Design, synthesis, anti-proliferative evaluation and docking studies of 1: H -1,2,3-triazole tethered ospemifene-isatin conjugates as selective estrogen receptor modulators

Article abstract of DOI:10.1039/c7nj04964a

A library of 1H-1,2,3-triazole-tethered ospemifene-isatin and ospemifene-spiroisatin conjugates have been synthesized and evaluated for their anti-proliferative activities against MCF-7 and MDA-MB-231 cell lines. The evaluation studies revealed that compound 11j was the most potent with an IC₅₀ value of 1.56 μM against the MCF-7 cell line. Compounds 11k and 11l also displayed a similar trend, with several-fold lower effective concentrations in ER+ cells than in ER- cells. SAR studies revealed that conjugates having a bromo-substituent at the C-5 and C-7 positions of the isatin ring with ethyl/propyl as the spacer were observed to be active with the most potent compound being ～30 times more potent than Tamoxifen against the MCF-7 cell line. The evaluation results were further supported by docking studies and the stronger binding affinity of the synthesized conjugates was attributed to their greater structural bulk and greater occupation of the ERα active site.

Full text of DOI:10.1039/c7nj04964a

View Article Online
View Journal
NJC
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: V. Kumar, S.
Kumar, L. Gu, G. Palma, M. Kaur, A. Singh and P. Singh, New J. Chem., 2018, DOI: 10.1039/C7NJ04964A.
Volume 40 Number
1
January 2016 Pages 1–846
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
NJC
New Journal of Chemistry
www.rsc.org/njc
A journal for new directions in chemistry
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
rsc.li/njc

Page 1 of 12
Pl Ne ae swe Jd oo u nr no at l ao dfj Cu sh te mm ai sr tgr iyn s
View Article Online
DOI: 10.1039/C7NJ04964A
Journal Name
COMMUNICATION
Design, synthesis, anti-proliferative evaluation and docking
studies of 1H-1,2,3-triazole tethered Ospemifene-isatin
conjugates as Selective Estrogen Receptor Modulators
Received 00th January 20xx,
Accepted 00th January 20xx
a
b
b
b
c
c
DOI: 10.1039/x0xx00000x
Sumit Kumar , Liang Gu , Gabriella Palma , Mandeep Kaur *, Ashona Singh-Pillay ,Parvesh Singh*
a
and Vipan Kumar*
www.rsc.org/
A library of 1H-1,2,3-triazole-tethered ospemifene-isatin and ospemifene-spiroisatin conjugates have been
synthesized and evaluated for their anti-proliferative activities against MCF-7 and MDA-MB-231 cell lines.
The evaluation studies revealed compound 11j found to be the most potent with an IC50 value of 1.56 µM
against MCF-7 cell line. Compounds 11k and 11l also displayed a similar trend, having several-folds lower
effective concentrations in ER+ cells than in ER- cells. SAR revealed that conjugates having bromo-substituent
at C-5 and C-7 position of the isatin ring with an ethyl/propyl as spacer were observed to be active with the
most potent compound being ~30 times more potent than Tamoxifen against MCF-7 cell line. The evaluation
results were further supported by docking studies attributing stronger binding affinity of synthesized
conjugates to their greater structural bulk and more occupation of the ER active site.
selective modulation of estrogensignaling depends upon the
balance between ERα and ERβ receptors. ERα is usually
expressed in the BC cells, while ERβ is expressed in the brain,
Introduction
1
0,
Breast cancer (BC) is the second leading cause of death among bones, lungs and kidney and share 55% sequence similarity.
1
11
women worldwide, after lung cancer.
The disease is
The selective inhibition of ERα has led to the identification of
aggressive and is characterized by abnormal cell growth in the a series of drugs known as Selective Estrogen Receptor
breast which is capable of spreading/invading surrounding Modulators (SERMs). The characteristic of an ideal SERM for its
tissues and metastasizing in other areas of the body. The major use as an anti-breast cancer agent should include anti-
symptoms of BC include a lump in the breast, bloody discharge estrogenic activity in breasts and estrogenic activity in the
1
2
from the nipple and changes in the shape/texture of the nipple bones and heart.
2
or breast. The incidence of BC has increased exponentially
Triarylethylenes
are
structural
and constitute
variants
the
of
since 2012 where nearly 1.7 million new cases were estrogendiethylstilbestrol
basic
diagnosed. In the United States (US) alone, it was estimated pharmacophoric features of SERMs. Raloxifene
that for about 252,710 new cases of BC in 2017, approximately toremifene are US Food and Drug Administration (FDA)
3,410 will be of carcinoma in situ with a mortality probability approved SERMs which shows anti-breast cancer activity in
, tamoxifen,
6
3
of 40,610.
Statistically two-thirds of BCs are an effect of being (Osphena), recently approved by the US FDA is
both pre-and post-menopausal women. Ospemifene
a
4
hormone receptor-positive. Binding of the hormone estrogen triphenylethylene derivative useful for the treatment of
to estrogen receptors (ERs i.e. isomeric forms ERα and ERβ); moderate to severe dyspareunia (vaginal and vulvar atrophy
3, 14
1
has been reported to stimulate proliferation of mammary cells. associated with menopause).
5
The drug has proven to be a
The inhibition of the binding of estrogen to ERs constitutes an novel SERM, acting as an estrogen agonist in the brain, bones
6
-9
important strategy in the treatment of breast cancer. The and vagina, and an estrogen antagonist in the breasts and
uterus. Part of ospemifene’s pharmacological potential is
attributed to its safety in clinical use as compared to other
active derivatives, Tamoxifen and raloxifene which have
known side effects, such as: hot flashes, insomnia, dizziness
1
5, 16
and depression.
implicated as causal agents in endometrial cancer.
Tamoxifen and raloxifene have also been
7
1
Isatin is a versatile scaffold present in human and other
mammalian tissues. It is a common structural feature in
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 2 of 12
View Article Online
DOI: 10.1039/C7NJ04964A
COMMUNICATION
Journal Name
avariety of dyes, agrochemicals and pharmacologically active Scheme 2: Synthetic route for N-alkyl-azidoisatins7 and N-alkyl-
molecules. The synthetic ingenuity of isatin makes it a perfect azidospiroisatins10
platform for structural alterations and derivatization. Isatin-
based compounds have displayed diverse biological properties,
such as: anti-cancer, anti-depressant, anti-convulsant, anti-
1
8-23
fungal, anti-HIV and anti-angiogenic activities.
Currently, an
isatin-based triple angio-kinase inhibitor BIBF1120 II is in phase
III clinical trials in the treatment of non-small cell lung cancer.
2
4
Another example of an isatin-based chemotherapeutic is
Sunitinib III (Sutent), which is a multi-kinase inhibitor targeting
VEGFR-1, VEGFR-2, PDGFRb and c-Kit. Sunitinib was approved
by FDA for the treatment of gastrointestinal stromal tumors
2
5, 26
(GIST) and advanced renal cell carcinoma (RCC).
