Synthesis and evaluation of anticancer effect of a novel molecule based-on pillar[5]arene including multi quinoline units

Article abstract of DOI:10.1007/s00044-020-02547-y

In this study, pillar[5]arene containing ten terminal alkynyl-functional group was prepared and carried out an optimization procedure for target molecule with using 5-hydroxyquinoline molecule known with biological activity. The novel molecule was named a

Full text of DOI:10.1007/s00044-020-02547-y

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-020-02547-y
ORIGINAL RESEARCH
Synthesis and evaluation of anticancer effect of a novel molecule
based-on pillar[5]arene including multi quinoline units
Canan Eroglu Gunes1 Mehmet Ali Karaselek2 Ahmed Nuri Kursunlu3 Mustafa Ozmen3 Ercan Kurar1
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Received: 11 March 2020 / Accepted: 16 April 2020
© Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
In this study, pillar[5]arene containing ten terminal alkynyl-functional group was prepared and carried out an optimization
procedure for target molecule with using 5-hydroxyquinoline molecule known with biological activity. The novel molecule
was named as iso-QP[5] and characterized by FT-IR, melting point, NMR, elemental analysis, and mass spectroscopy. The
aim was to evaluate the anticancer effects of iso-QP[5] on MCF7 human breast cancer cells. The IC50 dose of iso-QP[5] in
MCF7 cells was found to be 25 µM for 24 h using XTT assay. Expressions of eight genes for apoptosis were determined by
qPCR. The results showed a significant increase in the expression of BAX, CASP3, CASP9, CYCS, and P53 genes after
treatment with iso-QP[5] in MCF7 cells. However, iso-QP[5] treatment significantly decreased expression of BCL2 and
CASP8 genes. It is concluded that novel molecule iso-QP[5] caused apoptosis by regulating genes that are important in
apoptosis in human breast cancer cells.
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Keywords Apoptosis Cytotoxicity Pillar[5]arene Quinoline
Introduction
Min et al. 2019). Among these drug agents, macrocycles
have the most important position owing to their multi-
supramolecular interactions (Soor et al. 2018; Chen et al.
2019; Wintgens et al. 2019). The substitution of macro-
cycles with the organic groups having pharmacological
functions plays a crucial role in the effective of anticancer
agents. It was reported that new generation drug molecules
including quinoline derivatives may act as anticancer agents
through a variety of mechanisms such as cell cycle arrest in
topoisomerase inhibition (Cheng et al. 2008), the G2 phase
(Kim et al. 2005), inhibition of tyrosine kinases and tubulin
polymerization (Alqasoumi et al. 2009) and inhibition of
which is the most common mechanism (Mulvihill et al.
2008; Pannala et al. 2007; Nishii et al. 2010). Quinoline
scaffolds on macrocycles were emerged as potent multi
inhibitors of EGFR kinase and human Topo IIα activity at
very low concentrations against several cancer cell lines
comparable to erlotinib (Matsui et al. 2008; Kubo et al.
2005).
Cancer is a huge class of diseases determined by unrest-
rained and spread of the abnormal growth cells. The ratio of
breast cancer is 24.2% in all cancer types and it is the most
common diagnosed cancer in women worldwide. Moreover,
this disturbing disease causes death in women, which ratio
is 15.0% (Siegel et al. 2016; Verma et al. 2019; Vineis and
Wild 2014). In the past decades, the treatment of cancer by
drug molecules has evolved from general cytotoxic che-
motherapy to using drugs matching the specific targets of a
cancer kind (Eren et al. 2014; Nowak-Sliwinska et al. 2019;
Supplementary information The online version of this article (https://
doi.org/10.1007/s00044-020-02547-y) contains supplementary
material, which is available to authorized users.
* Ahmed Nuri Kursunlu
ankursunlu@gmail.com
Pillar[n]arene macrocycles as novel key player of
supramolecular chemistry are nominated to multi-
disciplinary areas such as pharmacology, biochemistry,
medicine, material science, etc. (Ogoshi et al. 2008; Xue
et al. 2012; Ogoshi et al. 2016; Ma et al. 2011; Yu et al.
