Nanoformulations of Coumarins and the Hybrid Molecules of Coumarins with Anticancer Effects

Abstract

Coumarins are the seconder metabolites of some plants, fungi, and bacteria. Coumarins and the hybrid molecules of coumarins are the compounds which have been widely studied for their anticancer effects. They belong to benzopyrone chemical class, more precisely benzo-α-pyrones, where benzene ring is fused to pyrone ring. In nature, coumarins are found in higher plants like Rutaceae and Umbelliferae and some essential oils like cinnamon bark oil, cassia leaf oil and lavender oil are also rich in coumarins. The six main classes of coumarins are furanocoumarins, dihydrofuranocoumarins, pyrano coumarins, pyrone substituted coumarins, phenylcoumarins and bicoumarins. As well as their wide range of biological activities, coumarins and the hybrid molecules of coumarins are proven to have an important role in anticancer drug development due to the fact that many of its derivatives have shown an anticancer activity on various cell lines. Osthol, imperatorin, esculetin, scopoletin, umbelliprenin, angelicine, bergamottin, limettin, metoxhalen, aurapten and isopimpinellin are some of these coumarins. This review summarizes the anticancer effects of coumarins and their hybrid molecules including the novel pharmaceutical formulations adding further information on the topic for the last ten years and basically focusing on the structure-activity relationship of these compounds in cancer.

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1797
REVIEW ARTICLE
Nanoformulations of Coumarins and the Hybrid Molecules of Coumarins with
Potential Anticancer Effects
Mukerrem Betul Yerer1,2,*, Serkan Dayan2, M. Ihsan Han3, Ajay Sharma4, Hardeep S. Tuli5 and Katrin Sak6
1Department of Pharmacology, Faculty of Pharmacy, Erciyes University, Kayseri, Turkiye; 2Drug Application and Research Center,
Erciyes University, Kayseri, Turkey; 3Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri,
Turkiye; 4Department of Chemistry, Career Point University, Tikker-kharwarian, Hamirpur, Himachal Pradesh 176041, India;
5Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana-133207, India;
6NGO Praeventio, Tartu, Estonia
A R T I C L E H I S T O R Y
Received: October 07 , 2019
Revised: November 04, 2019
Accepted: November 28, 201 9
DOI:
10.2174/187152062066620031009464
6
Abstract: Coumarins are the secondary metabolites of some plants, fungi, and bacteria. Coumarins and the hybrid
molecules of coumarins are the compounds which have been widely studied for their potential anticancer effects.
They belong to benzopyrone chemical class, more precisely benzo-α-pyrones, where benzene ring is fused to pyrone
ring. In nature, coumarins are found in higher plants like Rutaceae and Umbelliferae and some essential oils like
cinnamon bark oil, cassia leaf oil and lavender oil are also rich in coumarins. The six main classes of coumarins are
furanocoumarins, dihydrofuranocoumarins, pyrano coumarins, pyrone substituted coumarins, phenylcoumarins and
bicoumarins. As well as their wide range of biological activities, coumarins and the hybrid molecules of coumarins
are proven to have an important role in anticancer drug development due to the fact that many of its derivatives have
shown an anticancer activity on various cell lines. Osthol, imperatorin, esculetin, scopoletin, umbelliprenin, an-
gelicine, bergamottin, limettin, metoxhalen, aurapten and isopimpinellin are some of these coumarins. This review
summarizes the anticancer effects of coumarins and their hybrid molecules including the novel pharmaceutical for-
mulations adding further information on the topic for the last ten years and basically focusing on the structure-
activity relationship of these compounds in cancer.
Keywords: Coumarines, coumarine derivatives, coumarine nanoformulations, coumarine hybride molecules, anticancer effect, metabolites.
1. INTRODUCTION
The incidence of malignant disorders is increasing at an alarm-
ing rate worldwide. Although several therapeutically active molecules
have been investigated in the last decade, the curative treatment is
still not defined for many cancer types, especially for advanced and
metastatic malignancies. Moreover, the existing anti-cancer strate-
gies are known to possess a variety of side effects, while cancerous
cells may be or become resistant towards these therapies.
The existing anti-cancer strategies are known to possess a vari-
ety of side effects [1, 2]. Therefore, one of the greatest challenges
for the scientific community is to design novel therapeutic agents to
fight against cancer. Evidence has suggested that various plant
originated secondary metabolites such as coumarins, alkaloids,
terpenoids, phenolic, and polyphenols compounds possess promis-
ing anti-cancer activity [3, 4].
Coumarins consist of seven main classes including furanocou-
marins, dihydrofuranocoumarins, pyrano coumarins, pyrone substi-
tuted coumarins, phenylcoumarins and bicoumarins. Structurally
coumarins are classified under benzopyrone family with fused ben-
zene and pyrone ring [5, 6]. Furthermore, investigations are in pro-
gress to synthesize novel coumarins hybrid molecules with im-
proved anticancer activity and bioavailability [7-12].
However, due to the low bioavailability, the role of biologically
active moieties in the treatment of cancer is still undermined [13].
Therefore, to enhance the bio-availability and potency of drug,
*Address correspondence to this author at the Department of Pharmacology,
Faculty of Pharmacy, Drug Application and Research Center, Erciyes Uni-
versity, P.O. Box: 38039, Kayseri, Turkey; Tel/Fax: +903522076666/13852;
E-mail: mbyerer@erciyes.edu.tr
nano-formulation system could be a promising tactic. Recent inves-
tigations have stated that nano-formulations based on polymeric
micelles, polymeric brush, dendrimers, nanogels, and liposomes are
studied widely for drug delivery in the biological systems [14, 15].
Coumarins are found to upregulate and downregulate apoptotic
(Bax, caspase-3) and anti-apoptotic (Bcl-2) proteins, respectively
[16, 17]. Cell cycle regulatory proteins are also downregulated by
coumarins, which lead to the G0/G1 cell cycle arrest in cancer [17].
In addition, coumarins treatment results in the inhibition of angio-
genesis and metastasis in cancer via the downregulation of VEGF
and MMPs expression [18, 19].
Studies have revealed that coumarins suppress the expression of
inflammatory mediators such as iNOS and COX-2 by inhibiting
NF-κB, MAPK and Akt signaling [20]. It has been seen that phyto-
chemicals present in nanoformulation possess better biological
activity as compared to their native forms [13, 14]. Therefore, the
present review d escribes recent advancement in the nanoformula-
tions of coumarins and their derivatives against cancer.
1.1. Structural Features of Coumarins and Coumarin
Derivatives
Coumarins consist of six main classes including furanocoumar-
ins, dihydrofuranocoumarins, pyrano coumarins, pyrone substituted
coumarins, phenylcoumarins and bicoumarins (Table 1). They can
be either classified as:
• Benzene-Substituted Coumarins
• Pyrone-Substituted Coumarins
• Both benzene-substituted and pyrone-substituted coumarins
• Coumarins obtained by bonding other ring structures to the
benzene ring or the pyron ring,
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1798 Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 15 Yerer et al.
• Bicoumarins
• Furanocoumarins
Each coumarin sub-type is studied and valued by researchers.
As is known, coumarin derivatives have many application areas due
to their biological and chemical properties [21], which can be listed
as anticancer [22-27], carbonic anhydrase inhibitors [28-30], anti-
HIV [31-33], anti-inflammatory [34-36] fluorescence [37, 38] and
catalysis chemistry [39, 40].
These structures, which have many different features, both con-
tribute to technological developments and take place in many sys-
tems as qualified chemicals. In this context, coumarins, which are
also usable in nano-technological developments, have also contrib-
uted to nanoformulation or nanocapsulation studies in recent years
(Fig. 1).
Nanostructures and the guest molecules are the basis of nano-
formulation studies. The basis of nanoformulation studies is divided
into two main categories; guest molecules and nanocarriers. The
nanocarriers with some nanostructures such as multifunctional
nanocapsules, have the character of containers that can be loaded
with various cargoes and then become promising nanocarriers for
diagnostic and drug delivery, or some biomedical applications.
Such Nanoparticles (NPs) or nanocarriers can be charged with
many guest molecules, such as hydrophobic therapeutics, optically
active organic molecules, metal complexes, ultrasonic contrast
agents, metal oxides, etc. and the particles may also change the
potential solubility problems and biocompatibility of the guest
molecules.
The present positions of the manufactured nanoparticles allow
for combining different properties for the drug delivery and diag-
nostic systems. Thus, the guest molecules can be transported to the
desired sites and however, some modifications to the particles may
be required such as shape, stability, physical state, charge, perme-
ability, environmental responsiveness etc. In addition to the combi-
nation of all these properties, the nanocarrier and the guest mole-
cules must be in harmony and serve the same target. The coumarins
are also u sed in many research guest molecules and the use of cou-
marins in nanomaterials is also increasing (Fig. 2).
In the drug delivery system, there are mainly carrier particles,
guest molecules and support molecules for detecting/imaging the
system. In addition to being guest molecules, the coumarin and
their derivative compounds can also serve to visualize the formula-
tions. In this sense, the Coumarin-6 is one of the most commonly
used compounds in formulation studies [41-46]. This compound is
one of both benzene-substituted and pyrano-substituted coumarin
derivatives and has been used as a fluorescence molecule for mark-
ing NPs in many formulation studies.
By Paiva et al., a novel nanoformulation for p53-MDM2 inter-
action inhibitor was formed using several techniques and the toxic
potentials of the materials were investigated on MCF-7 cells. In this
Table 1. Some main coumarin structures.
Simple Coumarins
O O
R
Furanocoumarins
O O
O
Psoralen
O O
O
Xanthotoxin
OCH
3
Pyranocoumar ins
OO
Xa nthylet in
O O
Sesel in
O
Benzene-Substituted Co umarins
O O
H
3
CO
HO
Scopoletin
O O
H
3
CO
HO
Fraxetin
OH
Pyrone-Substituted Coumarins
O O
OH
O
Warfarin
O O
OH
Phenprocoumon
Bicoumarins
O
O
O
O
OHHO
C
H
2
Dicoumarol

