heracleum hemsleyanum Diels is
classified as angular furanocoumarin. Furanocoumarins are abundantly present in Umbelliferae, many
of which are the main ingredients of some plants such as Radix Angelicae dahuricae, Radix
Peucedanim, Angelica sinensis.[5]
2.3 Pyranocoumarins
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Pyranocoumarins refer to a series of compounds in which the 7-hydroxyl is condensed with an
isopentenyl substituted at the C-6 or C-8 positions of the coumarin parent nucleus. When the
7-hydroxyl and 6-isopentenyl form a pyran ring, the pyran ring, the benzene ring and the α-pyrone
ring are in a straight line, thus forming a linear pyranocoumarin such as xanthoxyletin.[5] As the
formation of the pyran ring is between 7-hydroxyl and 8-isopentenyl, the main body of the pyran ring,
benzene ring and α-pyrone ring is in a polyline, which is known as angular pyranocoumarin (Fig. 4),
such as praeruptorin C and pteryxin. According to the summary of this paper, the tetracyclic
pyrancoumarins (Fig. 5) and the khellactone derivatives (Fig. 6) have a variety of biological activity,
and are considered to be the lead compounds of studying the structure-activity relationships.[14]
2.4 Bicoumarins, isocoumarins and other coumarins
Dicoumarins are the dimer or trimer of coumarins (Fig. 7). Isocoumarins, the isomer of coumarins, are
often the derivatives of dihydro coumarins in plants. Other coumarins are often substituted by phenyl,
hydroxyl and isopentenyl at C-3 or C-4 positions in the α-pyrone ring (Fig. 1).[5]
3 Pharmacological effects and structure-activity relationships
3.1 Anti-human immunodeficiency virus (HIV) activity
Acquired Immune Deficiency Syndrome (AIDS), caused by HIV-1 (human immunodeficiency
virus), is a degenerative disease of the immune system and central nervous system. Food and Drug
Administration (FDA)-approved anti-HIV drugs include nucleoside reverse transcriptase inhibitors
(NRTIs/ NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs),
fusion inhibitors (FIs), co-receptor inhibitors (CRIs), integrase inhibitors.[15, 16]
In 1987, zidovudine, the first nucleoside drug of blocking the HIV reverse transcription (RT),
was born.[17] Subsequently, new drugs such as didanoside and zalcitabine continued to emerge.
Although these drugs contributed to a significant inhibitory effect on HIV, they had widespread
5
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serious drawbacks such as poor selectivity and HIV susceptibility. In 1992, Kashman et al. [18] first
discovered that the extract of Calophyllum lanigerum had a strong inhibitory effect on the replication
of HIV along with the protective effect on human normal cells. The active substances were the
coumarin monomers--Calanolide A (1) and Calanolide B (2) (Fig. 5), both of which belonged to the
tetracyclic pyrancoumarins. They were not only highly specific to HIV-1 RT with a low dose, but also
contributed to a strong inhibitory effect on commonly used anti-HIV drug resistant strains. The drug
is the first anti-HIV botanical extract that enters into clinical trials, followed by the gradual
appearance of a large number of structurally modified derivatives with increased activity.[19]
Afterwards, many structurally different coumarins used as new anti-HIV drugs are found to
display potent anti-HIV activity, most of which are identified from natural sources, especially green
plants. The studies of natural active ingredients of coumarins and their anti-HIV effects and
mechanisms in recent years are shown in Table 1. Coumarin plays a major role in inhibiting HIV
replication, of which the main target is HIV RT, HIV protease (PR) and HIV integrase (IN).[20]
Preliminary studies have shown that some coumarin derivatives work in combination with the active
sites of the enzymes to decrease the HIV activity, the IC50 of which is 0.5~2.5 μg/mL.[21]
Apart from tetracyclic pyranocoumarins, many other structures such as khellactone derivatives
and some active groups--C-5 epoxy group, C-3 phenyl group and C-4 phenyl group, attribute great
significance to the specific effect on the HIV. Gu et al.[22] extracted five kinds of coumarins from the
Angelica apaensis, which were oxypeucedanin (3), oxypeucedanin hydrate (4), isoimperatorin (5),
byakangelicol (6), byakangelicin (7) (Fig. 2). Oxypeucedanin (3), oxypeucedanin hydrate (4),
isoimperatorin (5) are different in C-5 substituents, resulting in differences in the anti-HIV activity.
The results showed that the activity of oxypeucedanin (3) exceeded that of oxypeucedanin hydrate (4)
and the isoimperatorin (5) (Table. 1). The C-5 position of the oxypeucedanin (3) (TI=17.59) is an
epoxy group, while the oxypeucedanin hydrate (4) (TI=3.61) and the isoimperatorin (5) (TI=4.54) are
6
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respectively the substituents of the opened epoxy ring and the phenyl group in C-5 position,
suggesting that the epoxy substituent in C-5 position plays an essential part of the effect on HIV.
The HIV-1 viral protein R (Vpr) is an accessory protein that has multiple roles in the
pathogenesis of HIV-1. 3-phenylcoumarins have been identified to inhibit Vpr-dependent viral
infection of human macrophages and the cell cycle arrest activity of Vpr in yeast, of which the
minimal pharmacophore and more potent derivatives through a structure-activity relationships study
also have been synthesised.[23] The hydrophobic region about residues Glu-25 and Gln-65 in Vpr
mutants might be potentially involved in the binding of the inhibitor of 3-phenylcoumarins. The small
molecule inhibitors like 3-phenylcoumarins may be the novel bioprobes to expose the targeting site on
Vpr, thus providing a convenient approach to explore more targeting sites on the protein.[23]
A series of coumarin derivatives as HIV-1 IN inhibitors are measured by quantitative
structure–activity relationship (QSAR) analysis.[24] Srivastav et al. built the regression models of two
different variable selection approaches. [25] The HIV-1 IN inhibition activity is predicted by the genetic
function approximation and sequential multiple linear regression. The study displayed that two
coumarin units linked via an aryl junction were the most important for HIV-1 IN inhibitory activity.
Removing any one coumarin unit would result in the lowering of activity. As the two of the original
four coumarin units were removed from compound 8 (Fig. 8), the potency was reduced (compound
9). In addition, if one more coumarin unit together with the joint was removed from the compound 9,
the effectiveness was significantly decreased. The effect was enhanced by replacing the central phenyl
ring with a more extended aromatic with higher lipophilicity. Presence of nitrogen in compound 10,
11 and 12 reduced the aromaticity and the value of LogP, thus showed low biological activity.[25]
The inhibitory effects and the structure-activity relationships of seven coumarins were studied on
the replication of HIV-1 RT, HIV-1 PR and HIV-1 IN. 11-desmethyl-inophyllum B (13) together
with its precursor compound----12-carbonyl-11-demethyl-inophyllum B (14) (Fig. 5), tricyclic
7
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linear intermediate and tricyclic angular intermediates all showed inhibitory effects on HIV-1 PR. The
other three compounds were tricyclic linear intermediates for the synthesis of calanolide A (1) and
11-desmethyl analogues. There was little inhibitory activity against HIV-1 PR for these three
compounds. In the chemical structure, the largest difference between the two groups is the C-4
position substituents, which are phenyl, n-propyl, aromatic and saturated alkanes.[26] It is therefore
speculated that the 4-position substituted phenyl contributes to the inhibition of HIV-1 PR. Similar
results were obtained by other studies, in the structural analogs of calanolide A (1), the functional
groups at C-10, C-11 and C-12 positions and their stereochemical structures played a key role in the
activity of these compounds, while the C-4 position also had a significant effect on the biological
activity of these compounds. [18], [27]
Tetracyclic pyranocoumarins can be considered a necessary structural skeleton for HIV-1
inhibitory activity. Calanolide A (1), inophyllum B (15) and cordatolide A (16) (Fig. 5) all had
inhibitory activities on HIV-1 RT in vitro. Calanolide A (1) had the strongest activity among them
with an IC50 of about 0.07 μg/mL.[18] Calanolide A (1) showed strong inhibition and high selectivity
on RT of recombinant HIV-1 recombinant virus, but in the range of test concentration, there was no
inhibitory activity against cellular DNA polymerase and HIV-2 RT. [28]
Khellactone derivatives (17) (Fig. 6) (C-3 cis-structure, C-4 cis-structure) is a
7,8-pyranocoumarin, whose structure is characterized by two chiral carbon atoms of 3',4' positions
connected with different acyloxy groups in the pyran ring. Suksdorfin (18) has a significant
inhibitory effect on HIV replication (EC50=1.3μM, TI>40).[29] Huang et al. tested and compared the
activities of 10-Di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK) (19) and its cis-trans isomers of
three different configurations, and results showed that the anti-HIV activity of DCK (19) was
stereoselective and its EC50 was more than a thousand times higher than that of other three isomers.