In continuation of our recent work published on the synthesis
and anti-proliferative evaluation of isatin-derivatives, as well
The target conjugates viz. 1H-1,2,3-triazole-tethered
ospemifene-isatin11/ospemifene-spiro-isatin 12 conjugates
were synthesized via Cu-promoted azide-alkyne cycloaddition
2
7, 28
as isatin-based molecular conjugates,
the present
manuscript describes the synthesis of 1H-1,2,3-triazole
tethered isatin-ospemifene conjugates along with their anti-
proliferative evaluation against MCF-7 (ER+) and triple-
reaction of appropriate precursors’
7 and 10 with 4 (Scheme
3).
negative MDA-MB-231 (ER-) cell-lines using MTT assay. Scheme 3: Synthetic route for 1H-1,2,3-triazole tethered
Molecular docking simulations were further employed to
ospemifene-isatin/ospemfene-spiroisatin conjugates.
explore the binding modes of test molecular conjugates into
the ligand binding domain (LBD) of estrogen receptor (ERα).
Results and Discussion
Synthetic Chemistry:
The synthetic methodology for the preparation of O-
propargylatedospemifene involved an initial McMurry reaction
of precursor’s viz. [4-(2-hydroxy-ethoxy) phenyl]-phenyl-
methanone
presence of Zn and TiCl
ospemifene . Sodium hydride promoted O-propargylation of
in dry THF afforded the corresponding O-
propargylatedospemifene Scheme 1).
1
and 3-chloro-1-phenyl-propan-1-one
2 in the
4
in anhydrous THF to afford
3
3
4
(
Scheme 1. Synthetic route for O-propargylatedospemifene:
The purification of the reaction mixture via column
chromatography using ethylacetate: hexane (60:40) mixture as
eluent, afforded the desired conjugates in good to excellent
yields. The structure to the synthesized conjugates was
assigned on the basis of spectral data and analytical evidence.
Compound 11e, for example, characterized as 1-[3-(4-{2-[4-(4-
chloro-1,2-diphenyl-but-1-enyl)-phenoxy]-ethoxymethyl}-
[
1,2,3]triazol-1-yl)-propyl]-5-methyl-1H-indole-2,3-dione
+
exhibited a molecular ion peak at m/z 660.2519 (M ) in its High
Resolution Mass Spectrum (HRMS). The salient features of its
1
H NMR spectrum included the appearance of characteristic
The second precursor viz. N-alkylazido-isatin derivative
prepared via base-promoted alkylation of isatins using J=7.0 Hz), 3.84 (t, J=4.8 Hz), 4.02 (t, J=4.4 Hz), 4.40 (t, J=6.4 Hz)
dibromoalkane to yield with subsequent reaction with and a singlet at 4.72 corresponding to different methylenes
sodium azide. Similarly, N-alkylazidospiro-isatin10 was along with a singlet at δ 2.33 corresponding to methyl
7 was absorptions at δ 2.93 (t, J=7.4 Hz), 3.42 (t, J=7.5 Hz), 3.78(t,
6
1
3
prepared via an initial preparation of spiroisatin
2
8
, as per the substituent at C-5 position of the isatin ring. C NMR spectrum
9
reported protocol, with its sequential alkylation using exhibited characteristic absorptions at δ 158.6 and 183.1
dibromoalkane and treatment with sodium azide (Scheme 2).
corresponding to isatin ring carbonyls further corroborating
the assigned structure.
2
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 12
Pl Ne ae swe Jd oo u nr no at l aod fj Cu sh te mm ai sr tgr iyn s
View Article Online
DOI: 10.1039/C7NJ04964A
Journal Name
COMMUNICATION
Figure 1: Three-dimensional representation of: A) ERα (PDB ID:
Anti-proliferative activities of conjugates 11 and 12, against 3ERT), and the three positive controls on the active site of the
MCF-7 (ER+) and MDA-MB-231 (ER-) cell lines
receptor, i.e. B) Plumbagin (green), C) Ospemifene (grey), and D)
The synthesized ospemifene-isatin conjugates were evaluated Tamoxifen (red)
for their anti-proliferative activities against MCF-7 (ER+) and
MDA-MB-231 (ER-) human breast cancer cell-lines using MTT
A
B
assay. The percentage growth inhibition of MCF-7 and MDA-
MB-231 cells was recorded at varying concentrations of the
synthesized conjugates and the results are depicted in Figures
3
-9(see supporting information) using plumbagin as the
positive control. The IC50 values showed that the compounds,
1j 11k and 11l were most effective against the MCF-7 cells at
1
,
lower concentrations when compared to the MDA-MB-231
cells (Table 1).
The most potent compound was 11j which had a measured
C
D
IC value of 1.56 µM in MCF-7 cells, whereas a concentration
5
0
of 48 µM was required to inhibit 50% growth against MDA-
MB-231 cells. Compounds 11j and 11l demonstrated a similar
trend, having several-fold lower effective concentrations in
ER+ cells than in ER-cells. From these observations, it may be
explicated that these compounds primarily target ER and its
pathways to induce cell inhibition. Structure-activity
relationship (SAR) studies of the synthesized conjugates
revealed the dependence of activity on the nature of a
substituent present at C-5/C-7 position of the isatin ring while
the activity seems to be independent on the length of the alkyl
The natural product is a source of novel drug which has a
measured activity of 3.2μM against MCF-7, the molecular
construct is simple. When docked in the LBD of ERα, four
major ligand-receptor interactions are observed. These
include: three hydrophobic interactions and a hydrogen bond.
The hydrophobic interactions were measured between Leu79,
Leu86 and Leu220 with the cluster of phenyl rings of the
tamoxifen scaffold at a bond distance of 3.80, 3.95 and 3.91 Å,
respectively. A distinct hydrogen bond exists between the
proton acceptor Leu41 and oxygen of the ligand (bond
distance = 1.91 Å and bond angle = 133.13˚). Ospemifene and
tamoxifen are prominent ER inhibitors which share similar
cytotoxic activities. The binding profile of ospemifene
chain introduced as a spacer. Evidently, the conjugates 11j
,
11k and 11l having a bromo- substituent at the C-5 and C-7
position of isatin ring proved to be the most potent among the
series exhibiting IC50 values of 1.56, 16.54 and 10.99 µM,
respectively against the MCF-7 cell-line. The anti-proliferative
activities of ospemifene-spiroisatin (12a-12f) compared to the
ospemifene-isatin conjugates did not result in any substantial
improvement, except for 12f, which was found to be cytotoxic
against the non-estrogen dependent breast cancer cell-line i.e.
MDA-MB-231 (ER-) cell-line, at lower concentrations (IC50
=
38.35 µM) compared to MCF-7 (IC >100 µM).
50
comprises
a significant contribution from hydrophobic
interactions Leu41, Ala45, Trp78, Leu82 and Leu220 (bond
distance = 3.93, 3.23, 3.70, 3.64 and 3.53, respectively); and a
hydrogen bond between the hydrogen bond donor Asp46 and
ligand (bond distance = 1.91 Å, bond angle = 133.13).
Tamoxifen has a more complex binding landscape. Inhibition
is dependent on the presence of hydrophobic interactions:
Leu41, Ala45, Trp78, Leu79, Leu82, Phe99, Leu123 and Leu220
Molecular Docking Studies:
The class of compounds investigated in this study has
demonstrated good inhibitory activity against the MCF-7 cell-
line when compared to the positive controls: ospemifene,
tamoxifen and plumbagin (Figure
compounds tested, compounds 11j
greatest pharmacological activity; with compounds 11a and
1e displaying potential as anti-breast cancer agents.