2012). Therefore, they may transform to excellent cages
having symmetrical and gifted arms, 10 and 12 effective
1
Department of Medical Biology, Meram Faculty of Medicine,
Necmettin Erbakan University, 42080 Konya, Turkey
2
Department of Hematology, Meram Faculty of Medicine
Necmettin Erbakan University, 42080 Konya, Turkey
3
Department of Chemistry, Faculty of Science, Selcuk University,
42250 Konya, Turkey

Medicinal Chemistry Research
organic fragments for all these applications (Park and Kim
2015; Yao et al. 2017).
Materials and methods
The fascinating host-guest properties of pillararenes have
been reported as polymer nanocapsule for drug delivery
system. Design of smart molecules for pharmacological
applications has been growing to be a hot topic (Duan et al.
2013; Zhang and Zhao 2016; Chang et al. 2014; Huang
et al. 2017). However, pillararene was not directly proposed
as a drug molecule for the anticancer studies when they
were first synthesized in 2008.
To the best of our knowledge, the anticancer properties
of this new kind of macrocycle, pillar[n]arene, have not
been investigated earlier. In here, pillar[5]arene derivative
having ten quinoline units, which pharmacologically active,
including suitable reaction conditions for this type of
compounds was designed and the chemical synthesis of the
precursors materials was conducted. Then, it was aimed to
investigate anticancer effects of the iso-QP[5]in MCF7
human breast cancer cells. For this, the cytotoxic effect of
pillar[5]arene derivative was primarily evaluated in MCF7
human breast cancer cells. The apoptotic effect of pillar[5]
arene derivative was determined by evaluate expression
levels of important some genes in apoptosis and annexin V
apoptosis assay.
Chemicals
The iso-QP[5] was prepared as a known synthesis steps
(Kursunlu et al. 2017). The synthesis route of 1,4-bis(2-
iodoethoxy)benzene, pillar[5]arene, and iso-QP[5] were
given in Fig. 1 where all reactions were performed in
nitrogen atmosphere. BF3OEt2, 4′-hydroxy-4-biphe-
nylcarboxylic acid, carbon tetraiodide, 5-hyroxyquinoline,
1,4-Bis(2-hydro-xyethoxy) benzene, paraformaldehyde, tri-
phenylphosphine, potassium carbonate, 1,2-dichloroethane,
and toluene were purchased from Acros and Sigma-Aldrich.
13C-NMR and H-NMR spectra were recorded at r.t. on a
1
Varian 400 MHz. The elemental analyses results were taken
from a TruSpec Elemental Analyzer. The infrared mea-
surements were performed on a Bruker Fourier Transform
Infrared FTIR (ATR). Also, the tested compounds and all
purchased reagents have to range between 95 and 100%
purity. For assays of cell culture, RPMI-1640 medium and
XTT [2,3-bis (2-methoxy-4-nitro-5-sulfophenyl) 2H tetra-
zolium-5-carboxanilide] kit were purchased from Biological
Industries. Penicillin/streptomycin mixture and phosphate-
buffered saline (PBS) were commercially obtained from
Gibco. Fetal bovine heat-inactivated serum (FBS) and
TRIzol reagent were purchased from Capricorn Scientific
Fig. 1 Synthesis of pillar[5]
arene (iso-QP[5]) and its
functionalization with 5-
hyroxyquinoline

Medicinal Chemistry Research
and Invitrogen, respectively. Transcriptor first strand cDNA
synthesis kit and SYBR® Green Supermix were commer-
cially supplied from Bio-Rad. FITC Annexin V Apoptosis
Detection Kit was purchased from BioLegend.
2 mM L-glutamine, 10% FBS, and 1% penicillin/strepto-
mycin mixture. MCF7 cells were treated with 25, 50, 75,
100, and 150 µM iso-QP[5]during 72 h, time- and dose-
dependent manner.