[30]
The data of other types of esters also indicate that the cis-ester activity is higher than the
corresponding trans-ester. In the cis structure, the activity of (+)-cis structure is higher than the (-)-cis
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structure. Therefore, (+)-cis is considered an important structural factor for the anti-HIV activity of
coumarins.[30] The khellactone mother nucleus structure (17) was used to be linked by different
substituents for the anti-HIV activity screening of the synthetic coumarin derivatives. [31, 32] It was
found that the C-3 methyl, C-4 methyl and C-5 methyl substituted compounds had higher activities,
while C-6 methyl substitution and alkoxy substituted compounds had lower activities, and other
alkyl-substituted compounds maintained certain anti-HIV activity. When the aromatic group and the
electron absorption group were replaced, the khellactone derivatives almost had no anti-HIV
activities.[31, 32]
3.2 Anti-tumor activity
In recent years, increasing natural coumarins with anticancer activity are isolated and identified from
plants. At present, the anti-tumor drugs targeting heat shock protein 90 (Hsp90) can not only
overcome the narrow tumor-inhibitory spectrum of the single target drug, but also identify and
distinguish normal cells from tumor cells. Studies have shown that coumarin antibiotics may become
another class of antineoplastic agents with Hsp90 inhibiting effect. [33]
4-methyl-7, 8-dihydroxycoumarin (DHMC) (20) (Fig. 1) cause apoptosis of non-small cell
lung carcinoma cells (NSCLC), where the mechanism of action was its partial inhibition of the
signaling pathways independent of reactive oxygen species [34] of the extracellular regulated protein
kinases/mitogen activated protein kinases(ERK/MAPK).[35] DHMC (20) inhibited the growth of
mononuclear leukemia cells (U-937) and myeloid leukemia cells (HL-60), and a preliminary study
indicated that phenolic hydroxyl was the active group of the DHMC-induced apoptosis.[36] In order to
further investigate the structure-activity relationships of the coumarins with the ortho-diphenol
hydroxyl group (ο-DHC), a series of DHMC (20) derivatives and their lactone ring-opening analogues
and δ-lactone analogues were synthesized to test their activities of differentiation and apoptosis of
induced U-937 cells.[37] It turned out that the δ-lactone was necessary for the activity of ο-DHC, and
9
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more importantly, the integrity of coumarin parent nucleus contributed to the biological activity of
ο-DHC.[37] Furthermore, DHMC (20) could reduce the production of ROS caused by doxorubicin in
human breast cancer cell (MCF-7) without reducing the anti-tumor effect.[38]
It was demonstrated that 5,7-dihydroxy-4-methyl-6-(3-methylbutanoyl)-coumarin (DMAC)
(21) (Fig. 1) exhibited proapoptotic activity in human colon cancer cells. [39] Jun N-terminal kinase
(JNK) activation was involved in the DMAC-mediated apoptosis initiation, which was independent of
the ROS generation. Furthermore, DMAC could improve the therapeutic effect as combined with
conventional anticancer drugs like 5-FU. A structure–activity relationship study showed that
DMAC-1 with a phenyl substitution at C-4 position, but not DMAC-3 with no alkyl substitution at
C-6 position, exhibited cytotoxicity, which is similar to the results for Ochrocarpin B (22) (Fig. 3),
which exhibits an alkyl group at C-6 position and a phenyl group at C-4 position. It is indicated that
the alkylation at C-6 position and the phenyl group substitution at C-4 position are necessary for
apoptosis-inducing activity and enhancing bioactivity.[39] This can be used to develop a novel
structure-based drug design for a coumarin-associated anticancer approach.
Gacche et al.[40] designed and synthesized a series of hydroxyl-substituted simple coumarins to
evaluate their antioxidant activities and anti-tumor activities. 4-methyl-6-hydroxycoumarin,
5-methyl-7-hydroxycoumarin and 6, 7-dimethyl-4-hydroxycoumarin were attributed outstanding
effects on HeLa-B75, HL-60, HEP-3B. The hydroxyl groups at C-4, C-6 and C-7 positions could
significantly enhance the inhibitory activities on tumor cells. The quantum chemical parameters of
these compounds showed that the stronger the molecular rigidity was, the worse their activities were,
with no obvious dose-effect relationships. Among the series of synthetic coumarin derivatives with
4-hydroxyl groups, 5, 7-dimethoxy-4-hydroxycoumarin showed significant inhibitory activity on
several tumor cells such as MCF-7, HL-60, U937 and Neuro2a,[41] further confirming that the
presence of C-4 hydroxyl groups enhanced the anti-tumor activities of coumarins.
10
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Two kinds of coumarins: osthole (23) and murraol (24) (Fig. 1) were extracted from
Phellolophium madagascariense Baker which is a Madagascar folk medicinal umbelliferous plant.
The proliferation of human hormone-sensitive prostate cancer cell line LNCaP, human prostate cancer
hormone-resistant cell lines PC3 and DU145, murine leukemia cell line L1210 were inhibited by both
of the two coumarins, whose aromatic rings all contained the isopentenyl groups.[42] Furthermore, the
antitumor activity against human pancreatic adenocarcinoma cell line PANC-1 of isoprenylated
coumarins also has been evaluated under nutrient-rich and nutrient-deprived conditions. It was found
that the length of the isoprene tail and the precise substitution position in the coumarin scaffold have a
significant effect on the efficacy of the isoprenylated coumarins. The ether coumarin farnesylated at
C-6 position (compound 25, n=3, Fig.9) was confirmed to have the highest cytotoxic activity with an
LC50 value of 4μM, which could induce morphological changes of apoptosis in PANC-1 cells after a
24h incubation. The structure-activity relationships demonstrated that the substitution at the C-6
position and the presence of a farnesyl isoprenyl tail are important structural features for enhanced
cytotoxicity. The high demand for these isoprenylated compounds for the treatment of pancreatic
cancer and selective cytotoxicity on nutrient-deprived cancer cells attach significant importance to the
development of lead compounds to target pancreatic cancer. [43]
Praeruptorin A (26) (Fig. 6) isolated from Peucedanum praeruptorum shows a reversal of
P-glycoprotein-mediated multidrug (MDR) activity. The expression of P-glycoprotein was
down-regulated at protein and mRNA levels, indicating that khellactone (17) coumarins are a class of
potential MDR reversal agents.[44] A series of compounds of the genus Praeruptorin A (26) analogues
were obtained by further structural modification, of which compound 27 showed a stronger reversal
activity of P-glycoprotein-mediated MDR resistance than that of Praeruptorin A (26) and
verapamil.[45] Compounds 28 obtained by the methoxylation of compound 27 cinnamoyl groups
could enhance its reversal of P-glycoprotein-mediated MDR activity.[46, 47]
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Lv et al. have reported the synthesis of 15 kinds of 2-phenylpyrimidine coumarin derivatives and
their antitumor activities (29-32) against CNE2, Cal27, and KB cell lines.[48] The study of
structure-activity relationships (Fig.10) indicated that compounds 29, 30, 31 and 32 possessed high
activities against the CNE2 cell lines; compounds 30, 31, and 32 exhibited potent activities against
the Cal27 cell lines; and compounds 29, 30, and 32 showed high activities against the KB cell lines,
which are comparable with doxorubicin. These compounds have strong effects on inhibiting tumor
cell proliferation in an in vitro antitumor study. Compound 32 displayed strong inhibitory activity
against CNE2 cells and the most potent inhibition activity on telomerase with an IC50 value of 0.82 ±
0.14μM. Cell proliferation was also blocked by compound 32, accompanied by shortened telomere
length. In a molecular docking assay, compound 32 was combined with the catalytic subunit of
telomerase human telomerase reverse transcriptase (TERT) via multiple modes and replaced the
nucleotide with an active substrate.[48] It is highly likely that 2-phenylpyrimidine coumarins and their
derivatives have the potential to become pilot compounds in antitumor drugs.
The anti-tumor activity of natural coumarins is closely related to their chemical structure, which
is influenced by the differences in the structures of the coumarins parent nucleus, the number and
location of hydroxyl substitutions, the mode and extent of hydroxylation. The antitumor activity of the
coumarin functional group can be summarized as o-DHC, alkyl group at C-6 position & phenyl group
at C-4 position, C-4 hydroxyl group, aromatic ring containing the isopentenyl group, khellactone
coumarins, the presence of a farnesyl isoprenyl tail, and 2-phenylpyrimidine coumarin derivatives etc.