1
).
Among the 18
,
11k and 11l offered the
(bond distance = 3.86, 3.29, 3.80, 3.97, 3.68, 3.75, 3.72 and
1
3.78 Å, respectively); hydrogen bonds between the ligand and
Molecular docking was performed on the set of test
compounds to identify ligand-protein interactions that are
critical for the selective inhibition of ERα. Plumbagin is a
naphthoquinone plant metabolite which has potent anti-
proliferative and apoptotic activity.
the proton acceptor Glu48 and proton donor Arg89 (bond
distance = 1.61 and 2.09 Å, bond angle = 142.53˚ and 157.43˚,
respectively); water bridges from the protein donor residues
Thr42 and Leu86 (donor bond distance = 2.59 and 3.90 Å,
acceptor bond distance = 3.73 and 3.07 Å, donor angle =
1
02.70˚ and 101.85˚, water angle = 85.54˚ and 83.93˚,
respectively); and a salt bridge between the negatively
charged Asp46 and the tertamine ligand group at a distance of
4.20Å.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 4 of 12
View Article Online
DOI: 10.1039/C7NJ04964A
COMMUNICATION
Journal Name
Table 1: IC50 values of tested compounds against MCF-7 and MDA-MB-231 cell lines with their percentage yield
Code
Structure
%
MCF-7
µM
MDA-MB-231
µM
Yield
(
)
(
)
O
N
O
O
O
N
N
N
1
1a
1b
80
75
53.10
>100
>100
>100
Cl
O
O
N
O
N
N
O
1
N
Cl
O
O
O
N
N
N
O
1
1c
N
74
>100
>100
Cl
O
O
N
O
N
N
O
1
1d
N
69
76
81
73
>100
70.71
>100
>100
>100
>100
>100
>100
Cl
O
O
O
N
N
N
O
N
1
1e
Cl
H3C
O
O
O
N
N
N
O
N
1
1f
Cl
Cl
O
O
N
O
N
O
1
1g
1h
N
N
Cl
Cl
O
O
N
O
N
O
1
Cl
N
N
69
71
80
>100
>100
1.56
>100
71.40
48.46
Cl
O
O
N
O
N
O
1
1i
1j
N
N
F
Cl
O
O
N
O
N
O
1
N
N
Br
Br
Cl
O
O
O
N
N
N
O
N
11k
76
16.54
>100
Br
Br
Cl
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 12
Pl Ne ae swe Jd oo u nr no at l aod fj Cu sh te mm ai sr tgr iyn s
View Article Online
DOI: 10.1039/C7NJ04964A
Journal Name
COMMUNICATION
O
O
N
O
N
N
O
1
1l
N
68
72
76
71
10.99
>100
>100
>100
>71.40
Br
Br
Cl
O
O
O
N
N
N
O
O
N
12a
>100
>100
>100
Cl
O
O
O
N
O
N
N
N
O
12b
Cl
O
O
O
N
O
O
N
1
2c
N
N
Cl
Cl
O
O
O
N
O
12d
O
69
>100
>100
N
N
N
Cl
Cl
O
O
O
N
O
N
O
70
73
>100
>100
>100
38.35
1
2e
N
N
Cl
Cl
O
O
O
O
N
N
N
N
1
2f
O
Cl
F
Ospemifene
Tamoxifen
Plumbagin
55
50
>100
75
3.5
4.4
The complexes of 11j, 11k and 11l (
Figure 2) have reflected Figure 2: Ligand-protein interaction profile of the ERα complexes
high binding affinities during docking with a measured energy of most active compounds 11j, 11k and 11l
of -10.7, -10.5 and -10.3 kcal/mol (Table 2) (see supporting
information) The RMSD’s is estimated to be 0.00 in each
complex. This reflects the thermodynamic stability of the pose
and conformation of the ligand in the binding site. Critical
residue interactions that resonate between these three
inhibitors which attribute to their biological activity include:
hydrophobic interactions with amino acids Leu41, Leu44,
Ala45, Trp78, Leu82, Phe99, Leu220, Lys224, Leu231; a
hydrogen bond with proton donor Leu231; and a halogen bond
interaction between Met217 and the respective halogen in
each complex. The improved activity in the MCF-7 cell-line as
compared to the positive controls can be attributed to the
structural bulk introduced via the linker to the tamoxifen
scaffold. The bulkiness and length of the linker may allow for
complete occupation of the active site, thus, implicitly blocking
11j
11k
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 6 of 12
View Article Online
DOI: 10.1039/C7NJ04964A
COMMUNICATION
Journal Name
ERα active site. Molecular docking also provided valuable
insight toward the essential binding residues pertinent to the
inhibitory effect.
Structural derivatization of these compounds may lead to the
development of selective inhibitors against ER+ and ER- cell
lines and may be useful in treating BC patients. An in-depth
investigation to understand the molecular mechanisms of
action of the active compounds (11j, 11k and 11l) is warranted.
Future studies may focus on deciphering the compound-ER
interactions in the cancer cells. Since drug resistance is a
significant problem in cancer cells, therefore, it would also be
useful to test these compounds against tamoxifen-resistant
cell line in future to examine if these compounds can inhibit
1
1l
the active site by ionic exchange between bromine (halogen growth of tamoxifen-resistant BC cells. Tamoxifen is the gold-
with highest activity against ERα) and methionine. This is standard long-term therapy given to BC patients to prevent
similar to the effect of the water and salt bridges highlighted recurrence of the disease but cancer cells become resistant to
with tamoxifen inhibition.
tamoxifen over time. Therefore, compounds that can kill
From Table 2, compounds 12d
,
12c
,
12b and 12f have scored tamoxifen-resistant cancer cells may well prove of immense
relatively high binding affinities towards ER, however, this is value for treatment and prevention of recurrence of BC
not reflected in their biological activity. This could be an effect
of a lack of bioavailability due to the presence of the 1,3- Experimental Section:
dioxolane moiety (Table 3) (see supporting information)that
General Note: Melting points were determined in capillaries and
highlights the flexibility and polarity features of the most
1
13
are uncorrected. H and C NMR were recorded on JEOL 400,
12b and 12f obtained from Bruker 500 and 125 MHz spectrometer respectively using CDCl as
active compounds 11j
,
11k and 11l as well as the least active
12d 12c
drug candidates 12e
0
,
,
,
3
3
LigandScout. The total polar surface area (TPSA) may lend solvent. Chemical shifts were reported in parts per million (ppm)
insight into the false positive binding profile of compounds using tetramethylsilane (TMS) as an internal standard and coupling
12e, 12d, 12c, 12b and 12f. The native substrates, oestrogen constants
J indicated in hertz. Spliting patterns were indicated as s:
and oestradiol are hydrophobic, coupled with the flexible singlet, d: doublet, t: triplet, m: multiplet dd: double doublet, ddd:
hydrophobic LBD of ERα facilitates binding of selective
inhibitors which possess significant hydrophobic functionality
doublet of a doublet of a doublet, and br: broad peak. Mass
spectrometric analysis was carried out on Bruker micrOTOF QII
equipment using ESI as the source. Column chromatography was
performed on a silica gel (60–120 mesh) using an ethyl acetate:
hexane mixture as eluent.