Synthesis of 1,4-bis(2-iodoethoxy)benzene
Cytotoxicity assay
1,4-bis(2-iodoethoxy)benzene was prepared as a known
synthesis procedure (Kursunlu et al. 2017). The white flake-
like crystals were dried in a desiccator (4.25 g, 83%), purity:
Cytotoxic effect of iso-QP[5] in MCF7 cells were deter-
mined by using XTT assay as indicated in manufacturer’s
instruction. The iso-QP[5] was dissolved in dimethylsulf-
oxide (DMSO) and the final concentration of DMSO did
not exceed 0.1%. Briefly, MCF7 cells were seeded in 96-
well plates at a number of 1 × 103 cells/well and incubated
for 24 h. Then, cells were treated with various concentra-
tions (0–150 µM) of iso-QP[5] and incubated for 24, 48, and
72 h. After the incubations, cell viability was determined by
using XTT mixture as recommended by supplier. After
XTT mixture was added to wells, plates were re-incubated
for 4 h. Then, amount of cell viability was determined with
absorbance at wavelength 450 nm (reference wavelength
630 nM) using a microplate reader. Viability was calculated
using the background-corrected absorbance as follows:
Viability (%) = A of experiment well/A of control well ×
100.
1
99% and characterized as H-NMR (400 MHz, chloroform-
d, r. t.) δ (ppm): 6.94 (s, 4H), 4.31 (t, J = 5.2 Hz, 4H), 3.53
(t, J = 5.7 Hz, 4H). 13C-NMR (100 MHz) δ (ppm): 150.44,
116.15, 75.22, 4.29.
Synthesis of pillar[5]arene having ten iodine units
Pillar[5]arene was also prepared as a known synthesis
procedure (Kursunlu et al. 2017) using column chromato-
graphy (SiO2; petroleum ether/CH2Cl2, 1:1) gave product
(0.90 g, 31%). Purity: 98% purity1H-NMR (400 MHz,
chloroform-d, r. t.) δ (ppm): 6.93 (s, 10H), 4.31 (t, J =
5.4 Hz, 20H), 3.85 (s, 10H), 3.53 (t, J = 5.4 Hz, 20H). 13C-
NMR (100 MHz) δ (ppm): 149.82, 125.89, 116.40, 67.41,
29.72, and 3.91. Elemental analysis calcd: C55H60I10O10: C,
30.72; H, 2.81; found: C, 30.56; H, 3.08.
RNA isolation, cDNA synthesis, and qPCR analysis
Synthesis of iso-QP[5]
Total RNA from MCF7 cells was extracted with TRIzol
reagent. cDNA synthesis was conducted using the Tran-
scriptor first strand cDNA synthesis kit according to the
manufacturer’s instructions. The primer sequences of target
and reference genes (Table 1) used in the qPCR were pre-
viously reported elsewhere (Eroğlu et al. 2018). Briefly,
qPCR mix for each gene was set up in 10 µL final volume
containing 5 µL 2X SYBR Green Supermix, 5 pMol of
forward and reverse primer, and 2 µL cDNA. PCR profile
was consist of an initial denaturation at 95 °C for 30 s,
followed by 40 cycles of denaturation at 95 °C for 5 s and
annealing/extension at 60 °C for 30 s.
Iso-QP[5] was synthesized by using a previously reported
procedure (Kursunlu et al. 2017). K2CO3 (1.6 g, 12 mmol)
was added to a solution of pillar[5]arene having ten iodine
units (0.86 g, 0.4 mmol) and 5-hydroxyisoquinoline
(0.608 g, 2.1 mmol) in acetonitrile/DMF (100 mL/6 mL)
and the mixture was refluxed for 120 h. Column chroma-
tography (SiO2; eluent-CH2Cl2) gave iso-QP[5] as a pale-
brown solid (0.376 g, 81%). Mp: 110–112.0 °C. Purity:
95%.1H-NMR (400 MHz, chloroform-d, room temperature)
δ (ppm): 8.88 (bs, 10H), 8.51 (bs, 10H), 7.35–7.10 (m,
40H), 6.93 (bs, 10H), 3.86 (m, 40H), 3.69 (bs, 10H). 13C-
NMR (100 MHz) δ (ppm): 166.12, 155.21, 147.32, 145.11,
139.46, 137.14, 133.26, 128.99, 128.31, 125.16, 123.42,
112.42, 106.32, 68.21, 66.37, 29.91. Elemental analysis
calcd C145H120N10O20: C, 74.98; H, 5.21; N, 6.03; found: C,
74.54; H, 5.56; N, 5.97. m/z calcd for [M + H]+, 2323.6;
found 2324.6.