The actions of these coumarin active groups on tumor cells including the molecular mechanisms
have been studied in detail through a variety of cell models, and results showed that they mainly acted
on cell cycles and multiple signaling pathways, or induced apoptosis to inhibit tumor cell
proliferation. Specifically, coumarins can inhibit tumor angiogenesis[49] and serine proteases,
down-regulate NF-kB, induce caspase-dependent apoptosis through mitochondrial pathway[50], inhibit
the activity of NAD(P)H benzoquinone oxidoreductase and the expression of HER2 and EGFR[51],
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and hence prevent tumorigenesis. Specific natural ingredients of coumarins with anti-tumor activity
are summarized in Table 2.
3.3
Antioxidant activity
Excessive free radicals in the human body can interact with numerous substances such as fatty acids,
proteins, DNA to capture their hydrogen atoms, causing damage to the relevant cell structure and
function, thereby leading to a variety of diseases.[52] Hydroxyl substituents on the basic skeleton of
coumarins are active radicals scavenging free radicals. Substitution positions and forms of hydroxyl
groups have a significant effect on the antioxidant activity. It is found that the hydroxyl on the
benzene ring is the main active sites of scavenging free radicals of antioxidant activity. The number of
hydroxyl groups on the benzene ring plays a significant role in scavenging free radicals, especially the
coumarins with the hydroxyl structure of ortho-diphenol possessing a superior antioxidant activity.
The intramolecular hydrogen bonds formed between ortho-diphenol hydroxyl and free radicals are
more stable.[53]
Esculetin (33) (Fig. 1) was isolated from the semen Euphorbiae lathyridis, and DPPH radical
scavenging experiments and anti-oxidation experiments using lard were carried out to measure its
antioxidant activity. The results indicated that the final concentration of scavenging DPPH free
radicals (IC50 =0.058μg/mL) was much lower than that of VC (IC50=0.542μg/mL).[54] Moreover, it
was found that the antioxidant activity of coumarins was related to the number and location of the
phenolic hydroxyl group, especially the ο-DHC. The reason for this is that the phenol hydroxyl group
possesses ortho-orientable electron donor groups to form a stable free radical after the hydrogen
supply.[55]
A density-functional theory was applied to describe the relationships between the antioxidant
activities and the coumarins structures, i.e. that the ο-DHC scavenged free radicals was dominated by
the direct transfer of H atoms, and the O-H dissociation enthalpy involved in this process could be
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used as an indicator of free radicals scavenging activity.[56] For the non-ortho-bisphenol-based
coumarins, their structures had little effect on the decrease of O-H dissociation enthalpy, therefore the
antioxidant abilities were weaker than that of ο-DHC. The B ring (1, 2-pyrone) of the coumarin parent
nucleus had little effect on the antioxidant activities of coumarins because of its weak electron
withdrawing group.[55]
Using a TLC DPPH assay, Vessela et al. analyzed the capacity of 4-hydroxy-bis-coumarins to
scavenge DPPH radicals and their activity of shortening the length of lipid oxidation chains.[55] It
turned out that only compounds 34 and 35 (Fig. 7) increased the oxidation stability of the lipid
sample and their efficiency and reactivity as chain-breaking antioxidants. All the other compounds
36, 37 and 38 (Fig. 7) had no ability as antioxidants. Compounds 36 and 37 have no free phenolic
groups in their molecules, causing them to be inactive as antioxidants. Compound 38 had a free
phenolic group, yet the NO2 substituent in ortho-position strongly reduced its antioxidant potency.
These results are in accordance with the theory of the lipid oxidation inhibition, namely, that the
substitution of the phenolic rings is important to the antioxidant capacity of the compounds.[57]
Obviously, only compounds containing free phenolic groups in the aromatic nucleus are capable of
clearing free radicals and shortening the lipid oxidation chain length. On the contrary, as there is no
free phenolic group in the aromatic nucleus, the OH group from the 4-hydroxy-bis-coumarin does not
have the ability of scavenging radicals. The molecule of the 4-hydroxy-bis-coumarin moiety without
free phenolic groups in the aromatic nucleus is insignificant to the antioxidant and antiradical
activity.[58]
There is a remarkable antioxidant effect of coumarins with C-4 methyl group. Pedersen et al.
studied the free radicals scavenging activities of the 22 structurally related 4-methyl coumarins and
found that ortho-dihydroxycoumarin (at 10 μmol/L) significantly reduced stress-induced intracellular
production-ROS, the effect of which was stronger than with the meta-dihydroxy and monohydroxy
substituted analogues. Moreover, ortho-diacetoxyl derivatives also have significant effects on free
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radical scavenging. Since 4-methyl coumarins did not produce toxic epoxide intermediates in vivo, it
was considered a promising antioxidant prodrug.[59] A similar result was obtained by Roussaki et al.
who synthesized and evaluated a series of coumarin analogues for their antioxidant and soybean
lipoxygenase (LO) inhibitory activity through structural modifications on the coumarin scaffold. It has
been revealed that 3-aryl-coumarin analogues bearing a bromine atom at C-6 position and a methyl
group at C-4 position behave as potent inhibitors of LO.[60] Prenyloxy-coumarins 39 and 40 (Fig. 11)
exhibited the best combinatorially pharmacological characteristics, which efficiently suppressed lipid
peroxidation and soybean LO. As for the chemical modifications of the 2-carbonyl group, compound
41 and 42 appropriately substituted by thiocoumarins are potential lipoxygenase inhibitors whereas
the hydrazone analogues 43 and 44 are not active in LO inhibition but efficient as DPPH radical
scavengers.[61]
Hence one can see that hydroxyl substitutions in the coumarin aromatic nucleus attach great
significance on the antioxidant activity, especially o-DHC, followed by C-4 methyl groups. The free
radicals take out a hydrogen atom from a group (usually hydroxyl) of antioxidant molecules to form
phenoxy radicals, i.e. hydrogen atom transfer mechanism.[62] One of the main pharmacological
activities of coumarins is the removal of excess oxygen free radicals in vivo, of which the antioxidant
effect is mainly through the hydrogen atom transfer mechanism to remove the body overfull oxygen
free radicals.[63] The coumarin monomer compounds in natural plants with obvious antioxidant effects
have strong activities of the inhibition of xanthine oxidase, the protection of light damage and the
scavenging of oxygen free radicals. Table 3 lists the antioxidative effects and mechanisms of natural
coumarin active ingredients studied in recent years. Antioxidant activities are not always directly
relevant in vivo as the glutathione (GSH)/ oxidized glutathione (GSSH) systems normally take care of
the potential. However they affect pathways in more indirect ways. Like the quercetin blocks
H2O2-decreased total intracellular GSH and JNK and p38 MAPK phosphorylation,[64] daphnetin (83)
effectively inhibited apoptosis, cytotoxicity, and mitochondrial dysfunction, which is related to the
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suppressed ROS generation, increased superoxide dismutase (SOD) levels and GSH/ GSSH ratio etc.