(Figure 7) (see supporting information). Due to the flexibility
of LBD, the binding pose of the false positive compounds
allows for interaction of the 1,3-dioxolane moiety with the
solvent, thus indicating greater solvent exposure of the
inhibitor as well as greater interaction with polar residues.
Compounds 11a and 11e, however, demonstrate promise as
potential anti-breast cancer agents through further
derivatization. Their inhibitory activities in the MCF-7 cell line
make these two candidates attractive targets for optimization.
Based on their molecular docking scores both ligands have a
high affinity for ERα. Perhaps the introduction of a greater
concentration or more ionic moiety on the indoline-2,3-dione
tail may induce higher anti-breast cancer potency.
General Procedure for synthesis of (Z)-2-(4-(4-chloro-1.2-
diphenylbut-1-en-1-yl)phenoxy)ethan-1-ol (3):
A solution of zinc (3.8 mmol) and TiCl
refluxed for 2 hours and brought to room temperature with
sequential addition of a mixture of compound (1mmol) and
1mmol) in dry THF. The reaction mixture was heated to reflux for 2
4
(2.5 mmol) in dry THF was
1
2
(
hours and the progress was monitored using TLC. On completion,
the reaction mixture was cooled to room temperature, charged
with toluene and quenched with 37% of HCl. The organic layer was
separated, washed twice with toluene and dried over anhydrous
Na SO . Evaporation of the solvent under reduced pressure gave
Conclusion:
2
4
A series of 1H-1,2,3-triazole-tethered ospemifene-isatin and
ospemifene-spiroisatin conjugates have been synthesized and
evaluated for their anti-proliferative activities against MCF-7
and MDA-MB-231 cell lines. The compounds having bromo-
substituent at C-5 and C-7 position proved to be active against
MCF-7 cell lines with the most potent compound being ~30
times more potent than Tamoxifen. Docking results revealed
that the most active compounds exhibit stronger binding
crude oil which was purified via column chromatography using ethyl
acetate: hexane (40:60) mixture to yield 2-(4-(4-chloro-1.2-
diphenylbut-1-en-1-yl)phenoxy)ethan-1-ol 3.
General Procedure for the synthesis of (Z)-(4-chloro-1-(4-(2-
prop2-yn-1-yloxy)ethoxy)phenyl)but-1-ene-1,2-diyl)dibenzene 4.
(
To the stirred suspension of NaH (1.2 mmol) in dry THF was added a
affinity with the ERα relative to the standard drugs attributed
to their greater structural bulk and more occupation of the
solution
of
(Z)-2-(4-(4-chloro-1.2-diphenylbut-1-en-1-
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 12
Pl Ne ae swe Jd oo u nr no at l aod fj Cu sh te mm ai sr tgr iyn s
View Article Online
DOI: 10.1039/C7NJ04964A
Journal Name
COMMUNICATION
0
+
yl)phenoxy)ethan-1-ol (1 mmol) (3) in dry THF at 0 C. The reaction 158.1, 183.1 HRMS Calcd for C H ClN O [M] 660.2503 and
3
9
37
4 4
+
was allowed to stir for 15 min. followed by dropwise addition of [M+2] 662.2474, found 660.2517 and 662.2463.
propargyl bromide (1.2 mmol). Reaction mixture was stirred for 6-7
0
(
Z)-1-(5-(4-((2-(4(4-choro-1,2-diphenylbut-1-en-
h at 60 C, with progress monitored via TLC. After usual work up
1
2
yl)phenoxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)pentyl)indoline-
with ethyl acetate and water, organic layers were combined, dried
0
1
,3-dione (11c): Yield 74 %; dark red solid; mp 97-98 C; H NMR
) δ 1.66-1.73 (m, 4H, 2x-CH -); 1.92-2.00 (m, 2H, -
=7.5 Hz, 2H, -CH ); 3.39 (t, =7.4 Hz, 2H, -CH -); 3.73
=7.0 Hz, 2H, -N-CH -); 3.79 (t, =4.8 Hz, 2H, -O-CH -);3.97 (t,
=4.4 Hz, 2H, -CH -O-); 4.39 (t, =6.8 Hz, 2H, -CH -N-); 4.67 (s, 2H, -O-
-N-triazole); 6.53 (d, =8.8 Hz, 2H, Ar-H); 6.76 (d, =8.8 Hz, 2H,
Ar-H); 6.83-6.89 (m,2H, Ar-H ); 6.97-6.99 (m,1H, Ar-H ); 7.08-7.13
over anhydrous Na
yield crude oil which was purified by column chromatography over
0-120 silica gel using ethyl acetate: hexane (40:60) mixture.
2 4
SO and evaporated under reduced pressure to
(
400 MHz, CDCl
3
2
CH
2
-); 2.89 (t,
J
2
-
J
2
6
(
t,
J
2
J
2
General Procedure for the synthesis of conjugates 11a-11l or 12a-
2f:
J
2
J
2
1
CH
2
J
J
To the stirred solution of (Z)-(4-chloro-1-(4-(2-(prop2-yn-1-
yloxy)ethoxy)phenyl)but-1-ene-1,2-diyl)dibenzene (1 mmol) and
-alkylazido-isatin (1 mmol) or -alkylazidospiro-isatin 10 (1
mmol) in ethanol: water (85:15) mixture, was added CuSO .5H
0.055 mmol) and sodium ascorbate (0.143 mmol). The reaction
(
m, 4H,Ar-H); 7.15-7.20 (m, 3H,Ar-H); 7.26-7.28 (m, 2H,Ar-H); 7.33-
1
3
4
7
3
.36 (m, 2H ,Ar-H); 7.52 (s, 1H, triazole-H ) C NMR (125 MHz,CDCl )
N
7
N
δ 24.1, 27.4, 29.0, 38.6, 39.2, 42.9, 49.3, 64.8, 67.0, 69.0, 110.1,
4
2
O
1
1
1
13.5, 114.4, 117.6, 124.0, 125.7, 126.6, 127.0, 128.3, 128.4, 129.4,
29.6, 130.6, 131.7, 135.1, 135.3, 138.6, 141.0, 141.7, 142.9, 150.5,
(
+
mixture was allowed to stir at room temperature for 7-8 h, with
progress monitored via TLC. On completion, the reaction mixture
was extracted with ethyl acetate and water and the combined
56.9, 158.4, 183.2 HRMS Calcd for C H ClN O [M] 674.2660 and
4
0
39
4 4
[
M+2] 676.2630, found 674.2649 and 676.2641.
2 4
organic layers were dried over anhydrous Na SO and concentrated
(Z)-1-(8-(4-((2-(4-choro-1,2-diphenylbut-1-en-
under vacuum to afford the desired conjugate which was purified 1yl)phenoxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)octyl)indoline-
1
via column chromatography using ethyl acetate: hexane (60:40) 2,3-dione (11d): Yield 69 %; dark red viscous liquid; H NMR (400
mixture.