Cell apoptosis assay
Apoptotic effect of iso-QP[5] in MCF7 cells was detected
using the FITC Annexin V Apoptosis Detection Kit (Bio-
Legend, BioLegend Inc., San Diego) according to the
manufacturer’s instructions. MCF7 cells were seeded in six-
well plates at density of 1 × 106 cells per well in 2 mL of
complete RPMI and incubated at 37 °C in a 5% CO2
humidified atmosphere for 24 h. After treating with iso-QP
[5] for 24 h, the cells were trypsinized and then washed
three times with cold PBS. The cells centrifuged and the
pellets were resuspended in Annexin V Binding Buffer at a
concentration of 1 × 106 cells/mL. Subsequently, 5 µL of
Cell culture
MCF7 (ATCC® HTB-22TM) human breast cancer cell line
was obtained from ATCC. Cells were proliferated in a cell
culture incubator including 37 °C, 5% CO2 atmosphere,
humidified 95% air in RPMI-1640 medium containing

Medicinal Chemistry Research
Table 1 Primers sequences used qPCR analysis
Gene Primer sequence
PCR
product
size (bp)
GAPDH F:5-TGAACGGGAAGCTCACTGG-3
307
151
125
R:5-TCCACCACCCTGTTGCTGTA-3
BAX
F:5-GGAGCTGCAGAGGATGATTG-3
R:5-GGCCTTGAGCACCAGTTT-3
BCL2
F:5-GTGGATGACTGAGTACCTGAAC-3
R:5-GAGACAGCCAGGAGAAATCAA-3
CASP3
CASP7
CASP8
CASP9
CYCS
F:5-GAGCCATGGTGAAGAAGGAATA-3 162
R:5-TCAATGCCACAGTCCAGTTC-3
Fig. 2 Effect of iso-QP[5] on the viability in the MCF7 cells. The cells
were treated with iso-QP[5] and at different concentrations and time
intervals and antiproliferative effect was evaluated by XTT assay. IC50
dose of iso-QP[5] in MCF7 cell line was found to be 25 µM. Data are
the average results of three independent experiments
F:5-CGAAACGGAACAGACAAAGATG-3 169
R:5-TTAAGAGGATGCAGGCGAAG-3
F:5-GCCCAAACTTCACAGCATTAG-3
R:5-GTGGTCCATGAGTTGGTAGATT-3
160
F:5-CGACCTGACTGCCAAGAAA-3
R:5-CATCCATCTGTGCCGTAGAC-3
153
(triplet), and 3.52 ppm (triplet). Following to the transforma-
tion of 1,4-bis(2-iodoethoxy)benzene to pillar[5]arene having
ten iodine units, the methylene bridge protons appeared at
F:5-GGAGAGGATACACTGATGGAGTA- 102
3
R:5-GTCTGCCCTTTCTTCCTTCTT-3
1
P53
F:5-GAGATGTTCCGAGAGCTGAATG-3
R:5-TTTATGGCGGGAGGTAGACT-3
129
3.86 ppm. In H-NMR iso-QP[5], the proton signals were
observed 8.88, 8.51, 7.35–7.10, and 6.93 for aromatic groups,
3.86 and 3.69 (bs, 10H) for the aliphatic fragments, respec-
tively. The –CH2 protons of pillar[5]arene having ten iodine
units give a singlet peak asserting that there is no barrier to
through-the annulus-rotation. After the reaction of pillar[5]
arene having ten iodine units with 5-hydroxyisoquinoline, led
FITC Annexin V and 7AAD added to 100 µL of cell sus-
pension and then cells incubated for 15 min at the room
temperature in the dark. Then, 400 µL of Annexin V
Binding Buffer was added to each tube. Obtained cell
suspensions were examined using the Becton Dickinson
Canto II (BD Biosciences, Heidelberg, Germany) flow
cytometry devices. The data analyses were performed using
FACSDiva software (version 6.1.3, BD Biosciences).
1
to the broadened singlet peaks in H-NMR iso-QP[5]. Actu-
ally, these differences are known that previous literatures
support to understand why this happens that they split at
higher or lower temperatures. The steric implications of the
conformation, the intermolecular interactions such as hydro-
gen bonds and aggregation had been reported as the causing
of these changes (Kursunlu et al. 2017).