This may be involved in the activation of JNK and ERK by the upregulation of Nrf2 antioxidant
signaling pathways to protect the oxidative damage and mitochondrial dysfunction triggered by
tert-butyl hydroperoxide.[65]
3.4
Antimicrobial activity
The antibacterial properties of coumarins were first recognized in 1945. Dicoumarol was found to
inhibit the growth of several strains of bacteria.[66] Bacteriostatic drugs can usually affect spore
germination, mycelial growth and the formation of various fruiting bodies.[67] It has been
demonstrated that the nature and position of substituent groups can determine the increased or
decreased antibacterial activity for these compounds. Particularly, many studies have shown that the
substitution on the coumarin aromatic ring effects the antibacterial activity. The C-7 free hydroxyl
group in the coumarin parent nucleus is important for its anti-bacterial activity, and a C-6 free
hydroxyl group is necessary for antifungal activity. However, studies have shown that C-6 free
hydroxyl group is also necessary for anti-bacterial activity. The free hydroxyl group at the C-6
position or C-8 position endows the coumarin with broad-spectrum antimicrobial activity in the
presence of a C-7 methoxy group.[68] The antibacterial activity of free hydroxycoumarin may be
related to the removal of free radicals from the phenolic hydroxyl structure. As for the antifungal
activities of coumarins, it was confirmed that 4-hydroxycoumarin had no antifungal activity. Among
many synthesized coumarins and angular furanocoumarins, the free 6-OH was found to be important
for antifungal activityactivity, i.e.-the antifungal ability was significantly decreased when C-6
hydroxyl had a protective group. However, the free hydroxyl group at C-7 position in the coumarin
parent nucleus is important for antibacterial activity. The antifungal activities of the 6, 7,
8-trisubstituted coumarins are connected the polarity of the C-8 position substituent.[69]
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Antimicrobial activity of the 3-ethylamino-coumarin (45) (Fig. 1) can be increased by the
extension of the chain length of acyl groups. In vitro studies have shown that superior antibacterial
activity of the compounds demand them to be fat-soluble (passive diffusion into the bacteria) and
have a planar structure and avoiding long-chain structure (assists compounds to enter the bacterial cell
wall).[70]
Okamoto et al. synthesized 28 kinds of osthole derivatives, and three compounds screened had
significantly inhibited the Con-A-induced increase of the plasma alanine aminotransferase [27]. [71]
Osthole (23) provided anti-hepatitis C virus activity. Using mice Con A-induced hepatitis at 100
mg•kg-1 dose of intraperitoneal injection of Osthole (23), the inhibition rate was 85% on Con
A-induced elevation of plasma ALT. Osthenol (46) (Fig. 1) showed an inhibition rate of 32% and
7-hydroxycoumarins inhibition rate was 9%. It verified that the methoxy group at the 7-position and
the 3-methyl-2-butenyl group at the 8-position were necessary for the activity of osthole (23). Many
synthetic compounds with similar structures of the osthole exhibit anti-hepatitis C virus activity. And
some 7-propyloxy derivatives with similar structures to osthole (23) also exhibited an inhibitory
activity on hepatitis C virus and hepatitis C related viruses.[72]
In a study of bactericidal activity of 7-hydroxycoumarin derivatives, it was found that at the
concentration of 50μg/mL, when the coumarin benzene ring had an allyl group, whether it was
O-hydrocarbylation or rearranged, Rhizoctonia solani and Fusarium graminearum showed a good
controlling effect. The inhibitory rate of 4, 8-dimethyl-7-allyl-coumarin and
4-methyl-6-chloro-7-hydroxy-8-allyl-coumarin on Rhizoctonia solani is more than 90%, suggesting
that the coumarin benzene ring with an allyl group has a better bactericidal activity.[73]
Some of the natural 4-aryl coumarins exhibit antibacterial activity. For example, the minimum
inhibitory concentrations of 5,7-dimethoxy-4-arylcoumarin and 5, 7-dimethoxycoumarin isolated
from Streptomyces aureofaciens on the plant pathogenic fungi Collectotrichum musae were 120μg/mL
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and 150μg/mL respectively.[74] Mesuarin (47) (Fig. 4) isolated from Mesua ferrea is active against
Bacillus firmis. Mesuagin (48) (Fig. 4), similar to the mesuarin (47) structure, can effectively inhibit
the growth of Staphylococcus aureus.[75] The antibacterial activity of containing a dihydroxyl on the
aryl coumarin is stronger than that containing only a single hydroxyl on the aryl coumarin. Among the
aryl-hydroxy-coumarins containing a single hydroxyl group, the antibacterial activity of the hydroxyl
group at the 6-position is slightly stronger than that of the hydroxyl group at the 7-position.
4-arylcoumarin which contains the aryl group in the 3-position and a hydroxyl group in 4-position has
a strong and a wide range of antibacterial activity.[75]
Song et al. first reported the antifungal properties of several new linear and angular
pyranocoumarins, anomalin (49), disenecioyl khellactone (50) and peuformosin (51) (Fig. 6), which
had high or weak antifungal activities against five plant pathogens.[76] In particular, disenecioyl
khellactone (50) revealed strong antifungal activity against S. sclerotiorum, T. cucumeris, B. cinerea
and F. graminearum (EC50=29.1, 36.2, 11.0 and 40.1 μg/mL respectively). Pd-D-V (52) (Fig. 6), a
linear pyranocoumarin, had preferential activity against S. sclerotiorum (EC50=13.2 μg/mL) and
favorable effect against C. capsici, B. cinerea and F. graminearum (EC50 =37.3, 35.5 and 33.5μg/mL
respectively).[76] Another report indicated that decursin (53) and decursinol angelate (54) (Fig. 4)
(linear pyranocoumarins isolated from A. gigas) can effectively restrain the rice blast by inhibiting the
spore germination instead of the mycelial growth to M.oryzae.[77] Furthermore, C-5 substituents have
different effects on the antifungal activity of angular furanocoumarins. Libanorin (55),
columbianedin (56) and columbianetin acetate (57) (Fig. 3), containing esters at their C-5 positions,
showed higher antifungal activities than the columbianetin (58) (Fig. 3) that contained a hydroxyl
group at its C-5 position correspondingly. Therefore, the C-5 position on the coumarin parent nucleus
may be one of its antifungal active sites.
Overall, free hydroxyl group in parent nucleus, C-3 acylamino group, C-4 aryl group, benzene
ring with allyl substituent coumarins, osthole analogues and several linear and angular
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pyranocoumarins, contribute to enhancing strong antimicrobial activities. Selected specific coumarin
monomers derived from plants are summarized in Table 4. These call for further studies, where these
coumarins can be examined as potential lead compounds for developing novel antimicrobial agents.
The coumarins that inhibit the mycelial growth, spore production and spore germination may be work
through the inhibition of bacterial glucose and calcium absorption, and destruction of a mycelial
calcium ion gradient, resulting in the synthesis and the transport block of cell wall chitin.[78] In
addition, coumarins can also inhibit bacterial proliferation via inhibiting the catalytic activity of
alkenyl acyl-ACP reductase (Fab I and Fab K). This is an enzyme that catalyzes the last step in the
bacterial fatty acid synthesis pathway (FAS-II), a rate-limiting enzyme for the entire synthetic
pathway, which has been identified as a target for antimicrobial agents.[79] Potential novel coumarin
antibiotics based on the natural product could be modified to further enhance their antimicrobial
potency.
3.5
Anti-inflammatory analgesic activity
At present, many studies have indicated that coumarins from plants have significant
anti-inflammatory analgesic activities, such as imperatorin (59) (Fig. 2) from Radix Angelicae
dahuricae, scopoletin (60) (Fig. 1) from Hypochaeris radicata.[80, 81] Six coumarins were isolated
from Murraya paniculata leaves, which were osthole (23), phebalosin (61), meranzin (62),
umbelliferone (63), scopoletin (60), murracarpin (64) (Fig. 1). Murracarpin (64) was found to have
a strong anti-inflammatory analgesic activity, which may be related to its C-7 methoxyl group, C-8
short chain containing double bonds and alcohol hydroxyl.[82] It was demonstrated that the substituents
at the C-7 position were one of the conditions for the anti-inflammatory activity of coumarins.[83]
Furthermore, coumarins showed anti-inflammatory activities when the methoxyl groups were at the
C-5 or C-7 position, short chain substitutions such as hydroxyl, oxygen or double bond were at the
C-8 position.[84] Anti-inflammatory and analgesic activities of coumarin compounds isolated from
three species of genus Daphne were measured. The results showed that the 7-linked glycosides were
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significantly anti-inflammatory while the 8-linked glycosides had no anti-inflammatory activity.
7-hydroxycoumarin had significant analgesic activity.[85] Based on these results, 7, 8-disubstituted
coumarins are compounds with anti-inflammatory and analgesic activities, and the 7, 8-position
substituents are closely related to the specific activities.
7-subsituted coumarin derivatives were synthesized by various aromatic and heterocyclic amines,
and their anti-inflammatory and analgesic activities in vivo were evaluated via the inhibition of the
5-lipoxygenase (5-LOX). It was revealed that compound 65 and 66 (Fig. 12) were the two of the
most potent compounds in all the screening methods. Compound 66 showed mixed or
non-competitive type of inhibition of 5-LOX in an in vitro kinetic study.[86] Substitutions of -OCH3
group in 66 and -Cl in 65 at C-6 position of benzothiazole ring were found to be crucial for potent
activity. The existence of a benzothiazole ring compared to the substituted phenyl ring with amino
alcohol linker at C-7 position of coumarin ring played a critical role in interaction with 5-LOX
enzyme in docking study as well as in all the pharmacological screening methods.[86]
Mohammed et al. designed and synthesized a new series of fused coumarin derivatives for the
test of their inhibition effects towards LPS-induced NO and PGE2 productions in RAW 264.7
macrophages. Three promising NO production inhibitors, 67, 68 and 71 (Fig. 13), played a part in
inhibiting the expression of iNOS protein, accompanied by an additional iNOS mRNA expression
inhibition of compound 71.[87] Bulkier rings fused on the coumarin nucleus were found more
favorable for activity. The three compounds, especially the tetracyclic analog 71, was more potent
than the previously reported tricyclic coumarin derivatives.[88] The other two derivatives, 69 and 70,
were inhibitors of PGE2 production via inhibiting the expression and activity of COX-2 enzyme.