MHz, CDCl
3
) δ 0.81-0.87 (m, 4H, 2x-CH
; 1.83-1.88 (m, 4H, 2x-CH2-); 2.89 (t,
=7.4 Hz, 2H, -CH -); 3.68 (t, =7.2 Hz, 2H, -N-CH
H, -O-CH -);3.97 (t, =5.0Hz, 2H, -CH -O-); 4.28 (t,
CH2-N-); 4.68 (s, 2H, -O-CH2-N-triazole); 6.53 (d, =8.7 Hz, 2H, Ar-H);
6.75 (d, =8.7 Hz, 2H, Ar-H); 6.85-6.90 (m,2H, Ar-H ); 6.97-6.99
m,1H, Ar-H ); 7.08-7.12 (m, 4H,Ar-H); 7.15-7.20 (m, 3H, Ar-H); 7.26-
.28 (m, 2H,Ar-H); 7.32-7.36 (m, 2H ,Ar-H); 7.50 (s, 1H, triazole-H )
2
-); 1.62-1.67 (m, 4H, 2x-CH
=7.4 Hz, 2H, -CH2-); 3.39 (t,
-); 3.79 (t, =4.8 Hz,
=7.2 Hz, 2H, -
2
-
)
J
(
Z)-1-(2-(4-((2-(4-chloro-1,
2-diphenylbut-1-en-1-
J
2
J
2
J
yl)phenoxy)ethoxy)methyl)-1H-1-yl)ethyl)indoline-2,3-dione (11a):
2
2
J
2
J
0
1
3
Yield 72 %; light red solid; mp 79-80 C; H NMR (500 MHz, CDCl ) δ
J
2
.13 (t,
.61 (t,
J=7.4 Hz, 2H, -CH2-CH ); 2.89 (t, J=7.5 Hz, 2H, -CH2-CH2-),
2
J
3
J
=4.6 Hz, 2H,-N-CH
-), 4.61 (t,
-N-triazole); 6.53 (d, =8.8 Hz, 2H, Ar-H); 6.78 (d,
Ar-H); 6.84-6.89 (m, 2H, Ar-H ), 6.99-7.02 (m, 1H,Ar-H); 7.13-7.16
2
-), 4.12 (t,
J
=4.2 Hz, 2H, -O-CH
-N-); 4.71 (s, 2H,-O-
=8.8 Hz, 2H,
2
-); 4.54 (t,
(
J=6.5 Hz, 2H, O-CH
2
J
=6.4 Hz 2H, -CH
2
7
1
3
CH
2
J
J
3
C NMR (100 MHz, CDCl )δ 26.3, 26.7, 27.2, 28.9, 29.7, 30.2, 38.6,
4
0.1 42.9, 50.3, 64.8, 67.0, 68.9, 110.3, 113.5, 114.4, 117.6, 123.7,
25.5, 126.7, 126.7, 127.0,128.2, 128.4, 129.4, 129.6, 131.7, 135.3,
38.4, 141.0, 141.7, 142.9, 145.0, 151.0, 156.9, 158.2, 183.7 HRMS
(m, 3H,Ar-H); 7.19-7.24 (m, 4H,Ar-H); 7.31-7.33 (m, 2H, Ar-H); 7.38-
1
1
3
7.40 (m, 2H, Ar-H); 7.61 (s, 1H, triazole-H ) C NMR (125 MHz,
1
+
+
CDCl
3
) δ 36.6, 41.8, 42.8, 47.2, 64.3, 67.5, 68.2, 103.6, 112.6, 114.7,
4 4
Calcd for C43H45ClN O [M] 716.3119 and [M+2] 718.3100, found
1
1
1
6
15.7, 117.5, 121.6, 122.8, 126.4, 126.8, 127.1, 127.6, 127.9, 128.2,
7
16.3134 and 718.3116.
28.9, 129.5, 130.1, 131.2, 139.9, 141.9, 146.0, 148.2, 156.1, 158.1,
+
+
82.8 HRMS Calcd for C H ClN O [M] 632.2190 and [M+2]
(Z)-1-(3-(4-((2-(4-(4-choro-1,2-diphenylbut-1-en-
1yl)phenoxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)propyl)indoline-
37
33
4 4
34.2161, found 632.2175 and 634.2199.
0
1
2
,3-dione (11e): Yield 76 %; orange solid; mp 87-88 C; H NMR (500
(Z)-1-(4-(4-((2-(4-(4-choro-1,2-diphenylbut-1-en-
MHz, CDCl ) δ 2.33 (s, 3H, -CH ); 2.35-2.40 (m, 2H, -CH2-), 2.93 (t,
3
3
1
2
yl)phenoxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)butyl)indoline-
J
-
)
=7.4 Hz, 2H, -CH
2
-
), 3.42 (t,
J
=7.5 Hz, 2H, -CH
2
-), 3.78 (t,
J
=7 Hz, 2H,
0
1
,3-dione (11b):Yield 75 %; light orange solid; mp 79-80 C; H NMR
) δ 1.87-1.92 (m, 2H, -CH -); 2.31 (m, 2H, -CH -),
=7.5 Hz, 2H, -CH2-); 3.37 (t, =7.4 Hz, 2H, -CH2-); 3.79 (t,
-); 3.89 (t, =3.6 Hz, 2H, -O-CH -);3.97 (t, =4.8
-O-); 4.291(t, =6.4 Hz, 2H, -CH -N-); 4.69 (s, 2H, -O-CH
N-triazole); 6.53 (d, =8.8 Hz, 2H, Ar-H); 6.78 (d, =8.8 Hz, 2H, Ar-
H); 6.87-6.90 (m,2H, Ar-H ); 6.99-7.01 (m, 1H, Ar-H) 7.10-7.13 (m,
H,Ar-H); 7.15-7.19 (m, 4H,Ar-H); 7.26-7.29 (m, 2H,Ar-H); 7.29-7.31
N-CH
; 4.40 (t,
=8.8 Hz, 2H, Ar-H); 6.79 (d,
m, 1H, Ar-H); 7.01-7.02 (m,1H, Ar-H ), 7.14-7.15 (m, 3H,Ar-H); 7.19-
2
-), 3.84 (t,
J
=4.8 Hz, 2H,-O-CH
2
-); 4.02 (t,
J=4.4 Hz, 2H, -CH
2
-O-
(500 MHz, CDCl
3
2
2
J=6.4 Hz, 2H, -CH2-N-); 4.72 (s, 2H, -O-CH2-N-triazole);
2.87 (t,
J
J
6.57(d,
J
J=8.7 Hz, 2H, Ar-H); 6.88-6.93
J=6.6 Hz, 2H, -N-CH
2
J
2
J
(
Hz, 2H, -CH
2
J
2
2
-
7
7
3
1
.23 (m, 3H,Ar-H); 7.30-7.31 (m, 2H,Ar-H); 7.38-7.43 (m, 3H,Ar-H);
1
3
J
J
3
.70 (s, 1H, triazole-H) C NMR (125 MHz, CDCl ) δ 26.6, 27.7, 37.4,
8.5, 42.8, 47.5, 64.7, 67.0, 68.9, 109.9, 113.5, 114.3, 117.6, 123.5,
26.0, 126.5, 126.9, 127.4, 128.2, 128.3, 129.3, 129.5, 131.6, 134.0,
3
1
3
(m, 2H ,Ar-H); 7.53 (s, 1H, triazole-H ) C NMR (500 MHz, DMSO-d )
6
135.2, 138.9, 140.9, 141.6, 142.8, 148.0, 156.8, 158.6, 183.1 HRMS
+
+
δ 28.4, 29.3, 37.6, 38.3, 43.9, 47.8, 64.7, 67.1, 69.1, 111.5, 112.4,
Calcd for C39
H37ClN
4
O
4
[M] 660.2503 and [M+2] 662.2474, found
1
15.3, 117.6, 124.1, 124.9, 126.3, 126.9, 128.1, 128.3, 129.1, 129.5,
30.2, 131.5, 134.5, 135.2, 137.6, 141.2, 141.9, 142.3, 149.5, 156.3,
6
60.2519 and 662.2485.