Statistical analysis
Statistical analysis of the data was previously described
(Eroğlu et al. 2018). Briefly, the qPCR analysis was con-
ducted with the ΔΔCT method. The comparisons of the
control and dose groups were performed with “Volcano
Plot” analysis in “RT2ProfilesTMPCR Array Data Analysis”,
which was assessed statistically using the “Student t test”.
Moreover, other analyses were done using the “Student t
test” in SPSS 20.0 statistical analysis program. If p < 0.05 or
less, was reported as statistically significant difference.
Antiproliferative effect of iso-QP[5] in MCF7 cells
The effect of iso-QP[5] on proliferation of MCF7 cell line
was determined by XTT assay. As shown in Fig. 2, iso-QP
[5] inhibited the cell viability of MCF7 breast cancer cells
time- and dose-dependent manner. The IC50 dose of iso-QP
[5] in MCF7 cells was found to be 25 µM for 24 h. In the
following experiments, dose of 25 µM, which inhibited 50%
of the cells, was used for in MCF7 cells.
By advantage of the multi-arms and bidirectional of pillar
[5]arenes, we prepared a new macrocycle by quinoline moi-
eties having outstanding biological efficiency and good
activity in cell lines. A number of studies were reported using
of pillar[n]arenes having multi-arms in the drug delivery
system owing to famous property with host–guest. Guo et al.
showed that water-soluble pillar[5]arene-cationic poly(gluta-
mamide) has negligible effect on the cell viability using
concentrations ranging from 5.0 to 20 µg/mL in normal and
Results and discussion
Characterization of compounds
The NMR (1H & 13C-NMR) spectra of the prepared com-
pounds were given in SI. The protons of 1,4-bis(2-iodoe-
thoxy)benzene were observed at 6.92 ppm (singlet), 4.33 ppm

Medicinal Chemistry Research
cancer cells (Guo et al. 2017). Chang et al. reported that a
charge-reversal amphiphilic pillar[5]arene bearing ten charge-
reversal head groups selectively destroyed cancer cells by
targeting the cancer cell membrane both in vitro and in vivo
(Chang et al. 2019). In this study, introduction of flexible
chains into bidirectionally bounded from para positions of
benzene fragments of pillar[5]arene (five-down and five-up
chains) of the quinoline nucleus improved the water solubility
features in living cell applications. The cunning modification
of pillar[5]arene by our research group has led to the dis-
covery of a potential next-generation anticancer agent iso-QP
[5]. In a continuing effort to improve new drug molecule
including quinoline derivatives endowed with better bio-
activity in recent investigations. Venkatarao et al. (2019)
designed and synthesized ten novel molecules of chalcone
fused quinoline derivatives. Moreover, their anticancer
activity was evaluated in some cancer cell lines using MTT
assay. Especially six of the newly synthesized molecules
exhibited more potent activity at very low doses in MCF7
(breast), A549 (lung), and A375 (melanoma) cancer cells. In
these cells, IC50 dose range of newly synthesized molecules
was 0.11–8.56 µM (Venkatarao et al. 2019). Thirunavukkar-
asua et al. synthesized quinoline based palladium (II) com-
plexes and found cytotoxic effect in A549 human lung cancer
and MCF7 breast cancer cell lines. It was reported that IC50
dose of palladium complex 1 synthesized was found to be 30
and 26 µM in A549 and MCF7 cells, respectively. IC50 doses
of palladium complex 2 were found to be 31 µM (A549) and
29 µM (MCF7) in these cancer cells. Complexes showed
cytotoxic effects at low concentrations (Thirunavukkarasu
et al. 2018). In the present study, IC50 dose of iso-QP[5], a
pillar[5]arene derivative having to quinoline units, was found
to be 25 µM for 24 h in MCF7 cells.
Apoptosis, defined by Kerr et al. in 1972, is natural form
of programmed cell death (Kerr et al. 1972). Moreover, it is
also an induced important cell death pathway in cancer
therapy such as chemotherapy and radiotherapy. Apoptosis
can occur via intrinsic pathway triggered by intracellular
stressors or extrinsic pathway induced with the activation of
death receptors. Cytochrome c release from mitochondria is
important process in the intrinsic pathway. Bcl-2 protein
family (like proapoptotic protein BAX and antiapoptotic
protein BCL2) plays an important role in release cyto-
chrome c to cytosol from mitochondria by changing mito-
chondrial membrane permeabilization in this process.