Moreover, compound 70 also displayed an inhibitory effect on COX-2 mRNA expression at 5 μM.
Both of them have methoxycoumarin and para-toluenesulfonate moieties which may facilitate proper
affinity and efficacy. The chloro and methoxy substituents on the coumarin nucleus generally
enhanced the activity compared to the corresponding unsubstituted coumarin derivatives. The
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cycloheptane ring was better for inhibiting PGE2 production than the bulkier cyclooctane or indene
rings.[87]
Coumarins can inhibit the production of pro-inflammatory cytokines interleukin-6 (IL-6) and
tumor necrosis factor-α (TNF-α), IL-1β, NO, enhance the production of anti-inflammatory cytokine
IL-10, and inhibit the production of pro-inflammatory mediators iNOS mRNA, cyclooxygenase-2
(COX-2) mRNA, and anti-inflammatory mediators HO-1 mRNA. The down-regulation of
pro-inflammatory cytokines is mediated by the inhibition of nuclear factor-kB (NF-kB) and inhibitory
factor-kB (I-kB),[89] which have positive regulatory effects against inflammatory factors, indicating
that their anti-inflammatory effects are attributed to a dual-phase regulatory mechanism of inhibition
of the production of pro-inflammatory factors and the promotion of the formation of
anti-inflammatory factors. The mechanism of analgesia is mainly related to its inhibition of the
synthesis of NO. NO as an important biological activity molecule plays an important role in the pain
modulation of the central and peripheral nervous system. The decrease of endogenous NO level in the
central nervous system shows a certain analgesic effect.[90] However, the inhibition of the NO
synthesis can bring about the analgesic effect in the modulation of the peripheral pain. Table 5
summarizes the studies on natural coumarins involving anti-inflammatory and analgesic effects and
mechanisms in recent years. The main active groups in the structure-activity relationships of the
anti-inflammatory analgesic are C-5 and C-7 methoxy groups, C-7 hydroxyl, C-8 short chain
substitutions such as hydroxyl, oxygen and double bond, o-DHC etc. It was observed that
replacements of substituents in the coumarin positions C-5 and C-7 exhibited higher activity, which
was considered in a QSAR study as the lead optimization in the design of coumarins as potent
non-steroidal anti-inflammatory agents.[91]
3.6
Anti-cardiovascular disease
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Dyslipidemia characterized by abnormal blood lipid levels (i.e., cholesterol and fatty acids) and/or
circulating lipoprotein abnormalities is one of the hazards factors for cardiovascular disease.[92]
Oxidative stress has been implicated in the pathogenesis of various illnesses including cardiovascular
disease. The potential therapeutic or preventive effects of antioxidant agents have recently attracted
great attention.[93] Studies have shown that some coumarins have beneficial effects on cardiovascular
disease, and the results of relevant recent studies are shown in Table 6.
Khellactone derivatives (17), a new type of Ca2+ antagonist for expanding coronary arteries in the
treatment of cardiovascular disease, have broad application prospects. The coumarins with the effect
of treating cardiovascular diseases generally contain a khellactone structure.[94] Pteryxin (72) (Fig. 6)
isolated from the Umbelliferae Pteryxinterebinthina root has a strong effect of expanding coronary
arteries, dilating blood vessels, lowering blood pressure, slowing down the frequency of heart systolic,
and reducing cholesterol and lecithin.[95] Suksdorfin (18) isolated from the Lumatium suksdorfin fruit
has significant antispasmodic and coronary dilatation effects. A common feature of the above active
ingredients is that C-3 and C-4 positions are cis-structures, which thus may be necessary for the
dilation of coronary arteries.
(+) Praeruptorin C (73) (Fig. 6) is an angular pyranocoumarin isolated from Peucedanum
praeruptorum. In recent years, it has been found that praeruptorin C (73) has a prominent effect in
lowering blood pressure and diastole of coronary arteries through Ca2+ antagonism.[96] Wu et al.[97]
studied the structural modification of praeruptorin C (73) in order to explore its structure-activity
relationships. They partially or fully hydrolyzed the two acyl groups of the praeruptorin C (73) in C-3
and C-4 positions to get one only-hydrolysed C-4 acetyl product and two fully hydrolysed products.
The acylations of the total hydrolyzates were carried out by making use of the different conditions of
the acylation reaction to change the structures of the C-3 and C-4 acyl groups. 15 new compounds
were obtained and showed different degrees of Ca2+ antagonistic activity, but all were lower than
those of praeruptorin C (73).[97]
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In 2003, structural modification of praeruptorin C (73) was carried out to synthesize 17 kinds of
C-3' and C-4' trans-structures.[98] Like praeruptorin C, some of the synthetic trans-khellactone
coumarins also displayed significant Ca2+ antagonistic activity, and the highest inhibition rate on rat
arterial ring contraction reached 62.40%. This report not only modified the view that the C-3', C-4' cis
structure of khellactone coumarins was a necessary structure for Ca2+ antagonistic activity, but also
amended some scholars’ statement that acetoxy was the necessary group of Ca2+ antagonist, which
had provided an important reference for the subsequent research and development of khellactone
coumarins.[98]
Furthermore, studies of the lipid-lowering effects of coumarins and their derivatives (esculetin
(33), scoparone (74), and 4-methylumbelliferone (75) (Fig. 1) in rats indicated that
4-Methylumbelliferone had no recovery effects on serum TC(cholesterol) levels, but significantly
prevented CCl4-induced hyperlipidemia by reducing triglyceride (TG) and very low-density
lipoprotein cholesterol (VLDL-C) levels.[99] In addition, most coumarins were confirmed to have no
recovery effect on any of the lipid parameters against CCl4-induced hyperlipidemia in serum, only
esculetin (33) and scoparone (74) with no methyl at C-4 position could prevent HDL-C in
CCl4-induced dyslipidemia.[99] The results indicate that the chemical structure of coumarins is of great
importance to the regulation of serum lipid profiles.
Hybridization of the coumarin with the indole moiety, present in various synthetic statins such as
fluvastatin, has generated the coumarin-indole compound. Compound 76 (Fig. 1) had potent
antihyperlipidemic activity among the 12 tested compounds, which significantly decreased the plasma
TG levels by 55% and TC levels by 20%, meanwhile, increased the HDL-C/TC ratio by 42% in
hyperlipidemic rats.[100] The research group has also synthesized coumarin-chalcone fibrates that are
found to reverse the triton-induced increase in plasma lipid levels. These hybrids inhibited the
biosynthesis of TC and enhanced the activity of lipolytic enzyme and lipoprotein lipase, facilitated
early clearance of lipids from circulation in triton-induced hyperlipidemia. Compound 77 (Fig. 1)
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showed the highest percentage of 26%, 24% and 25% in lowering in TC, PL and TG levels at the dose
of 100 mg/kg, respectively.[101]
Natural coumarins can block the calcium influx and open potassium channels involved in
cardiovascular disease. Calcium flow obstruction and potassium channel opening both can relieve the
cytoplasmic Ca2+ overload, maintain intracellular and extracellular calcium balance and mitochondrial
stability, resulting in antihypertensive, antiarrhythmic, negative inotropic effects and other biological
effects.[94, 98] Altogether, khellactone derivatives (17) are a class of major compounds against
cardiovascular disease among coumarins, of which the other two categories are coumarin-indole
compounds and coumarin-chalcone fibrates. It is suggested that these natural coumarins and novel
hybrids will be a potential new class of therapeutic agents against cardiovascular disease.
3.7 The electronic and steric effect
An important method which can be applied to develop new drugs is computer-assisted drug design
(CADD). The method involves traditional or classic QSAR and 3D QSAR. The chemical structure
can be described with experimental and theoretical steric, electronic, and hydrophobic parameters for
QSAR. It presents the electronic or steric (spatial) effects in the coumarins molecules studied.[102, 103]
Fig. 14 shows the pharmacological effects and structure-activity relationships of the coumarins
mentioned in the text. Research has suggested that DCK analogues can remarkably decrease the
HIV-1 replication in H9 lymphocytes, and 5-methoxy-4-methyl DCK is the most promising structure.