Nanoformulations of Coumarins and the Hybrid Molecules of Coumarins Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 15 1799
study, the monitoring of nanoparticle penetration into the cell was
carried out by monitoring the coumarin-6 green fluorescence mole-
cule [47].
Bazylinska et al. reported the encapsulation of chemotherapeu-
tic (colchicine) and imaging agent (coumarin-6) in oil-core nanocar-
riers stabilized by surfactants and the cytotoxicity potentials were
evaluated by CLSM analysis on some human cancer cells such as
skin melanoma (MEWO), doxorubicin-sensitive breast cancer
(MCF-7/WT), and alveolar basal epithelial cells (A549) [48].
Zhao and co-workers fabricated Paclitaxel-loaded (PTX-
loaded) [PGA-co-PCL]-b-TPGS2k nanoformulation for lung cancer
therapy and the antitumor activity of the nanomaterial was exam-
ined both in vitro and in vivo on human lung cancer A549 cells.
Herein, the coumarin-6 in place of PTX was encapsulated and in
this way, Confocal Laser Scanning Microscopy (CLSM) images of
tumor cells were observed [49].
Su and co-workers recorded the Paclitaxel (PTX)-loaded star-
shaped copolymer bearing coumarin-6 as fluorescence biomarker
Fig. (1). Evolution of number of publications for ‘nanoformulation or nanocapsulation’ keywords. Source: ISI Web of Science, Thomson Reuters. (A higher
resolution / colour version of this figure is available in the electronic copy of the article).
Fig. (2). Evolution of publication number for ‘coumarin and nano’ keywords. Source: ISI Web of Science, Thomson Reuters. (A higher resolution / colour
version of this figure is available in the electronic copy of the article).
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1800 Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 15 Yerer et al.
nanoformulation for improving chemotherapy of Malignant Mela-
noma (MM), which is the dangerous skin cancer type. The anti-
tumor efficiency of the fabricated nanomaterial, studied in vitro
with the MTT assay and in vivo with xenograft tumor model,
showed that the star-shaped PTX-loaded CA-PLGA-TPGS nano-
material was importantly superior to commercial PTX formulation
[50].
Kushwah et al. recorded the self-assembled nanomaterial for
improved breast cancer therapy with the dual drug conjugation
which included Docetaxel (DTX) and Gemcitabine (GEM). Simi-
larly, the coumarin-6 (3-2′-benzothiazolyl-7-diethylaminocoumarin)
was used as a model fluorescent dye. Herein, the results demon-
strated significant decrease in both the volume of tumor and hepato-
and nephro-toxicity [51].
Although the coumarin-6 fluorescence molecule is used
frequently, other coumarin molecules such as coumarin-153,
coumarin-314 or coumarin-blue, which have similar properties and
are used in nanoformulation studies, are also used as fluorescence
biomarkers (Table 2). These molecules, like coumarin-6, are both
benzene substituted and pyrano substituted coumarin derivatives
[52-54].
In addition to these studies, some synthetic benzene-substituted
coumarin-derived compounds have found their place in nanoformu-
lation studies as guest molecules. Lee and co-workers demonstrated
that self-assembled coumarin (both benzene-substituted and py-
rone-substituted coumarins) nanoparticles have anti-cancer poten-
tials with selective mitochondrial-targeting. Herein, the encapsula-
tion of cancer therapy drug Doxorubicin (DOX) into the fabricated
Triphenylphosphonium-appended Coumarin nanomaterial (TPP-C),
which showed non-cytotoxicity toward cancer cell line, was
achieved and determined that the doxorubicin was effectively de-
livered to the mitochondria. This study also clearly demonstrated
that such a drug delivery system is the preferred system for the
treatment of cancer [55].
1.2. Classification of Coumarin Derivatives and Hybrid
Molecules under Several Cancer Types
1.2.1. Lung Cancer
Maiti et al. designed, synthesized and characterized gemcit-
abine-coumarin-biotin conjugate for in vitro biological evaluation.
This molecule is a multifunctional molecule composed of a thiol-
specific cleavable disulfide bond, a coumarin moiety as a fluores-
cent reporter, Gemcitabine (GMC) as a model active drug, and
biotin as a cancer-targeting unit. The active molecule is preferen-
tially taken up by A549 cells rather than WI38 cells according to
the Confocal microscopic experiments. This drug delivery system is
a novel theranostic agent. By two photon fluorescence imaging,
both a therapeutic effect and drug uptake could b e monitored [56].
In their study, Khaghanzadeh et al. researched the impact of
umbelliprenin on the predominance of Th1 and Th2 responses in
the Lewis Lung Cancer (LLC) mouse model. The cytotoxic effect
of umbelliprenin (7-prenyloxycoumarins) was discovered on LLC
cells and mouse splenocytes by MTT assay. On normal splenocytes,
results displayed the cytotoxic effects of umbelliprenin on LLC cells
(IC50= 51.6±5.4µM), whereas no side effects were screened at this
concentration. TNF-α mRNA expression in both lung and tumor
tissues was increased. Umbelliprenin has displayed a partly Th1
preconception with a reduction in regulatory immune response [57].
Table 2. Some fluorescence coumarins used in nano formulation st udies.
Chemical Name Chemical Structure
3-(2-Benzothiazolyl)-7-(diethylamino)
coumarin
O O
S
N
N
CH
3
CH
3
Coumarin-6
2,3,6,7-Tetrahydro-9-trifluoromethyl-1H,5H-quinolizino
(9,1-gh)coumarin
O O
Coumarin-153
CF
3
N
2,3,5,6-1H,4H-Tetrahydr o-9-carbetho xyquinolizino-
[9,9a,1-gh]coumarin
O ON
O
OCH
3
Coumarin-314
7-(diethylamino)-coumarin-3-carboxylic
acid-N-succinimidyl ester
O ON
CH
3
CH
3
Coumarin-blue
O
O
N
O
O