Furthermore, tumor suppressor protein p53 activates proa-
poptotic genes such as BAX in case of DNA damage in the
cells. Cytochrome c forms a complex with Apaf-1 protein in
cytosol and this complex cleaves initiator caspase-9. Then,
executioner caspases 3, 6, and 7 are activated to induce cell
death. However, activation of death ligands and death
receptors on the cell surface is important in the extrinsic
pathway (Wuest et al. 2019). Expression levels of important
genes for apoptosis were analyzed by qPCR in this study.
According to qPCR results, it was observed a significant
increase in the expression of BAX, CASP3, CASP9, CYCS,
and P53 genes, after treatment with 25 µM iso-QP[5] in
MCF7 cells. However, treatment of 25 µM iso-QP[5]
caused a significantly decrease in expression of BCL2 and
CASP8 genes. Although CASP7 gene expression was
downregulated, this finding was statistically insignificant. It
was seen that iso-QP[5] can cause apoptosis by regulating
these genes that are important in apoptosis in MCF7 cells.
Apoptotic effect of iso-QP[5] in MCF7 cells
Annexin V and 7AAD were used to evaluate the apoptotic
effect of iso-QP[5] in MCF7 cells. Only annexin V positive
Gene expression analysis with qPCR
After total RNA isolation was conducted from control and
iso-QP[5]-treated cell groups, cDNA synthesis was per-
formed using the Transcriptor first strand cDNA synthesis
kit. The changes in expression of BAX, BCL2, CASP3,
CASP7, CASP8, CASP9, CYCS, and P53 genes that play an
important role in apoptosis relative to the control group after
treatment with 25 µM iso-QP[5] in MCF7 cells were eval-
uated with qPCR analysis. It was observed that iso-QP[5] in
MCF7 cells compared with the control group cells caused a
significant increase in the expression of BAX (1.32 fold),
CASP3 (1.04 fold), CASP9 (1.53 fold), CYCS (1.86 fold)
and P53 (2.78 fold) genes, and a significant decrease in the
expression of BCL2 (2.92) and CASP8 (1.52) genes (Fig. 3,
p < 0.05). In the iso-QP[5]-treated MCF7 cells compared
with the control group cells was observed a decrease in
CASP7 gene expression, however it was not statistically
significant.
Fig. 3 The changes in expression of genes that play an important role in
apoptosis relative to the control group after iso-QP[5] treatment in MCF7
cells. An asterisk indicates statistically important (p < 0.05) difference

Medicinal Chemistry Research
Fig. 4 Flow cytometric
apoptosis image
area shows early apoptosis, only 7AAD positive area
shows necrosis, annexin V and 7AAD show positive area
late apoptosis. In the light of this information, early
apoptosis rate was 5.6%, late apoptosis rate was 0.1%, and
necrosis rate was 0.1% in the control group. After 25 µM
iso-QP [5] treatment, early apoptosis, late apoptosis, and
necrosis rates were 20.8, 3.1, and 1.9%, respectively. The
flow cytometry image of the control and iso-QP [5] is
shown in Fig. 4.
Phosphatidylserine (PS) is located on inner surface of
cell membrane in normal cells. However, PS translocated to
outer surface from inner of cell membrane in process of
apoptosis. Annexin V is an important protein, which binds
to PS in the presence of Ca2+ ions (Wuest et al. 2019). Su
et al. reported that new synthesized quinoline derivatives
exhibited antiproliferative activity with low IC50 value
against seven human tumor cell lines. Moreover, N-(3-
methoxyphenyl)-7-(3-phenylpropoxy)quinoline-4-amine
was found to be the most potent antiproliferative agent.
Furthermore, it was showed that this compound induced
apoptosis in HCT116 human colon cancer cells using the
annexin V-FITCH/PI assay (Su et al. 2019). In the present
study, annexin V assay indicated that iso-QP[5] treatment
caused early and late apoptosis in MCF7 cells.
Acknowledgements The authors express their appreciation to Prof
ErsinGuler for helpful discussions. This research was supported by the
Scientific Research Projects Foundation of Necmettin Erbakan Uni-
versity (BAP; #1512180023).
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Publisher’s note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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