Conformational analysis indicated that the resonance of the coumarin system is a vital structural
feature of the potent anti-HIV activity.[32] The spatial compression of the C-4 and C-5 substituents in
coumarins can reduce the overall planarity and bring about the resonance of the coumarin parent
nucleus, resulting in reduction or lack of anti-HIV activity.[104] Among the series of tested coumarins,
the most active scavengers were the hydrazone analogues 43 and 44 with the 84–86% DPPH
scavenging ability compared to that of the positive control nordihydroguaiaretic acid (84%). This
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phenomenon was attributed to the extended conjugation system of the benzhydrazone group that
could increase the ability of the coumarin radical, of which the conjugated system were formed after
H transfer from the DPPH radical, to accommodate the free electron.[61] The substitution of alkyl
groups at the C-6 position in coumarins commonly decreases the anti-inflammatory activity, except a
methyl group. Some aspects of the electronic effects of these substitutions are not clear. TNF-α
inhibitory activities can be improved or diminished by the substitutions of electron-withdrawing
groups such as CHO, CN, NO2 and COOH, whereas electron-donating groups like OCH3 increased
the activity by threefold similar to the CN group.[105] The C-6 position of the coumarin-chalcone
fibrates in the benzopyran moiety substituted with the strong electron-withdrawing nitro group is
more stable than electron-donating groups, halogens, and sterically-hindered groups,[106] which is
consistent with previous reports that chalcone fibrate with a nitro group was a very potent
antidyslipidemic agent.[107]
4. Conclusion and perspectives
The physiological activities of coumarins are closely related to their chemical structure characteristics.
The basic parent nucleus, substituents, substitution patterns and substitution numbers of coumarins
may have a significant effect on their pharmacological activities. Currently, structural modifications
of coumarins are mostly concentrated on the benzene ring, a little less on the α-pyrone, via
introducing a variety of different substituents such as hydroxyl, methoxyl, methylene-dioxy,
isopentenyl, and aryl groups to improve their bioactivities. It turns out that the o-DHC on benzene
ring has remarkable antioxidant and anti-tumor activities through scavenging free radicals. The free
hydroxyl groups are effective against the inflammation, pain, and pathogenic microorganisms. The
presence of aryl groups at the nucleus of coumarin is significant for several biological activities.
Coumarins with aryl groups at the C-4 position have good anti-HIV, anti-tumor, anti-inflammatory,
and analgesic activities. C-3 phenylcoumarins have a highly beneficial effect against HIV and
oxidation. In addition, some specific classes of coumarin have specific efficiency, for example,
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tetracycline pyranocoumarins can significantly inhibit HIV, osthol structural analogues have
antimicrobial activity, praeruptorin C and its derivatives play a prominent role in lowering blood
pressure and dilating coronary arteries, and khellactone derivatives can remarkably react on AIDS,
cancer and cardiovascular disease. A summary of pharmacological activities of main coumarins
discussed in this article is listed in Table 7.
This review is an attempt to address the potential vista of the strategically placed coumarin
scaffold in pharmaceutical chemistry, which can be used to further investigate in order to facilitate the
use of its maximum potential. It is conducive for the rational design and development of more active
and less toxic drugs with a coumarin scaffold. Owing to the precise planarity and flexibility, the
coumarin nucleus can be seamlessly designed to target specific receptors or can also be used to target
multiple sites utilizing a synergistic reaction. This review should provide a new perspective for the
study of coumarin-derived drugs and get better access to the function of these molecules in diseases.
The study of the clinical application of coumarins, the elucidation of pharmacological mechanisms,
the exploration of structure-activity relationships and the structural modifications may open up fresh
important avenues for further rational application and development of related novel drugs.
5
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Figure 1.
Molecular Nutrition & Food Research
Structures of simple and other coumarins.
48
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Figure 2.
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Molecular Nutrition & Food Research
Structures of linear furanocoumarins. (3-7, 59, 78-81, 84)
49
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Figure 3.
Figure 4.
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Molecular Nutrition & Food Research
Structures of angular furanocoumarins. (22, 55-58, 89)
Structures of angular pyranocoumarins(47-48, 88) and linear pyranocoumarins(53-54).
50
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Figure 5.
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Molecular Nutrition & Food Research
Structures of tetracyclic pyrancoumarins. (1-2, 13-16)
51
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Figure 6.
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Molecular Nutrition & Food Research
Structures of khellactone derivatives. (17-19, 26-28, 49-52, 72-73)
Figure 7.
Structures of bicoumarins (34-38, 87, 90)
52
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Figure 8.
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Molecular Nutrition & Food Research
Structures(8-12) and their IC50 values for quantitative structure–activity relationship analysis
Figure 9.
Key structural components of isoprenylated coumarins
53
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Figure 10.
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Molecular Nutrition & Food Research
Synthesis of compounds 29-32 and their IC50 values as inhibitors against CNE2, Cal27 and KB cell
lines.
Figure 11.
Synthesis of compounds 39-44
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Figure 12.
Figure 13.
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Molecular Nutrition & Food Research
Synthesis of compounds 65-66. Reagents and conditions: (d) Br2 in CH3COOH; (e) C2H5OH,
Reflux, 5 h.
Structures(67-71) and their IC50 values as inhibitors of NO and PGE2 productions in LPS-induced
RAW 264.7 macrophages.
55
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Figure 14.
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Molecular Nutrition & Food Research
The pharmacological effects and structure-activity relationships mechanisms mentioned in this
article
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Graphic Abstract
Coumarins are naturally occurring, versatile synthetic compounds with potential anti-HIV, anticancer,
antioxidant, antimicrobial, anti-inflammatory analgesic, and anti-cardiovascular disease activities.
This review compiles information from publications on the coumarin and its derivatives and proposes
structure-activity relations and the structural modification to open up an important way for the further
rational application of coumarins and the development of related new drugs.
57
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Table 1.
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Molecular Nutrition & Food Research
The coumarins with anti-HIV activities and their mechanisms determined on the EC50 of inhibiting the formation
of syncytia, taking TI as the testing index
Active Ingredients
Source
Result
Mechanism
References
Imperatorin(59)
Radix Angelicae
dahuricae
Inhibit the HIV-1
virus replication
Strongly inhibit
the cyclin D1
expression and
arrest the cells
at the G1 phase
of the cell cycle
[108]
Calanolide A(1),
Calophyllum
inophyllum
Good selectivity,
have strong
inhibitory effects
on HIV-1 virus, but
invalid for HIV-2
virus
Calanolide A (1)
[28]
is homologous to
the HIV-1 RT and
the DNA
polymerase in
the alpha
binding site.
Angelica
apaensis
Oxypeucedanin (3)
has the best
anti-HIV activity, TI
is 17.59. TI of the
other coumarin
monomers is
small, less than 5
Inhibit the HIV
replication,
mainly acting on
HIV RT, HIV PR
and HIV IN
[22]
Imperatorin(59)
Ferula sumbul
27 kinds of
coumarins are
isolated from the
methanol extract,
in which the
imperatorin (59) TI
is 1000 with the
best activity
Inhibit the HIV
replication
[109]
Suksdorfin(18)
Lomatium
suksdorfii
TI>40
Significantly
inhibit the HIV
replication in H9
lymphocytes
[29]
calanolide B(2)
Oxypeucedanin(3)
oxypeucedanin
hydrate(4)
isoimperatorin(5)
58
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Prangos
tschimganica
Psoralen(78)
bergapten(79)
Table 2.
TI respectively is
191, 11.7.
Molecular Nutrition & Food Research
Inhibit the
replication of
HIV-1 in H9
lymphocytes
[110]
The coumarins with anti-tumor activities and their mechanisms
Active
Ingredients
Source
Experimen
tal Model
and
Method
Result
Mechanis
m
Refere
nces
Imperatori
n(59)
Fructus
cnidii
KBV200
cells/
Vincristine
(VCR)
The reversal factor for VCR was 8.27
Reverse
tumor
cells
[111]
Hela-S3
cells
Inhibit the proliferation of cancer cells
as the content is greater than 5μg/mL.