Nanoformulations of Coumarins and the Hybrid Molecules of Co umarins Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 15 1801
1.2.2. Breast Cancer
Because of their skill to ensure spatial and temporal control
over the drug release, photoresponsive nanoparticles have admitted
important care. Photoresponsive multifunctional Magnetic
Nanoparticles (MNPs) were noticed utilizing coumarin-based pho-
totrigger and Fe/Si MNPs for checked delivery of anticancer drug
chlorambucil. Produced photoresponsive multifunctional MNPs
were also discovered for cell luminescence imaging. In vitro bio-
logical works displayed that coumarin connected Fe/Si MNPs of
9nm size d elivered the anticancer drug chlorambucil into cancer
cells, thereby influencing the drug action to kill the cancer cells
upon irradiation. Cell viability was evaluated utilizing MTT assay
in breast cancer cell line MDA-MB-231. Cells were incubated with
chlorambucil, chlorambucil-loaded MNPs (7-HC-Cbl-MNPs), and
Fe/Si MNPs for 4h over a range of concentrations between 0 and
110μM. It was considered that IC50 values of MDA-MB-231 cells
reduced from 67.38±1.45μM for chlorambucil to 53.84±1.12μM for
the 7-HC-Cbl-MNPs [58].
Dlugosz et al. appraised anticancer features of a novel synthetic
hybrid compound AD-013, which associates a coumarin moiety and
an α-methylene-δ-lactone subject with a natural antibiotic novobio-
cin. They assessed cytotoxic activities of compound AD-013 using
MTT assay and found the mechanism of anticancer activity of ana-
log AD-013 with RT-PCR. Against two cancer cells, MCF-7 (breast
cancer) and HL-60 (leukemia) and normal human cells MCF-10A
and HUVEC, AD-013 was much more cytotoxic than novobiocin in
both cancer cell lines and showed some selectivity against MCF-7
cancer cells as compared with MCF-10A healthy breast cells [59].
1.2.3. Prostate Cancer
Lalitha et al. synthesized and characterized three distinct cou-
marin-pyrene derivatives with changing hydrophobic connections.
Among these derivatives, the one which is not having any hydro-
phobic tail showed effective gelation. The investigation of absorp-
tion and emission spectra of these compounds displayed that in
dissimilar solvents, the photo-physical properties were significantly
impacted by the self-assembly protocol. They derived nano-flakes
from coumarin coupled pyrene derivatives. They researched their
potential applications in the field of cell imaging by taking a hint
from the self-assembly mechanism in dissimilar solvents. For fibro-
blast and PC3 prostate cancer cell imaging applications, the nano-
materials got utilized via the self-assembly protocol. Investigation
revealed that these molecules decreased the proliferation of PC3
cells [60].
1.2.4. Hepatocellular Carcinoma
Ji et al. designed a fluorescent and multi-functional gelator
precursor with high photosensitivity. Between overexpressed galac-
tose and ASGP-R, cancer cells could be selectively targeted owing
to the receptor mediated interaction by cancer cells. The precursor
could release hydrogelators inside cells under photo-irradiation via
leading to intracellular self-assembly and inducing cell death. With
near infrared light (non-invasive wavelength), coumarin derivatives
had the feature of two-photon absorption, facilitating irradiation of
the precursors which is going on. In order to assess the anticancer
effects, intracellular self-assembly was started by light. CCK-8
assay quantified the viability of both HepG2 and HeLa cells [61].
1.2.5. Ovarian Cancer
By inducing apoptosis and inhibiting cell growth, Docetaxel
(DOC) generates antitumor effects but its clinical practice is limited
by its nominal biocompatibility and hydrophobicity. Through
computer simulations, Gao et al. prepared DOC and methoxy
poly(ethylene glycol) (MPEG)/polycaprolactone (PCL) (MPEG-
PCL) that demonstrated fine compatibility. In vitro DOC/MPEG-
PCL micelles inhibited cell growth. It induced apoptosis more effi-
ciently than free DOC. DOC/MPEG-PCL micelles inhibited ovar-
ian tumor growth more importantly than free DOC. Immunohisto-
chemical analysis indicated that DOC/MPEG-PCL micelles en-
hanced DOC's anti-tumor impact by advancing tumor cell apoptosis
and suppressing tumor cell proliferation [62].
1.2.6. Colon Cancer
Xu et al. designed and synthesized four coumarin-containing
telodendrimers for self-assembling into the corresponding nanopar-
ticles. In order to target drug delivery of 7-ethyl-10-hydroxy camp-
tothecin (SN-38), two nanoparticles (P-II and P-IV micelles) were
viewed and chosen for the treatment of colon cancer. In aqueous
solution, the nanoparticle encapsulation importantly increased the
solubility of SN-38. The size of these SN-38 nanoparticles was
found to be around 50nm and rod-shaped micelles were found util-
izing Transmission Electron Microscopy (TEM) by Dynamic Light
Scattering (DLS). Similar in vitro cytotoxic activities against colon
cancer cells were found for these two novel nanoformulations of
SN-38/P-II and SN-38/P-IV as compared to the basic drug (SN-38
in DMSO). These NPs preferentially accumulated in tumors when
compared with healthy tissue. In HT-29 human colon cancer
xenograft models, SN-38 loaded nanoformulations showed superior
anti-tumor efficacy when compared with Irinotecan at equivalent
SN-38 dose [63].
The possibilities to inhibit a drug's metabolism and thereby
increasing its efficient dose was further evaluated as a new applica-
tion of nanomedicines. Natural furanocoumarin 6′,7′-
Dihydroxybergamottin (DHB), a known CYP450 inhibitor encapsu-
lated in micelles, were explored to transiently block hepatic
CYP450-mediated drug metabolism for the increase in the bioavail-
ability of the oncology drug docetaxel. When compared to the par-
ent drug, DHB-micelles increased antitumor effect in the tumor
xenograft models HT-29 (colon cancer) and MDA-MB-231 (breast
cancer) in mice, when administered 24h prior to the drug [64].
1.2.7. Gastric Cancer
Aas et al. utilized dendrosome nano-particles to overcome the low
bioavailability of farnesiferol C limiting its therapeutic potential.
They evaluated the anticancer impact of Dendrosomal Farnesiferol
C (DFC) on the AGS gastric cancer cell line. In order to define the
antiproliferative features of DFC and expression ratio of Bax/Bcl-2
as a characteristic of apoptosis, MTT assay and Reverse Trans-
criptase-Polymerase Chain Reaction (RT-PCR) were used, respec-
tively. The study demonstrated that DFC importantly suppressed
the proliferation of AGS cells in a time- and dose-dependent man-
ner compared to the void Farnesiferol C (FC). DFC significantly
increased the expression ratio of Bax/Bcl-2 in AGS cells [65].
1.2.8. Melanoma
In their study, Bhattacharya et al. encapsulated 4-methyl-7-
hydroxy coumarin (SC) with Poly Lactide-co-Glycolide Acid
(PLGA) nanoparticles to test if nano-encapsulated SC can be a
more efficient anti-cancer agent. As revealed from scanning elec-
tronic and atomic force microscopies, they studied its potentials
with various protocols. Nanocoumarins (NC) showed more efficient
drug uptake and demonstrated anticancer potentials in melanoma
cell line A375. The combined data of Circular Dichroism spectra
(CD) and melting temperature profile (Tm) of calf thymus DNA
treated with NC were analyzed in order to test its feasible interac-
tion with target DNA. Results indicated a dose dependent interac-
tion of NC with calf thymus DNA, forming a novel complex that
increased its stability and bringing in efficient modification in struc-
ture and conformation [66].
1.2.9. Cervical Cancer
Due to their multiple functionalization features among polym-
eric NPs, star-shaped branched polymers have attracted a great