1
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 8 of 12
View Article Online
DOI: 10.1039/C7NJ04964A
COMMUNICATION
Journal Name
(
Z)-5-chloro-1-(3-(4-((2-(4-(4-chloro-1,2-diphenylbut-1-en-1-
2H, -CH2-), 2.89 (t,
3.72 (t, =7 Hz, 2H, -N-CH
=3.8 Hz, 2H, -CH -O-); 4.39 (t,
=7.5 Hz, 2H, -CH2-); CH2-N-triazole); 6.53 (d, =8.6 Hz, 2H, Ar-H); 6.76 (d,
-); 3.81 (t, H); 6.82-6.85 (m, 1H, Ar-H); 6.97-6.99 (m,1H, Ar-H ), 7.10-7.13 (m,
J
=7.4 Hz, 2H, -CH2-), 3.39 (t,
-), 3.79 (t, =4.7 Hz, 2H, -O-CH
=6.7 Hz, 2H, -CH -N-); 4.67 (s, 2H, -O-
=8.6 Hz 2H, Ar-
J
=7.4 Hz, 2H, -CH2-),
yl)phenoxy)ethoxy)methyl)-1
H
-1,2,3-triazol-1-yl)propyl)indoline-
J
2
J
2
-); 3.97 (t,
0
1
2
,3-dione (11f) : Yield 64 %; orange solid; mp 91-93 C; H NMR (400
J
2
J
2
MHz, CDCl ) δ 2.32-2.39 (m, 2H, -CH2-), 2.89 (t,
J
J
J
3
3
.39 (t,
=5.1 Hz, 2H, -O-CH
Hz, 2H, -CH2-N-); 4.68 (s, 2H, -O-CH2-N-); 6.53 (d,
H); 6.76 (d, =8.8 Hz, 2H, Ar-H); 6.84-6.90 (m,2H, Ar-H ); 6.97-6.99 24.0, 27.4, 29.7, 38.6, 39.3, 42.9, 49.2, 64.8, 67.0, 69.0, 111.4,
m,1H, Ar-H ); 7.10-7.13 (m, 3H,Ar-H); 7.15-7.20 (m, 3H,Ar-H); 7.26- 112.9, 113.5, 114.4, 122.6, 125.0, 126.6, 127.0, 127.5, 128.3, 128.4,
J
=7.3 Hz, 2H, -CH
2
-); 3.77 (t,
J
=6.6 Hz, 2H, -N-CH
2
J
2
-);3.99 (t,
J=4.2 Hz, 2H, -CH
2
-O-); 4.37 (t, J=6.3 3H,Ar-H); 7.15-7.20 (m, 4H,Ar-H); 7.27-7.28 (m, 2H,Ar-H); 7.33-7.36
1
3
J
=8.8 Hz, 2H, Ar- (m, 2H,Ar-H); 7.51 (s, 1H, triazole-H) C NMR (125 MHz, CDCl ) δ
3
J
(
7
.28 (m, 2H,Ar-H); 7.33-7.37 (m, 2H ,Ar-H); 7.55 (s, 1H, triazole-H 129.4, 129.6, 130.5, 131.7, 135.3, 141.0, 141.7, 142.9, 145.4, 146.5,
1
3
+
)
3 4 4
C NMR (100 MHz, CDCl ) δ 27.5, 37.7, 38.6, 42.9, 47.5, 64.7, 67.0, 156.9, 158.2, 182.7 HRMS Calcd for C39H36ClFN O [M] 678.2409
+
6
1
1
6
9.1, 111.6, 113.5, 114.4, 118.5, 125.6, 126.6, 127.0, 127.5, 128.3, and [M+2] 680.2380, found 678.2416 and 680.2393.
28.4, 129.4, 129.6, 130.1,130.5, 131.7, 135.3, 138.1, 140.9, 141.1,
+
(
Z)-5,7-dibromo-1-(2-(4-((2-(4-(4-chloro-1,2-diphenylbut-1-en-1-
2 4 4
42.9, 148.5, 156.9, 158.0, 182.0 HRMS Calcd for C38H34Cl N O [M]
+
yl)phenoxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)ethyl)indoline-
80.1957 and [M+2] 682.1928, found 680.1943 and 682.1937.
0
1
2
,3-dione (11j) :Yield 70 %; dark red solid; mp 84-85 C; H NMR (500
MHz, CDCl ) δ 2.93 (t, =7.4 Hz, 2H, -CH ), 3.43 (t, =7.6 Hz, 2H,-CH
), 3.78 (t, =4.6 Hz, 2H, -N-CH2-), 4.00 (t, =4.2 Hz, 2H, -O-CH2-); 4.64-
yl)butyl)indoline-2,3-dione (11g): Yield 73 %; orange solid; mp81- 4.66 (m, 2H, -CH ); 4.69-4.74 (m, 4H, 2x-CH ); 6.57 (d, =8.6 Hz, 2H,
=7.5 Hz, 2H, Ar-H); 6.89-6.94 (m,1H, Ar-H ), 7.01-
=7.4 7.03 (m, 1H,Ar-H); 7.14-7.16 (m, 3H,Ar-H); 7.19-7.24 (m, 3H,Ar-H);
=4.6 Hz, 2H, - 7.30-7.31 (m, 2H, Ar-H); 7.37-7.40 (m, 2H, Ar-H); 7.63 (s, 1H,
(Z)-5-chloro-1-(4-(4-((2-(4-(4-chloro-1,2-diphenylbut-1-
3
J
2
-
J
2
-
en-1-yl)phenoxy)ethoxy)methyl)-1 -1,2,3-triazol-1-
H
J
J
2
2
J
0
1
8
2 C; H NMR (500 MHz, CDCl
.36-2.41 (m, 2H, -CH2-), 2.99 (t,
-); 3.88 (t, =6.8 Hz, 2H, -N-CH
-);3.98 (t, =4.8 Hz, 2H, -CH -O-); 4.31 (t,
; 4.71 (s, 2H, -O-CH2-N-triazole); 6.59 (d,
d, =8.8 Hz, 2H, Ar-H); 6.82-6.89 (m,2H, Ar-H ); 6.99-7.01(m, 1H, 126.9, 127.4, 127.9, 128.2, 128.3, 129.3, 129.5, 130.5, 131.6, 140.9,
3
) δ 1.97-2.00 (m, 2H, -CH
2 2
-CH -); Ar-H); 6.80 (d, J
2
J=7.5 Hz, 2H, -CH2-); 3.31 (t,
J
Hz, 2H, -CH
2
J
2
-); 3.91 (t,
J
13
O-CH
2
J
2
2 3
J=6.4 Hz, 2H, -CH -N- triazole-H ) C NMR (125 MHz, CDCl ) δ 38.5, 41.0, 42.2, 48.8, 64.5,
)
(
J=8.8 Hz, 2H, Ar-H); 6.77 67.0, 68.7, 104.7, 113.5, 114.4, 116.1, 117.6, 121.5, 123.1, 126.5,
J
Ar-H); 7.09-7.12 (m, 3H,Ar-H); 7.16-7.19 (m, 3H,Ar-H); 7.25-7.29 (m, 142.8, 145.0, 149.5, 156.8, 157.9, 180.2 HRMS Calcd for
1
3
+
2
H,Ar-H); 7.31-7.33 (m, 2H ,Ar-H); 7.61 (s, 1H, triazole-H ) C NMR C H Br ClN O [M] 790.0380 and [M+2] 788.0401, found
37 31 2 4 4
3
(125 MHz, CDCl ) δ 27.6, 29.5, 36.5, 39.6, 43.8, 48.3, 64.6, 67.2, 790.0371 and 788.0417.