The inhibition intensity order is
osthole(23)>xanthotol(80)>bergapten(
79)>xanthotoxin(81)
Inhibit
the Hela
cell
proliferati
on
[112]
Human
lung
adenocarci
noma and
squamous
carcinoma
in mice
The inhibitory rate of lung
adenocarcinoma was 50.0%; the
inhibitory rate of squamous carcinoma
was 69.5%
Have a
certain
inhibitory
effect on
the
invasion
of cancer
tissue
[113]
HL-60 cells
in G1
phase
The proliferation of HL-60 is slowed
down
Induce
the G1
phase cell
cycle
[114]
Osthole(23
)
xanthotol(8
0)
bergapten(
79)
xanthotoxi
n(81)
Osthole(23
)
Esculetin(3
3)
Cortex
Fraxini
59
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Molecular Nutrition & Food Research
arrest
Human
oral
cancer SAS
cells
10μg/mL of esculetin reduce the
number of SAS cells by 30% after 48h
of incubation and a 60% decrease in
cell number for 72 h of treatment
Enhance
TRAIL-ind
uced
apoptosis
primarily
through
upregulat
ion of
DR5
[115]
Human
colon
cancer
cells
Result in significant growth inhibition
and G1 phase cell cycle arrest
Block the
Ras/ERK1
/2
signaling
pathway
and
decrease
G1 phase
cell cycle
protein
levels
[116]
[117]
Scopoletin(
60)
Porana
racemos
a
PC3 cells,
PAa cells,
Hela cells
IC50 are 157, 154 and 294μg/mL, the
inhibition of PC3 cells proliferation is
time-dependent and
concentration-dependent, the G2
phase cells are significantly decreased
Decrease
intracellul
ar protein
content
and
reduce
acid
phosphat
ase
activity
Psoralen
(78)
Fructus
psoralea
e
MCF-7/
ADR
Decrease the IC50 of MCF-7/ ADR cells
to ADR, increase the intracellular ADR
concentration
Reverse
[118]
the MDR
to
improve
the effect
of
chemothe
60
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Molecular Nutrition & Food Research
rapy
Xanthotoxi
n (81)
Radix
Angelica
e
dahurica
e
K562/ADR
Significantly reduce the IC50 of ADR to
K562 after combined 3h
Have a
[119]
reversal
effect on
MDR
resistance
EMT6 cells
Show significant growth inhibition of
EMT6 at the dose concentration of
2.23μg/mL both in vivo and in vitro
May be
related to
the
relative
reduction
of cell
DNA
content,
cell
mitochon
drial
degenera
tion and
cell
vacuolati
on
MEC-1
cells
MEC-1 cells are dose-dependent
inhibited when the dose is greater
than 25μg/mL
Act on
[121]
the cell
cycle
regulatio
n
mechanis
m
associate
d with the
G1/S
conversio
n
restrictio
n point to
inhibit
cell
proliferati
61
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Molecular Nutrition & Food Research
on
Isoimperat
orin(5)
Fructus
aurantii
Aflatoxin
B1(AFB1)
Significantly inhibit the cytotoxic effect
of AFB1 when the dose is greater than
0.3μM
Enhance
[122]
the
activity of
glutathio
ne
S-transfer
ase to
inhibit
the
cytochro
me P-448,
thereby
inhibit
the
toxicity of
AFB1,
reduce
the
incidence
of liver
cancer
Decursin(5
3)
Koren
Angelica
gigas
Nakai
LNCaP
cells
IC50 is similar to 7μg/mL after 48
hours exposure
Selectivel
y induce
LNCaP
cells
division
to stop at
G1 phase,
inducing
apoptosis
[123]
Praeruptori
n C(73)
Peuceda
num
praerupt
orum
HL-60 cells
Can promote HL-60 cells apoptosis in
the 10~30μg/mL and the degree of
apoptosis increase
Cause
apoptotic
DNA and
nuclear
fragment
ations in
HL-60
cells
[124]
62
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Molecular Nutrition & Food Research
Capillarin(8
2)
Artemisi
a
capillarie
s
PAa cells
The inhibitory rate are most obvious,
reaching 52.4% ,at the dose of
0.16μg/mL
Inhibit
the DNA
synthesis,
block the
cells in
the
G0/G1
phase,
thereby
inhibit
the
proliferati
on of PAa
cells
[125]
Imperatori
n(59)
Changiu
m
smyrnioi
des
Hep-G2
The anti-tumor effect of
isoimperatorin(5) is the best, IC50 is
0.39~4.11μg/mL
Induce
the
apoptosis
of
Hep-G2
[126],[
127]
Bergapten(
79)
Angelica
e
pubesce
ntis
Human
breast
cancer cell
lines
MCF-7 and
SKBR 3
Induce the block in the G0/G1 phase
Increase
the
mRNA
and
protein
levels of
p53 and
p21waf
[128]
Daphnetin(
83)
Daphne
Korean
Nakai
Hep-G2
cells
Low dose inhibits the cell cycle to
stagnate in the S phase, high dose is to
stagnate in the late G1 and S early
Inhibit
the
activity of
PKA and
PKC, and
up-regula
te the
activity of
p38MAPK
[129]
Isoimperat
orin(5)
Tabla 3.
The coumarins with antioxidant activities and their mechanisms
63
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Molecular Nutrition & Food Research
Active Ingredients
Source
Experimental
Model and
Method
Result
Mechanis
m
Referenc
es
Alloisoimperatorin(
84)
Angelicae
dahuricae
DPPH/AAPH
/Renal
epithelial cells
Inhibit the
damage of
DPPH-induced and
AAPH-induced
renal epithelial
cells
Generate
peroxyl
radicals in
vitro
[130]
Psoralen (78)
Fructus
psoraleae
Fenton-Like
Reaction
Can improve the
ROS in vivo at the
1 mM dose
High dose
of
psoralen(7
8) may
have an
oxidative
effect in
vivo
[131]
Xanthotoxin (81)
Radix
Angelicae
dahuricae
First-instar
larvae of
Galleria
mellonella
SOD, GST and GPX
in blood increase,
catalase activity
decrease
Mediate
the
eicosanoid
s
antioxidant
enzymes
[132]
Esculetin(33)
Cortex
Fraxini
ROS
the most potent
radical scavenger
among the eight
tested compounds
Protect
cells
against
ROSmediated
protein
damage
[133]
Semen
Euphorbiae
Lathyridis
DPPH
The final
concentration of
clearing the DPPH
(IC50=0.058μg/mL
)is far below the
final
concentration of
VC system
With
o-phenolic
hydroxyl
structure,
easy to
combine
with free
[54]
64
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Molecular Nutrition & Food Research
(IC50=0.542μg/mL
)
radicals
Praeruptorin C(73)
Peucedanu
m
praeruptoru
m
Mice
Remove the •OH
and O2－•, inhibit
the MDA
production in
mouse liver
homogenate
Its
anti-lipid
peroxidatio
n may be
related to
the
scavenging
free radical
effect
[134]
Coumarins from
Angelicae
Pubescentis
Angelicae
Pubescentis
Parkinsonian
disease(PD) rat
models
Significantly
reduce the
content of MDA
and Glu in serum
and brain tissue of
PD rats, increase
the activity of
T-SOD in serum
Inhibit the
lipid
peroxidatio
n in serum
and brain
tissue,
improve
antioxidant
enzyme
activity
[135]
Isofraxidin(85)
Negundo
Chastetree
Fruit
Lard
The antioxidant
effect is w
(BHT)=0.02%
when the addition
amount is 0.04%
in lard
Ortho
phenolic
hydroxyl
has
electron
donor
groups,
forming a
stable free
radicals
after
hydrogen
generation
; polarity is
not large
with better
solubility
[136]
65
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Fraxetin(86)
Page 66
Fraxinus
sieboldiana
Table 4.
Fe2+-cysteine/r
at liver
microsomes
lipid
peroxidation
model
Molecular Nutrition & Food Research
The inhibition of
the lipid
peroxidation
product MDA is
more than 50% at
10-6 mol L-1
concentration
Unkown
[137]
The coumarins with antimicrobial activities and their mechanisms
Active Ingredients
Source
Experiment
al Model
and
Method
Result
Mechanism
Refere
nces
Oxypeucedanin(3)
Anethu
m
graveol
ens
Mycobacte
ria
The MIC values in
the range
2-128μg/mL
The
antimycoba
cterial
activity of
the
substances
is
dependent
on the
position and
polarity of
the geranyl
moiety
[138]
Fructus
cnidii
Fusarium
graminear
um
EC50=56.94μg/mL
. When the
concentration is
more than
25μg/mL, the dry
weight of mycelial
growth is
inhibited, the
spore germination
is significantly
May be
through the
inhibition of
the calcium
absorption,
affect the
transport of
vesicle to
the
mycelium
top, the
[139]
oxypeucedanin hydrate(4)
Osthole(23)
66
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Molecular Nutrition & Food Research
inhibited
spore
germination
is blocked
Fraxetin(86),esculetin(33)
Cortex
Fraxini
Staphyloco The order of
ccus aureus antibacterial
activity is
fraxetin(86)>escul
etin(33)
Fraxetin(86)
can inhibit
the
synthesis of
nucleic acid
and soluble
proteins in
the cells.