1802 Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 15 Yerer et al.
Table 3. Classification of coumarin derivatives and hybrid molecules with anti-cancer effect.
Name and Chemical Structure of Coumarins Pharmacological Activity Refs.
Osthole
7-methoxy-8-(3-methylbut-2-enyl)chromen-2-one
• Osthole treatment significantly reduced the expression of the antiapoptotic protein Bcl-2 and
increased the expression of the proapoptotic proteins Bax, Bak, BimL, BimS, and t-Bid. Osthole
treatment also increased the expression of Fas, FADD, TNF-R1, TNF-R2, DcR2, RIP, and DR5.
In addition, osthole treatment significantly increased the expression levels of phosphorylated
ERK1/2 and JNK1/2.
• Osthole reduced the levels of matrix metalloproteinase-2 (MMP-2) and matrix metallopepti-
dase-9 (MMP-9) in the A549 human lung cancer cells
• Osthole inhibited cells proliferation via inducing apoptosis and G2/M arrest
[72-74]
Imperatorin
9-(3-methylbut-2-enoxy)furo[3,2-g]chromen-7-one
• Imperatorin induced a dose-dependent growth inhibition of the SGC-7901 gastric cancer cells
with an IC50 value 62.6μM via cell cycle arrest targeting PI3K/Akt/m-TOR signalling pathway.
• Imperatorin inhibited HIF-1α protein synthesis by downregulating the mTOR/p70S6K/4E-BP1
and MAPK pathways in colon cancer.
• 33 coumarins, mainly the simple isopentenylated coumarins and derived pyrano- and
furanocoumarins, were examined for their antiproliferative activity towards several cancer and
normal human cell lines.
[75-77]
Esculetin
6,7-dihydroxychromen-2-one
• Biological studies by dihydroxycoumarins as fluorescent probes performed on prostate cancer
cells, breast cancer cells, and normal skin fibroblasts revealed significant anticancer properties
of esculetin, which caused a considerable decrease in the viability and number of cancer cells,
and affected their morphology, contrary to normal fibroblasts. Furthermore, the experiment per-
formed on prostate cancer cells showed that fluorescence emission of esculetin is closely related
to intracellular pH.
• Esculetin exhibits selective anticancer effects in THP-1 human leukemia cells and led to signifi-
cant apoptosis induction, inhibition of cancer cell migration and decrease in Bcl-2/Bax ratio.
• Esculetin binds to KEAP1 and inhibits its interaction with Nrf2 in pancreatic cancer cells. This,
thereby, promotes nuclear accumulation of Nrf2 in PANC-1 cells that induces antiproliferative
and apoptotic response possibly by attenuating NF-κB
[78-80]
Scopoletin
7-Hydroxy-6-methoxy-2H-chromen-2-one
• Scopoletin inhibited the growth of all the cell lines and the IC50 ranged between 7.5 to 25µM.
Scopoletin exerted its anticancer effects on human cervical cancer cell lines by triggering apop-
tosis, cell cycle arrest, inhibition of cell invasion and PI3K/AKT signaling pathway.
• Scopoletin caused significant suppression of sprouting of micro vessels in rat aortic explants
with IC50 (median inhibitory concentration) 0.06μM. Scopoletin (100 and 200mg/kg) strongly
inhibited (59.72 and 89.4%, respectively) vascularization in matrigel plugs implanted in nude
mice. In the tumor xenograft model, scopoletin showed remarkable inhibition on tumor growth
(34.2 and 94.7% at 100 and 200mg/kg, respectively).
[81, 82]
Angelicin
Furo[2,3-h]chromen-2-one
• In human SH-SY5Y neuroblastoma cells, angelicin increased cellular cytotoxicity in a dose-
and time-dependent manner with IC50 of 49.56μM at 48h of incubation. Angelicin dose-
dependently down-regulated the expression of anti-apoptotic proteins including Bcl-2, Bcl-xL
and Mcl-1.
[83]
Bergamottin
4-[(2E)-3,7-dimethylocta-2,6-dienoxy]furo[3,2-g]chromen-
7-one
• Bergamottin has potent antiproliferative effects on the A549 cells. Bergamottin shows both
concentration-dependent as well as time-dependent growth inhibitory effects against these cells.
• The anticancer efficacy of Bergamottin under in vivo conditions using female BALB/c nude
mice was determined and in xenograft NSCLC model it reduced the tumor size significantly.
[84]
(Table 3) contd….

Nanoformulations of Coumarins and the Hybrid Molecules of Co umarins Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 15 1803
Name and Chemical Structure of Coumarins Pharmacological Activity Refs.
Limettin
(Citropten)
5,7-dimethoxychromen-2-one
• Citropten conjugated with NDs showed antimitotic properties in B16F10 cells. [85]
Methoxalen
9-methoxy-7H-furo(3,2-g)chromen-7-one
• Microemulsions vs. chitosan derivative-coated microemulsions for dermal delivery of 8-methoxypsoralen
(8-MOP) was investigated and the dermal delivery of microemulsion of 8-MOP was more efficient, which
might also be important for phototherapy applications in dermal carcinomas.
[86]
Aurapten
7-((E)-3, 7-Dimethylocta-2, 6-dienyloxy)-2H-
chromen-2-one
• Aurapten decreases the secretion of Matrix Metalloproteinase-2 (MMP-2) as well as key inflammatory
mediators, including IL-6, IL-8, and chemokine (C-C motif) ligand-5(CCL5)
[87]
İsopimpinellin
4,9-Dimethoxy-7H-furo[3,2-g]chromen-7-one
• Isopimipnellin inhibited the growth of human bladder carcinoma cell line [88]
Marmesin
O O
O
H
H
3
C
CH
3
HO
(2S)-2-(2-hyd roxypropan-2-y l)-2,3-d ihydrofuro [3,2-
g]chromen-7-one
• Cytotoxic effects against the human leukemia (U937) cell line with IC50 of 40µM
• Lower cytotoxic effects against normal human monocytes with IC50 of 125µM
• Increase in the Bax/Bcl-2 ratio through the upregulation of Bax and downregulation of Bcl-2
• Induce ROS mediated alterations in mitochondrial membrane potential, G2/M cell cycle arrest and signifi-
cantly inhibited leukemia cell migration potential
[89]
Rutamarin
O
OO
CH
3
CH
3
OO
CH
3
H
3
C
CH
3
CH
2
2-[6-(2-methylbut-3-en-2-yl)-7-oxo-2,3-
dihydrofuro[3,2-g]chromen-2-yl]propan-2-yl acetate
• Extraction of Rutamarin from Ruta angustifolia Pers. and evaluated the cytotoxic activity against two
human carcinoma cell lines (HT29) and a normal human colon fibroblast cell line (CCD-18Co) using sul-
forhodamine B cytotoxicity assay.
• Rutamarin exhibited remarkable cytotoxic activity against HT29 cells (IC50 value of 5.6μM) but was not
toxic to CCD-18Co cells.
[90]
Chalepin
O
OO
CH
3
CH
3
HO
H
3
C
CH
3
CH
2
2-(2-hydroxypropan-2-yl)-6-(2-methylbut-3-en-2-
yl)-2,3-dihydrofuro[3,2-g]chromen-7-one
• Chloroform extract of Ruta angustifolia showed higher cytotoxic activity against MCF7, HT29, HCT116,
but mild cytotoxicity against MDA-MB231 and no activity against MCR5 (IC50>100μg/mL).
• Chalepin and rutamarin isolated from Ruta angustifolia. Chalepin displayed remarkable cytotoxicity against
all tested cancer cell lines but no activity against MCR5. Rutamarin, on the other hand, showed remarkable
cytotoxicity activity against MCF7, HT29, and HCT116, whereas no activity against MDA-MB-231 and
MRC5.
• Chalepin exhibited excellent cytotoxicity against A549 cell line with an IC50 value of 8.69±2.43μg/ml
(27.64μM).
• A549 cells were treated with 36μg/ml of chalepin caused the decrease of anti-apoptotic proteins Bcl-2,
survivin, XIAP, Bcl-XL, cFLIP in a time-dependent manner and also level of PARP
• Chalepin isolated from the chloroform extract Ruta angustifolia L and tested its ability to inhibit molecular
pathways of human lung carcinoma (A549) cells.
• It causes S phase cell cycle arrest, NF-κB pathway inhibition, and STAT-3 inhibition, induces an extrinsic
apoptotic pathway.
• Cytotoxic activity against MCF7 cells, whereas, it shows moderate cytotoxic activity against MDA-MB231
cells. Interestingly, chalepin did not present any toxicity against MRC5 normal cell line
• Displays typical apoptotic features such as membrane blebbing, DNA fragmentation, chromatin condensa-
tion and apoptotic bodies' formation following chalepin treatment against MCF7 cells at different concen-
tration for 48h.
• The protein expressions of caspases-8, -9 and cleaved PARP1 were upregulated, which correlated well with
increased caspase-3 activity.
[91-
94]
(Table 3) contd….