6
1
1
6
9.3, 110.8, 112.5, 114.5, 118.6, 124.5, 127.1, 127.8, 127.5, 128.2,
(
Z)-5,7-dibromo-1-(3-(4-((2-(4-(4-chloro-1,2-diphenylbut-
-en-1-yl)phenoxy)ethoxy)methyl)-1H-1,2,3-triazol-1-
yl)propyl)indoline-2,3-dione (11k): Yield 76 %; dark red solid;
28.5, 129.1, 129.5, 130.0,131.3, 131.5, 135.4, 137.2, 139.9, 141.3,
+
1
2 4 4
43.2, 147.5, 156.8, 157.9, 183.3HRMS Calcd for C39H36Cl N O [M]
+
94.2114 and [M+2] 696.2084, found 694.2123 and 696.2071.
0
1
mp82-83 C; H NMR (500 MHz, CDCl
2.89 (t, =7.5 Hz, 2H, -CH ), 3.47 (t,
=4.4 Hz, 2H, -N-CH -), 4.14 (t, =4.2 Hz, 2H, -O-CH
yl)octyl)indoline-2,3-dione (11h) : Yield 69 %; red coloured viscous Hz 2H,-CH -O-); 4.71-4.76 (m, 4H, 2x-CH -); 6.54 (d,
-); 1.71- H); 6.79 (d, =8.8 Hz, 2H, Ar-H); 6.81-6.85 (m,1H, Ar-H ), 6.95-6.98
=7.4 Hz, (m, 1H,Ar-H); 7.12-7.15 (m, 3H,Ar-H); 7.17-7.22 (m, 3H,Ar-H); 7.29-
=7.0 Hz, 2H, -N-CH 7.31 (m, 2H, Ar-H); 7.38-7.41 (m, 2H, Ar-H); 7.61 (s, 1H, triazole-H )
=4.6 Hz, 2H, -CH -O-); 4.32
=7.2 Hz, 2H, -CH2-N-); 4.68 (s, 2H, -O-CH2-N-triazole); 6.53 (d, 68.3, 103.5, 111.6, 113.4, 115.9, 117.3, 121.8, 123.1, 126.1, 126.3,
=8.8 Hz, 2H, Ar-H); 6.75 (d, =8.7 Hz, 2H, Ar-H); 6.85-6.90 (m,1H, 127.2, 127.6, 127.9, 128.1, 129.1, 129.4, 131.5, 133.7, 141.1, 142.2,
Ar-H ); 6.96-6.99 (m,1H, Ar-H ); 7.06-7.12 (m, 3H,Ar-H); 7.15-7.20 145.1, 148.2, 156.2, 157.3, 181.3 HRMS Calcd for C38 ClN
m, 4H,Ar-H); 7.26-7.28 (m, 2H,Ar-H); 7.32-7.36 (m, 2H ,Ar-H); 7.50 [M] 804.0537 and [M+2] 806.0516, found 804.0524 and 806.0534.
3
) δ 1.94-1.98 (m, 2H, -CH
=7.5 Hz, 2H, -CH -), 3.83 (t,
-); 4.69 (t, =6.4
=8.8 Hz, 2H, Ar-
2
-);
(Z)-5-chloro-1-(8-(4-((2-(4-(4-chloro-1,2-diphenylbut-1-
J
2
-
J
2
en-1-yl)phenoxy)ethoxy)methyl)-1H-1,2,3-triazol-1-
J
2
J
2
J
2
2
J
1
liquid; HNMR (500 MHz, CDCl
3
) δ 0.86-0.90 (m, 4H, 2x-CH
.75 (m, 4H, 2x-CH2-); 1.91-1.94 (m, 4H, 2x-CH2-); 2.87 (t,
H, -CH ); 3.31 (t, =7.5 Hz, 2H, -CH -); 3.61 (t,
=4.4 Hz, 2H, -O-CH -);3.91 (t,
2
J
1
2
J
2
-
J
2
J
2
-
1
3
); 3.76 (t,
t,
J
2
J
2
3
C NMR (125 MHz, CDCl ) δ 31.3, 37.2, 41.3, 42.1, 47.9, 64.3, 67.1,
(
J
J
J
H
33Br
2
4 4
O
+
+
(
(
13
s, 1H, triazole-H ) C NMR (125 MHz, CDCl
3
) δ 24.4, 26.2, 26.8,
(
Z)-5,7-dibromo-1-(4-(4-((2-(4-(4-chloro-1,2-diphenylbut-
-en-1-yl)phenoxy)ethoxy)methyl)-1H-1,2,3-triazol-1-
yl)butyl)indoline-2,3-dione (11l): Yield 68 %; dark red solid; mp 85-
2
1
1
1
7.6, 28.4, 29.1, 37.4, 38.9, 40.1, 48.9, 64.1, 67.3, 69.0, 111.2,
1
12.4, 114.3, 118.7, 122. 4, 123.6, 124.5, 125.9, 126.2, 127.4, 128.3,
28.4, 129.3, 129.5, 130.2, 134.3, 137.4, 140.9, 141.3, 143.8, 149.9,
0
1
+
8
6 C; H NMR (500 MHz, CDCl
m, 2H, -CH -); 2.93 (t, =7.4 Hz, 2H,-CH
, 3.83(t, =4.4Hz, 2H, -N-CH2-), 4.01(t,
=7.2Hz, 2H, -O-CH -); 4.42 (t, =6.9Hz, 2H, -CH
-N-triazole); 6.57 (d, =8.7 Hz, 2H, Ar-H); 6.80 (d,
fluoroindoline-2,3-dione (11i) : Yield 71 %; red solid; mp87-88 C; H Ar-H); 6.89-6.93 (m,1H, Ar-H ), 7.01-7.03 (m, 1H,Ar-H); 7.14-7.16 (m,
3
) δ 1.75-1.82 (m, 2H, CH
), 3.43(t, =7.5 Hz, 2H, -CH
=5.1 Hz, 2H, -N-CH2) 4.16(t,
-O-Ph); 4.71 (s, 2H, -
=8.7Hz, 2H,
2
-); 1.97-2.01
56.3, 158.4, 183.5 HRMS Calcd for C43
H44Cl
2
N
4
O
4
[M] 750.2740
+
(
)
J
2
J
2
-
J
2
-
and [M+2] 752.2710, found 750.2759 and 752.2721.