[140],[1
41]
4,4′-biisofraxidin (87),
Sarcan
dra
glabra
Porphyrom
onas
gingivalis,
Streptococ
cus mutans
The antibacterial
effect of
isofraxidin(85) on
Porphyromonas
gingivalis is the
best,
MIC=78μg/mL;
the antibacterial
effect of
4,4'-biisofraxidin(
87) on
Streptococcus
mutans is the
best,
MIC=125μg/mL
unkown
[142]
Viola
philippi
ca
Escherichia
coli (E.coli),
The activity of
esculetin(33) is
the best, and the
MIC=31~313μg/m
L,
MBC=313~625μg/
mL
7-hydroxyl is [143]
the main
active group
against
E.coli,
Salmonella
and
S.agalactiae
, 6-hydroxyl
is the main
active group
against
S.dysgalacti
esculetin(33),
fraxetin(86),
scoparone(74), isofraxidin(85)
Esculetin(33),scoparone(74),s
copoletin(60)
Streptococ
cus
agalactiae
(S.agalacti
ae),
Streptococ
cus
dysgalactia
e
(S.dysgalac
67
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Molecular Nutrition & Food Research
tiae),
Salmonella
Table 5.
a
The coumarins with anti-inflammatory analgesic activities and their mechanisms
Active Ingredients
Sourc
e
Experime
ntal
Model
and
Method
Result
Mechan
ism
Seselin(88)
Plumb
ago
zeylan
ica
Phytolecti
n(PHA)/
human
periphera
l blood
mononucl
ear
cells(PBM
C)
That PHA
stimulates the
proliferation
of PBMC is
inhibited,
IC50=(53.87±
0.74) μM
Inhibit
[144]
the
PBMC
prolifera
tion by
inhibitin
g
inflamm
atory
cytokine
s IL-2
and
IFN-γ
Total coumarins from Peucedanum
praeruptorum Dunn
Peuce Rats
danu
m
praeru
ptoru
m
Significantly
inhibit the
rats toe-swell
by egg
albumen; 3h
is the
strongest
inhibitory
effect after
inflammation,
sustained
more than 6h
unkown
[145]
Imperatorin(59)
Radix
Angeli
Reduce the
amount of
Inhibit
the
[146]
68
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Carragee
nan-induc
Refe
renc
es
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Molecular Nutrition & Food Research
cae
dahuri
cae
ed acute
pleurisy
in rats
pleural
effusion,
decrease the
number of
white blood
cells and
neutrophils,
increase the
number of
lymphocytes
release
of
TNF-α,
PGE2 in
inflamm
atory
tissue
Columbianetin(58)
Angeli
ca
biserr
ata
Human
mast
cells(HMC
-1)
Regulate
allergic
inflammatory
responses
mutagenized
of the the
HMC-1
Significa
ntly
inhibit
the
expressi
on of
TNF-α
and
COX-2;
regulate
d by
substan
ce P,
activate
(or
inhibit)
the
release
of
histami
ne
[147]
Isoimperatorin(5)
Angeli
cae
dahuri
cae
Bone
marrow-d
erived
mast cells
(BMMC)
IC50=10.
7mM
Inhibit
the
producti
on of
COX-1
that is
COX-2-d
epende
nt and
[148]
69
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PGD2-d
epende
nt
Libanoridin (89)
Coryd
alis
yanhu
suo
Lipopolys
accharide
stimulate
d HT-29
cells
Inhibit the
transcriptiona
l activity of
lipopolysacch
aride-stimulat
ed nuclear
factor
Inhibit
the
expressi
on of
protein
in
inflamm
atory
mediato
rs such
as NOS,
COX-2,
TNF-α,
IL-1β
Osthole(23),phebalosin(61),meranzin(62),u
mbelliferone(63),scopoletin(60),murracarpi
n(64)
Murra
ya
panicu
lata
Kunming
mice with
writhing
analgesia
and
xylene-in
duced ear
swelling
mice
model
Murracarpin(
64) has the
strongest
anti-inflamma
tory and
analgesic
activity
May be [82]
related
to its
C-7
methox
yl
group,
C-8
short
chain
containi
ng
double
bonds
and
alcohol
hydroxyl
Daphnoretin(90), umbelliferone(63)
Daphn
e
tangu
tica
Maxi
Rat toe
swelling
test and
rat
primary
Umbelliferon
e(63) with
analgesic
activity,
daphnoretin(
7,8-disu
bstitute
d
coumari
ns are
70
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[149]
[85]
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Scopoletin(60)
Table 6.
Molecular Nutrition & Food Research
m
arthritis
model
90) with
anti-inflamma
tory analgesic
activity
of
anti-infl
ammato
ry and
analgesi
c
activitie
s
Erycib
e
obtusi
folia
Benth
Rat
adjuvant-i
nduced
arthritis
Reduce the
numbers of
new blood
vessels in the
synovium and
the
production of
important
endogenous
angiogenic
inducers
Down
regulate
the
over
expressi
on of
vascular
endothe
lial
growth
factor,
basic
fibrobla
st
growth
factor
and IL-6
[150]
The coumarins with anti-cardiovascular disease activities and their mechanisms
Active
Ingredients
Source
Experimen
tal Model
and
Method
Result
Mechanism
Referenc
es
Praeruptorin C
(73)
Peucedanu
m
praeruptor
um
Renal
hypertensi
ve rats
Significantly lower
blood pressure,
reduce the
norepinephrine-indu
ced and KCl-induced
contraction
Inhibit the
voltage-depende
nt calcium
channels and
receptor-induced
calcium channels,
[151]
71
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Molecular Nutrition & Food Research
reactivity in rat tail
artery
decrease the
intracellular Ca2+
content
Praeruptorin A
(26)
Peucedanu
m
praeruptor
um
Male
Wistar rats
Reduce the levels of
IL-6
Block the calcium
influx, open the
potassium
channels,
alleviate
ischemia-reperfus
ion caused
cytoplasmic Ca2+
overload,
maintain
intracellular
calcium balance
and
mitochondrial
stability
[152]
4-phenylcoumar
ins
Mammea
africana
Rat aorta
Relaxation of blood
vessels
Interfered with
the liberation of
Ca2+ into the
muscle cell
[153]
Osthole (23),
xanthotol (80)
Fructus
cnidii
White
rabbits,
toads
Significantly improve
the threshold of
ventricular
fibrillation current of
rabbit, reduce action
potential amplitude
of the sciatic nerve
in toads
Block the sodium [154],[15
channels and
5]
calcium channels
of cardiomyocyte
membrane,
inhibit the sodium
current and
calcium current,
hinder the
myocardial cell
depolarization
Oxypeucedanin
(3)
Radix
Angelicae
dahuricae
Adult
sprague
dawley
rats
Have a slow,
dose-dependent
hypotensive effect
of the anesthetized
rats, conscious
normal blood
May be related to
the relaxation of
vascular smooth
muscle
72
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pressure rats and
conscious kidney
hypertensive rats
Total coumarins
from Melilotus
suaveolens
Ledeb.
Melilotus
suaveolens
Ledeb.
Table 7.
Have a significant
antihypertensive
effect on the
symptoms of
hypertension
Rats
unkown
[157]
The summary of pharmacological activities of main coumarins in this article
Coumarin
monomers
Anti-HI
V
Anti-tum
or
Antioxida
nt
Antimicrob
ial activity
Anti-inflammat
ory analgesic
Anti-cardiovasc
ular disease
Esculetin (33)
+[3]
+
+
+
+[158]
+[159]
Fraxetin (86)
–
+[160]
+
+
+[161]
+[162]
Isofraxidin (85)
–
+[163]
+
+
+[164]
–
Meranzin (62)
–
+
–
–
+
–
Murracarpin
(64)
–
–
–
–
+
+[165]
Osthole (23)
–
+
+[166]
+
+
+
Scoparone (74)
+[167]
+[168]
+
+
+[169]
+[170]
Scopoletin (60)
–
+
+[171]
+
+[81]
+[172]
Umbelliferone
(63)
–
+[173]
+[174]
+[175]
+
–
Bergapten (79)
–
+
+[176]
+[177]
+[176]
–
Imperatorin
(59)
+
+
+[178]
+[179]
Isoimperatorin
(5)
+
+
+
+[33]
73
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＋[80]
+
+[180]
–
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Oxypeucedanin
(3)
+
+[181]
–
+
–
+
Psoralen (78)
+
+
+
+[182]
+[183]
+[184]
Xanthotoxin
(81)
–
+
+
+[185]
+[186]
–
Calanolide B (2)
+
–
–
+[187]
–
–
Praeruptorin A
(26)
–
+
+
+[188]
+[189]
+
Praeruptorin C
(73)
–
+
+[190]
–
–
+
Suksdorfin (18)
＋
–
–
–
+[191]
+
4-phenylcouma
rins
+[192]
+[193]
+[194]
+
+[195]
+
Capillarin (82)
－
＋
－
+[196]
–
–
Calanolide A
(1)/
This table is used to list what kinds of pharmacological effects coumarin monomers correspondingly have, "+" means yes,
"-" means no or unknown.
74
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