1804 Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 15 Yerer et al.
Name and Chemical Structure of Coumarins Pharmacological Activity Refs.
Columbianadin
O
OO
O
CH3
CH3
O
H3C
H3C
2-[(8S)-2-oxo-8,9-dihydrofuro[2,3-h]chromen-8-
yl]propan-2-yl (Z)-2-methylbut-2-enoate
• Columbianadin isolated from Angelica decursiva (Umbelliferae) and evaluated anticancer activity
against HCT-116 human colon cancer cells.
• At low concentration (25μM), it induced apoptosis (modulation of caspase-9, caspase-3, Bax, Bcl-
2, Bim and Bid) and high concentration (50μM), it induced necroptosis (RIP-3, and caspase-8).
• It also causes the accumulation of ROS and imbalance in the intracellular antioxidant enzymes
such as SOD-1, SOD-2, catalase and GPx-1.
[95]
Nodakenetin
O
OO
H
3
C
H
3
C
HO
(2R)-2-(2-hydroxypropan-2-yl)-2,3-dihydrofuro[3,2-g]
chromen-7-one
• Nodakenetin could significantly inhibit the proliferation of the leukemia HL-60 cells (IC50 of
16µM).
• G2/M cell cycle arrest and induction of apoptosis, prompted mitochondrial apoptosis, alteration in
the apoptosis-related protein expression (Bax and Bcl-2).
[96]
(-)-deltoin
O O
O
CH
3
O
H
3
C
O
Isoxazolines and aziridines Derivatives of (-)-deltoin
O O
O
CH
3
O
H
3
C
O
N
OCH
3
R
H
3
C
OO
O
CH
3
O
H
3
C
O
N
CH
3
H
3
C
R
R= C
6
H
5
, 4-ClC
6
H
4
, 4-CH
3
C
6
H
4
R= C
6
H
5
, 2-ClC
6
H
3
N
• (-)-deltoin exhibited good cytotoxic activity against the colon cell line HCT-116 (IC50 of
14.3±0.2µM) and a moderate cytotoxic activity against the ovary cell lines IGROV-1 and
OVCAR-3 with IC50 values of 49.0±2.1 and 49.0±1.8µM, respectively.
• Phenyl substituted Isoxazolines derivative of (-)-deltoin is more potent than other with IC50 of
3.3±0.1µM (HCT-116), >100µM (IGROV-1), 63.0± 5.3µM (OVCAR-3) as well as the diastereoi-
someric mixture of 2-Chloropyridine substituted Isoxazolines derivative showed more potency
against HCT-116 with IC50 of 4.3±0.1.
• Diastereoisomeric mixture of substituted phenyl aziridines derivative of (-)-deltoin showed more
potency against HCT-116 than the other two cell lines.
IC50 (µM) Phenyl group
HCT-116 IGROV-1 OVCAR-3
C6H5 5.9± 0.1 39.8 ±3.0 71.0± 2.6
4-ClC6H4 6.1± 0.7 31.6± 2.1 56.0± 2.9
4-CH3C6H4 7.3± 0.9 6.3± 0.5 18.0 ±0.7
[97]
(-)-5-hydroxyprantschimgin
O O
O
OH
O
H
3
CCH
3
O
CH
3
H
3
C
(-)-5-hydroxydeltoin
O O
O
OH
O
H
3
CCH
3
O
CH
3
H
3
C
• (-)-5-hydroxyprantschimgin and (-)-5-hydroxydeltoin phytochemicals investigation of the roots of
Ferula lutea (Poir.) Maire and evaluation of cytotoxicity against human colorectal cancer cell lines.
• The mixture of both compounds showed cytotoxic activity with IC50 values of 0.29±0.05 and
1.61±0.57µM against the cell lines HT-29 and HCT 116, respectively.
[98]
(Table 3) contd….

Nanoformulations of Coumarins and the Hybrid Molecules of Co umarins Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 15 1805
Name and Chemical Structure of Coumarins Pharmacological Activity Refs.
8-methoxysmyrindiol
OO
O
CH
3
H
3
C
HO
OH
OCH
3
• 8-methoxysmyrindiol extracted from Gerbera anandria (Compositae) and tested its cytotoxicity against
HeLa (human cervical cancer), MCF-7 (human breast cancer), HepG2 (Hepatocellular carcinoma),
HCT116 (human colon cancer), A549 (human lung adenocarcinoma), A375-S2 (human melanoma),
HT1080 (human fibrosarcoma), HL60 (myeloid leukemia).
• 8-methoxysmyrindiol showed more cytotoxicity against MCF-7, HCT11 and A549 cells with the highest
potency in HepG2 cells (IC50 = 5.3±0.2μg/ml).
[99]
Decursin
O OO
CH
3
H
3
C
O
OCH
3
H
3
C
Decursinol Angelate
O OO
CH
3
H
3
C
O
OCH
3
CH
3
Decursinol
O OO
CH
3
H
3
C
HO
4ʹʹ-hydroxytigloyldecursinol
O OO
CH
3
H
3
C
O
OHOH
2
C
CH
3
4ʹʹ-hydroxydecursin
O OO
CH
3
H
3
C
O
OCH
3
HOH
2
C
(2ʹʹR,3ʹʹR)-epoxyangeloyldecursinol
O OO
CH
3
H
3
C
O
O
CH
3
O
CH
3
(2ʹʹS,3ʹʹS)-epoxyangeloyldecursinol
O OO
CH
3
H
3
C
O
O
CH
3
O
CH
3
• Ethanolic extract of Korean Angelica gigas Nakai majorly includes Decursin, Decursinol angelate, De-
cursinol and minor amount of other pyranocoumarins. In vivo as well as in vitro efficacy of this extract
was studied against bladder, breast, colon, lung and prostate cancers, sarcoma, myeloma and leukemia.
• Angelica gigas Nakai (AGN) root ethanolic extract starting 8 weeks of age inhibited the growth of prostate
epithelium and Neuroendocrine carcinomas (NE-Ca) in the Transgenic Adenocarcinoma of Mouse Pros-
tate (TRAMP) model.
• The growth of TRAMP Dorsolateral Prostate (DLP) in Angelica gigas Nakai and decursin with its isomer
decursinol angelate treated mice was inhibited by 66% and 61% at 16 weeks and by 67% and 72% at 28
weeks, respectively.
[100-
103]
Xanthyletin
OO O
H
3
C
H
3
C
• Xanthoxyletin was isolated from Erythrina variegate and antiproliferative effects of Xanthoxyletin were
studied against SGC-7901 cells
• induce apoptosis and cell cycle arrest, DNA damage and apoptosis through mitochondrial dysfunction, and
cell cycle arrest at S phase in a dose-dependent manner and production of reactive oxygen species in SGC-
7901 cells
• Xanthoxyletin arrested the cell cycle of SGC-7901 cells at the S phase. The percentages of cells were
increased from 25.58% (in untreated cells) to 37.52% and 58.61% in cells treated with 200 and 400µM of
Xanthoxyletin respectively for 48h.
• Xanthoxyletin induced apoptosis in SGC-7901 cells and the percentage of apoptotic cells was 41.47%
after the exposure of 400µM of Xanthoxyletin for 48 h as compared to 2.6% in the control group.
• The fluorescence intensity was 97.30%, 70.09%, and 53.17% after treatment with 0, 200, and 400µM of
Xanthoxyletin respectively for 48h
[104]
(Table 3) contd….

1806 Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 15 Yerer et al.
Name and Chemical Structure of Coumarins Pharmacological Activity Refs.
Angular-type pyranocoumarin
OO O
H
3
C
H
3
COR
1
OR
2
R
1
OCH
3
CH
3
R
2
OCH
3
CH
3
OO
CH
3
OO O
H
3
C
H
3
COR
1
OR
2
R
1
R
2
O
CH
3
O
CH
3
H
3
C
O
CH
3
O
H
3
CCH
3
O
CH
3
O
CH
3
• Isolation of new Angular-type pyranocoumarin from the roots of Peucedanum praeruptorum and evalua-
tion of the Multidrug-Resistance (MDR) reversal in human sarcoma MES-SA/Dx5 and Lipopolysaccha-
ride (LPS)-induced RAW 264.7 cells.
• These inhibited the efflux of drugs by MDR protein, indicating the reversal of MDR and became an effec-
tive candidate for MDR forms of cancer.
[105]
Praeruptorin A
O OO
H
3
C
H
3
C
OO
CH
3
CH
3
O
CH
3
O
• Significantly inhibited cell proliferation, colony formation, migration, invasion, and wound closure of
HeLa and SiHa cells
• Induced cell cycle arrest at G0/G1 phase
• Upregulated Rb, p16, p21 and p27 proteins
• Downregulated cyclin D1 and S-phase kinase-associated protein 2 (Skp2) proteins.
• Reduced expression of Matrix Metalloproteinase-2 (MMP-2) and increased expression of Tissue Inhibitor
of Metalloproteinase-2 (TIMP-2)
• Suppressed ERK1/2 activation
• Increased the effect of PD98059 (a specific MEK1/2 inhibitor) in downregulation of MMP-2 and upregu-
lation of TIMP-2
• Inhibited the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on upregulation of ERK1/2 activation,
MMP-2 expression, cellular migration, and invasion of HeLa cells.
[106]
(±) Praeruptorin A
O OO
H
3
C
H
3
C
OO
CH
3
CH
3
O
CH
3
O
(±) Praeruptorin B
OO
O
H
3
C
H
3
C
OO
CH
3
CH
3
O
O
CH
3
H
3
C
• Methanolic extract of Peucedanum praeruptorum DUNN contains mainly (±) praeruptorin A and (±)
praeruptorin B
• At 300µg/ml, PPME inhibited cell growth by 51.2% (P<0.01), probably linked to the high concentration
of PA and PB and exhibited antiproliferative and cytotoxic activities on the SGC7901 cells (gastric cancer
cells)
• Enhanced the actions of doxorubicin on SGC7901 cells and reduced the dose of DOX for the desired
effects.
[107]
(Table 3) contd….

Nanoformulations of Coumarins and the Hybrid Molecules of Coumarins Anti-Cancer Agents in Medicinal C hemistry, 2020, Vol. 20, No. 15 1807
Name and Chemical Structure of Coumarins Pharmacological Activity Refs.
(+)-Praeruptorin A
O OO
H3C
H3C
OO
CH3
CH3
O
CH3
O
(+)-Praeruptoirn B
O OO
H
3
C
H
3
C
OO
CH
3
CH
3
O
O
CH
3
H
3
C
(+)-Praeruptoirn E
O OO
H
3
C
H
3
C
OO
CH
3
CH
3
O
O
CH
3
H
3
C
• Ethanolic extract two-herb medicine formula consisting of Descurainiae sophia Semen and Peucedani
praeruptorum Radix
• It consists of (+)-Praeruptoirn A (10.88mg/g), (+)-Praeruptoirn B (3.37mg/g), (+)-Praeruptoirn E
(1.32mg/g), Isoquercitrin (1.17mg/g), and Isorhamnetin-3-o-β-glucopyranoside (0.91mg/g)
• The combination treatment of this extract with oxaliplatin or irinotecan remarkably enhanced the antitumor
activity of each anti-cancer drug and delayed tumor growth by 47.1-74.6% or by 74.4-82.9%, respectively
• The Ki-67 expression for tumor cell proliferation and the CD31 for angiogenesis were decreased, and
tunnel staining for tumor cell apoptosis was remarkably increased.
[108]
Anomalin
O OO
O
O
CH
3
H
3
C
H
3
C
H
3
CO
O
CH
3
CH
3
• Isolation of Anomalin from the roots of Peucedanum japonicum Thunb. (Umbelliferae) and evaluate its
efficacy against the human cancer (HeLa, HepG2, SNU-16, and AGS) cell lines.
• Anomalin showed most potent cytotoxic activity against SNU-16 cells (IC50 of 18.24μg/mL) with no sig-
nificant cell death observed in the CCD-25Lu human normal lung fibroblast cells.
[109]
cis-khellactone
OO
O
H
3
C
H
3
COH
OH
• Cytotoxic activities of cis-khellactone were evaluated on the proliferation and viability of MCF7 and
MDA-MB-231 human breast cancer and MCF10A normal cell lines and showed three types of pro-
grammed cell death that is apoptosis, autophagy-mediated cell death, and necrosis/necroptosis
• The cis-khellactone at 10 or 20μg/ml concentration showed the best induction of cell death in the MCF7
and MDA-MB-231 cells, while normal cell is much less sensitive than cancer cell lines.
[110]
Dentatin
OO O
OCH
3
CH
3
CH
3
H
2
C
H
3
C
H
3
C
• Antiproliferative potential of dentatin (a natural coumarin isolated from Clausena excavata Burm. F)
against prostate cancer
• Treatment with dentatin dose-dependently inhibited cell growth of PC-3 and LNCaP prostate cancer cell
lines, whereas it showed less cytotoxic effects on the normal prostate epithelial cell line (RWPE-1)
• Downregulated expression levels of antiapoptotic molecules (Bcl-2, Bcl-xl, and Survivin)
• Disruption of mitochondrial membrane potential, cell membrane permeability, and release of cytochrome c
from the mitochondria into the cytosol
• Inhibited TNF-α-induced nuclear translocation of p65, suggesting dentatin as a potential NF-κB inhibitor
• Strong cytotoxicity against an activity with IC50 ranging from 5-10µg/ml against human promyelocytic
leukemia (HL-60), human breast cancer (MCF-7), human cervical cancer (HeLa), and human colon cancer
(HT-29) cells
• Dentatin showed the IC50 values at 24, 48 or 72 hours against PC-3 cells (9.60±1.53μM, 8.15±2.41μM,
3.47±0.58μM, respectively); whereas against LNCaP cella (7.32±2.56μM, 6.79±1.90μM, 3.76±1.21μM),
respectively. It showed a less cytotoxic effect on RWPE-1 normal prostate epithelial cell line with IC50>
20μM at 24, 48 or 72 hours.
[111,
112]
(Table 3) contd….

1808 Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 15 Yerer et al.
Name and Chemical Structure of Coumarins Pharmacological Activity Refs.
Xanthoxyletin
O O O
H
3
C
H
3
C
OCH
3
Braylin
OO O
H
3
CO
H
3
C
H
3
C
6-methoxyseselin
OO O
H
3
CO
H
3
C
H
3
C
Xanthyletin
OO O
H
3
C
H
3
C
• Xanthoxyletin, braylin, 6-methoxyseselin and other coumarins from ethanol extract of bark of Juglans
mandshurica and evaluated in vitro cytotoxicity against two liver cancer cell lines (HepG2 and Hep3B)
• Xanthoxyletin and 6-methoxyseselin induced apoptosis and showed moderate antitumor activity against
both cell lines with IC50 values for HepG2 (62.30μM, 76.12μM) and Hep3B (66.53μM, 66.14μM) for 48h,
respectively.
• Braylin and Xanthyletin showed cytotoxicities against Hep3B cell line with IC50 of 74.08 and 62.86μM,
respectively.
[113]
3',4'-Disenecioylkhellactone
O OO
H
3
C
H
3
CO
O
O
H
3
C
CH
3
CH
3
H
3
C
O
• 3′,4′-Disenecioylkhellactone strongly suppressed cell proliferation and induced caspase-mediated apoptosis
in AGS human gastric cancer cells.
• It effectively suppressed signal transducer and activator of transcription 3 (STAT3) tyrosine phosphoryla-
tion, decreased STAT3 translocation to the nucleus and expression of STAT3 target genes.
[114]
visnadin
O OO
H
3
C
H
3
CO
H
3
C
O
O
O
CH
3
CH
3
• The petroleum ether and CHCl3 fractions of Ammi visnaga L. flowering aerial parts consisting of khellin,
visnagin (furanochromones) and visnadin (pyranocoumarins) showed the most significant cytotoxic activ-
ity against malignant melanoma (HT 144) cell lines with an IC50 value of 0.400mg/ml using doxorubicin as
a reference anticancer drug.
[115]
O OO
H
3
C
H
3
C
OR
OR
OO
H
3
CO
H
3
CO
O
H
3
CO
H
3
CO
H
3
CO
O
R=
• 7,8-pyranocoumarins exhibited activity in modulating Pgp. At 4µM achieved 91%~99% decrease in IC50
value of anticancer agent’s vinblastine, doxorubicin, puromycin and paclitaxel.
• Pgp-overexpressing human tumor cell lines HepG2/Dox (hepatocarcinoma), K562/Dox (leukemia) and KB
V1 (epidermoid carcinoma).
[116]
OO O
OH
R
CH
3
H
3
C
H
3
C
R= C
2
H
5
, C
3
H
7
, C
6
H
13
,
C
7
H
15
, C
10
H
21
• 3-alkyl,4- methylpyranocoumarins inhibited the cell proliferation of MDA-MB-468 and SK-OV-3 cells by
53-74%.
[117]
(Table 3) contd….

Nanoformulations of Coumarins and the Hybrid Molecules of Co umarins Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 15 1809
Name and Chemical Structure of Coumarins Pharmacological Activity Refs.
O OO
H
3
C
H
3
CO
O
CH
3
O
O
• 4-methyl-(3'S,4'S)-cis-khellactone derivatives were asymmetrically synthesized and evaluated
with respect to cytotoxic activity through MTT assay against HepG-2 (human liver carci-
noma), SGC-7901 (human gastric carcinoma), LS174T (human colon carcinoma) cell lines.
• Among these, tigloyl derivative was the most potent and exhibited strong cytotoxicity, with
IC50 values ranging from 8.51 to 29.65μM.
[118]
Alloxanthoxyletin fatty acids esters
O O
CH
3
O
H
3
CCH
3
OR
O
• Synthesis of alloxanthoxyletin fatty acids esters and evaluation of in vitro anticancer activity
against HTB-140 and A549 cancer cells using cisplatin doxorubicin as reference drugs.
• Among these, Oleic (R=C17H33), α - linolenic acid (R= C17H29), Conjugated linoleic acid
(R=C17H31) and Docosahexaenoic acid (R=C21H31) derivatives showed a stronger inhibi-
tory effects on cancer cells (HTB-140 and A549) than in normal cells (HaCaT).
• These derivatives possessed the highest cytotoxic potential against HTB-140 cells with IC50
of 14.4-35.4μM.
• These agents showed statistically significant effect against both tumor cell lines when oleic
derivative used in the concentration of 40μM, linolenic derivatives in concentration of 20μM
and docosahexaenoic acid at 10μM concentration.
[119]
Alloxanthoxyletin O-aminoalkyl derivatives
O O
CH
3
O
H
3
CCH
3
OR
Seselin O-aminoalkyl derivatives
OO
CH
3
O
H
3
C
H
3
C
OR
• Synthesis of O-aminoalkyl substituted alloxanthoxyletins and seselins and evaluated for their
anticancer toxicity against HaCaT, A549 and HTB-140 cells lines.
• Seselin and alloxanthoxylein derivatives increase the sensitivity of tumor cells to drug-
induced cell death as well as tumor cells showed a higher sensitivity to tested compounds than
normal cells.
• Diethylamine, dimethyl amine and piperidine Alloxanthoxyletin derivatives showed the
highest cytotoxic potential against HTB-140 cells with IC50 of 2.48, 2.80 and 2.98μM, re-
spectively.
[120]
Gemcitabine−Coumarin−Biotin conjugate
OOO
OO SSO
O
OO
OH FF
N
N
O
NH
2
NN
H
NH
NH
O
S
NH
NH
O
• The active molecule is preferentially taken up by A549 cells [56]
Umbelliprenin
O
O
O
• The cytotoxic effect of umbelliprenin (7-prenyloxycoumarins) was discovered on LLC cells
and mouse splenocytes
[57]
Coumarin-Chlorambucil Conjugate
O
O
OH
O
ONCl
Cl
• Cell viability was evaluated utilizing MTT assay in breast cancer cells MDA-MB-231 [58]
(Table 3) contd….

1810 Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 15 Yerer et al.
Name and Chemical Structure of Coumarins Pharmacological Activity Refs.
AD-013
OO
O
O
• Compound showed some selectivity against MCF-7 cancer cells as compared with MCF-
10A healthy cells
[59]
OOR
O
• These molecules decreased the proliferation of PC3 cells [60]
7-(benzyloxy)-4-(hydroxymethyl)-2H-1-ben zopyran -2-one
OOO
OH
• Anticancer effects of intracellular self-assembly started by light. CCK-8 assay quantified
the viability of both HepG2 and HeLa cells
[61]
OOO
NH
O
• Drug delivery of 7-ethyl-10-hydroxy camptothecin (SN-38), two nanoparticles (P-II and
P-IV micelles) were viewed and chosen for the cure of colon cancers.
[63]
Farnesiferol C
OOO
O
• The anticancer impact of Dendrosomal Farnesiferol C (DFC) on the AGS gastric cancer
cell line.
[65]
4-methyl-7-hydroxy coumarin
OOOH
• Encapsulated 4-methyl-7-hydroxy coumarin (SC), to test if nano-encapsulated SC can be
a more efficient anti-cancer agent.
[66]
Matrix metalloproteinase-2 (MMP-2) probe
OON
O
NH
O
R
• For the detection of cervical cancer, it ensures the probability based on MMP-2 [68]
Squaric acid-Coumarin-Chlorambucil
(Sq-Cou-Cbl) nanoconjugates
O
O
O
NH
O
O
OH NCl
Cl
( )
• On HeLa cells in vitro works demonstrated that Sq-Cou-Cbl nanoconjugates showed an
advanced anticancer activity
[70]
(Table 3) contd….

Nanoformulations of Coumarins and the Hybrid Molecules of Co umarins Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 15 1811
Name and Chemical Structure of Coumarins Pharmacological Activity Refs.
7-hydroxy-6-methoxy-2H-chromen-2-one (Scopoletin);
O O
H
3
CO
HO
3-acrylamido-6-methoxy-2-oxo-2H-chromen-7-yl acetate (7a);
O O
H
3
CO
AcO
H
N
O
N-(7-hydroxy-6-methoxy-2-oxo-2H-chromen-3-yl)acrylamide (7b);
O O
H
3
CO
HO
H
N
O
N-(7-hydroxy-6-methoxy-2-oxo-2H-chromen-3-yl)-2-(piperidin-1-
yl)acetamide (7e);
O O
H
3
CO
HO
H
N
O
N
N-(7-hydroxy-6-methoxy-2-oxo-2H-chromen-3-yl)-2-(4-methylpiperidin-
1-yl)acetamide (7f);
O O
H
3
CO
HO
H
N
O
N
3-(2-chloroacetamido)-6-methoxy-2-oxo-2H-chromen-7-yl acetate (8a);
O O
H3CO
AcO
H
N
O
Cl
6-methoxy-3-(2-(4-methylpiperazin-1-yl)acetamido)-2-oxo-2H-chromen-
7-yl acetate (8e);
O O
H3CO
AcO
H
N
O
N
N
• Scopoletin derivatives were fabricated from the reaction of β-aminopropamide, α-
aminoacetamide, acrylamide, and pure scopoletin and carried out in vitro cyto-
toxic activities by MTT.
IC50 (µM)
Molecules
A549 MDA-MB-
231 HEPG2
Scopoletin >100 >100 >100
7a >100 8.882±0.93 8.710±0.94
7b >100 21.96±2.29 4.80±0.11
7e >100 25.46±1.42 58.20±2.16
7f >100 8.579±0.48 14.15±0.71
8a 3.961±0.89 2.195±0.21 3.721±0.61
8e 41.16±1.73 71.86±2.45 30.97±1.49
[121]
attention. Ganghopadyay et al. made use of a multi-arm 15 PEG,
functionalized with a targeting unit biotin and a coumarin fluoro-
phore for site-specific and image guided synergic treatment of can-
cer cells. UV/vis light (≥365nm) with a moderate quantum yield of
~0.37, anticancer drug chlorambucil was released by coumarin
chromophore in a photo-controlled way. In addition to that, cou-
marin created singlet oxygen upon irradiation. In vitro application
of prepared organic polymeric nanoparticles (PEG-Bio-Cou-Cbl) in
Hela cell line demonstrated a reduction in cell viability of up to
~5% in the case of combined treatment of PDT and chemotherapy
while analogous organic polymeric NPs without the chemothera-
peutic drug (PEG-Bio-Cou) resulted in ~49% cell viability by PDT
protocol only [67].
The development of new strategies with high sensibility and
specificity is needed to improve the therapeutic rate of cervical
cancer. In normal cervical epithelial cells, Matrix Metalloprotein-
ase-2 (MMP-2) is low or absent, whereas it is overexpressed in
cervical intraepithelial neoplasia and cervical cancer. This provides
the possibility for the detection of cervical cancer based on MMP-2.
Connecting a fluorophore with a quencher via a MMP-2 substrate
peptide, a novel coumarin-based fluorescence resonance energy
transfer probe targeting MMP-2 was prepared to investigate cervi-
cal cancer by cell imaging. This MMP-2 probe potentially ensures a
specific and sensitive optic method for cervical cancer screening,
prognostic and diagnostic evaluation [68].
Nanogels with coumarin as a photocleavable group were de-
scribed as promising drug delivery systems in order to improve
anticancer treatment with hydrophobic drugs. Multi-stimuli respon-
sive nanogels based on biocompatible hydrophilic polymers have
been shown to increase circulating-time in the bloodstream, tumor-
targeting and reduction of systemic toxicity. Stefano et al. studied
the synthesis, characterization and biological perspectives of light-
and thermoresponsive Hyaluronic Acid (HA)-based nanogels con-
taining coumarin as photocleavable group. These gel particles were
obtained by temperature-induced self-assembly of dual stimuli
(light and temperature)-responsive HA derivatives. On the polysac-
charide backbone, it was prepared by grafting DEGMA and CMA-
based copolymer chains. In vitro biological studies showed that the
nanogels and their hydrophobic load are internalized by HeLa cells
(cervical cancer) in a concentration-dependent manner. No more
circulating nanogels were explored 24 h-post administration. A
hydrophobic dye accumulation was verified in tumoral tissues near
the blood vessels [69].
Chadhuri et al. improved photoresponsive fluorescent organic
nanoconjugates based on a single-component system by a synergis-
tic combination of Photodynamic Therapy (PDT) and chemother-
apy in order to efficiently cure cancer. They synthesized single-
component system by coupling the squaric acid and the coumarin-
chlorambucil conjugate. Multifunctional squaric acid-coumarin-
chlorambucil (Sq-Cou-Cbl) nanoconjugates were prepared by
“simple reprecipitation technique”. On HeLa cells, in vitro works
demonstrated that Sq-Cou-Cbl nanoconjugates showed an advanced
anticancer activity by the synergistic cytotoxic impact of PDT and
chemotherapy [70].

1812 Anti-Cancer Agents in Medicinal Chemistry, 2020, Vol. 20, No. 15 Yerer et al.
1.2.10. Fibrosarcoma
In nanomedicine, the potential applications of Fe3O4 Magnetite
Nanoparticles (MNPs) are well known as drug delivery systems.
Khorramizadeh et a l. prepared umbelliprenin-coated Fe3O4 MNPs.
The antiproliferative effect of the combination was evaluated in
vitro. Using transmission electron microscopy, energy-dispersive
spectroscopy, and X-ray diffraction spectroscopy techniques, Fe3O4
MNPs were characterized after synthesis. Umbelliprenin (the natu-
ral candidate coumarin compound) was isolated and identified.
Umbelliprenin-coated Fe3O4 MNPs were prepared, utilizing pre-
cipitation method. In vitro, HT-1080 cells (fibrosarcoma) were
cultured and MTT assay was carried out for evaluating the possible
cytotoxic effects of umbelliprenin-coated Fe3O4 MNPs in viable
cells. The results showed that umbelliprenin had middle antiprolif-
erative effects with IC50 value of 50µg/ml. The combination of
umbelliprenin and Fe3O4 MNPs demonstrated the IC50 value of
9µg/ml [71].
Taking into account the anticancer effects of coumarin deriva-
tives and hybrid molecules and the nanoformulations, these com-
pounds are summarized in Table 3 [72-121].
CONCLUSION
In this review article, antitumor activities of nanoformulations
of different coumarins are thoroughly described in diverse experi-
mental models of both solid tumors and hematological malignan-
cies. These data clearly demonstrate the power of joining the poten-
tial anticancer properties of natural plant compounds and novel
technological advances to hopefully achieve safe and efficient mo-
dalities for the treatment of malignant disorders. In fact, there are
numerous data available about the in vitro anticancer properties of
structurally diverse coumarins. However, efforts to translate these
findings to the human systems have mostly failed due to the issues
of bioavailability and biotransformation of natural polyphenolic
compounds. As shown in this review, nanotechnology might be the
key to overcome these obstacles, improving the delivery of coumar-
ins specifically to cancerous sites and thereby facilitating the im-
plementation of anticancer potential of these plant-derived agents.
Nevertheless, despite the promising results described so far in
applying nanoformulations in preclinical studies, there are still sev-
eral aspects needed to unravel before achieving an ideal nanovehi-
cle for coumarins. The important factors at this probably involve
not only the specificity and efficiency of antican cer action, but also
the long-term safety and cost-effectiveness. Therefore, besides the
continuation of intense preclinical studies for identification of the
best composition of coumarins-loaded nanoformulations, clinical
trials should also be designed in the future, to comprehend the real
potential of nanoformulations of coumarins in controlling cancer
development, progression and spread.
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of
interest.
ACKNOWLEDGEMENTS
Declared none.
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