J
J
(Z)-1-(4-(4-((2-(4-(4-chloro-1,2-diphenylbut-1-en-1-
2
J
2
yl)phenoxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)butyl)-5-
O-CH
2
J
J
0
1
NMR (400 MHz, CDCl
3
) δ 1.64-1.72 (m, 4H, 2x-CH
2
-); 1.92-1.99 (m, 3H,Ar-H); 7.19-7.24 (m, 3H,Ar-H); 7.29-7.32 (m, 2H, Ar-H); 7.37-7.40
8
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 9 of 12
Pl Ne ae swe Jd oo u nr no at l aod fj Cu sh te mm ai sr tgr iyn s
View Article Online
DOI: 10.1039/C7NJ04964A
Journal Name
COMMUNICATION
1
3
13
(
m, 2H, Ar-H); 7.56 (s, 1H, triazole-H ) C NMR (125 MHz, CDCl ) δ 1H, triazole-H ) C NMR (125 MHz, CDCl ) δ 29.7, 36.9, 38.5, 42.8,
3
3
2
1
1
1
6.6, 29.7,38.6, 40.6, 42.9, 49.5, 64.8, 67.0, 68.9, 104.7, 113.5, 47.4, 64.6, 66.0, 67.0, 68.8, 101.7, 109.9, 113.5, 114.3, 123.5, 125.7,
14.4, 117.2, 121.3, 126.6, 127.0, 127.7, 128.3, 128.4,129.4, 129.6, 126.5, 126.9, 127.4, 128.2, 128.3, 129.1, 129.3, 129.5, 130.5, 131.6,
30.6, 131.7, 135.1, 135.3, 140.9, 141.7, 142.9, 145.2, 146.4, 156.9, 135.0, 135.2, 140.9, 141.8, 142.8, 144.9, 156.8, 173.4 HRMS Calcd
+
+
+
58.1, 181.3 HRMS Calcd for C39
H
35Br
2
ClN
4
O
4
[M] 818.0693 and for C41
2 4 5
H40Cl N O [M] 738.2376 and [M+2] 740.2346, found
+
[M+2] 820.0673, found 818.0679 and 820.0689.
738.2363 and 740.2355.
(
Z)-1-(5-(4-((2-(4-(4-chloro-1,2-diphenylbut-1-en-1-
yl)phenoxy)ethoxy)methyl-1H-1,2,3-trazol-1-
yl)pentyl)spiro[indoline-3,2’-[1,3]dioxolan]-2-one (12a): Yield 72 yl)hexyl)spiro[indoline-3,2’-[1,3]dioxolan]-2-one (12d): Yield 69 %;
(Z)-5-chloro-1-(6-(4-((2-(4-(4-chloro-1,2-diphenylbut-1-
en-1-yl)phenoxy)ethoxy)methyl-1 -1,2,3-trazol-1-
H
0
1
1
%
; off white solid; mp 93-94 C; H NMR (500 MHz, CDCl
.91 (m, 4H, 2x-CH -); 1.86-1.90 (m, 2H, -CH -); 2.26-2.33 (m, 2H, - 4H, 2x-CH
=7.4 Hz, 2H, -CH ); 3.43(t, =7.5 Hz, 2H, -CH -); 3.72(t, CH ); 3.43(t,
-); 3.83(t, =4.5Hz, 2H, -O-CH -); 4.01(t, =5.0Hz, 3.83(t, =4.4 Hz, 2H, -O-CH
H, -CH2-O-); 4.31-4.36(m, 4H, 2x-CH2); 4.72 (s, 2H, -O-CH2-N- 4.33 (m, 6H, 3x-CH2-); 4.57(t, J=7.0 Hz, 2H, -CH2-N-); 4.71(s, 2H, -O-
=8.7 Hz, 2H, Ar-H); 6.79 (d, =8.7 Hz, 2H, Ar-H); CH -N-triazole); 6.57 (d, =8.7 Hz, 2H, Ar-H); 6.78 (d, =8.7 Hz, 2H,
.89-6.93 (m,2H, Ar-H ); 7.01-7.03 (m,1H, Ar-H ); 7.11-7.16 (m, Ar-H); 6.89-6.93 (m,1H, Ar-H ); 7.01-7.03 (m,1H, Ar-H ); 7.14-7.16
H,Ar-H); 7.19-7.23 (m, 3H,Ar-H); 7.29-7.32 (m, 2H, Ar-H); 7.37-7.40 (m, 3H,Ar-H); 7.19-7.24 (m, 3H,Ar-H); 7.29-7.32 (m, 2H,Ar-H); 7.37-
3
) δ 0.87-- off white viscous liquid; H NMR (500 MHz, CDCl
-); 2.26-2.33 (m, 2H, -CH ); 2.93(t, =7.4 Hz, 2H, -C=C-CH
=7.5 Hz, 2H, -CH -); 3.60(t, =7.1 Hz, 2H, -N-CH -);
-); 4.01(t, =5.0Hz, 2H, -CH -O-); 4.30-
3
) δ 1.86-1.90 (m,
0
2
2
2
2
J
2
-
CH
2
); 2.93 (t,
J
2
-
J
2
2
J
2
J
2
J
=7.4Hz, 2H, -N-CH
2
J
2
J
J
2
J
2
2
triazole); 6.57 (d,
J
J
2
J
J
6
4
1
3
13
(
m, 2H ,Ar-H); 7.53 (s, 1H, triazole-H ) C NMR (125 MHz, CDCl
3
) δ 7.40 (m, 2H ,Ar-H); 7.56 (s, 1H, triazole-H ) C NMR (125 MHz,
2
1
1
1
7
4.3, 28.2, 29.6, 37.3, 39.6, 43.9, 48.3, 64.8, 65.3, 67.1, 68.3, 102.1, CDCl ) δ 22.8, 26.9, 29.7, 32.0, 38.6, 39.5, 42.9, 50.2, 62.0, 64.8,
3
08.9, 113.1, 114.5, 117.2, 122.8, 123.9, 125.2, 126.1, 127.5, 127.9, 66.0, 67.0, 68.2, 109.9, 113.5, 114.4, 125.6, 125.8, 126.6, 127.0,
28.1, 128.8, 129.2, 129.7, 130.7, 131.2, 135.0, 135.2, 141.1, 141.5, 127.4, 128.3, 128.4, 128.7, 129.4, 129.6, 130.6, 131.5, 131.7, 135.1,
+
42.7 143.4, 156.6, 173.1 HRMS Calcd for C42
H
43ClN
4
O
5
[M]
135.3, 140.9, 141.7, 142.5 142.9, 156.9, 173.0 HRMS Calcd for
+
+
+
18.2922 and [M+2] 720.2892, found 718.2939 and 720.2873.
C H ClN O [M] 766.2289 and [M+2] 768.2659, found 766.2271
43 44 4 5
and 768.2643.
(
Z)-1-(8-(4-((2-(4-(4-chloro-1,2-diphenylbut-1-en-1-
yl)phenoxy)ethoxy)methyl-1H-1,2,3-trazol-1-
yl)octyl)spiro[indoline-3,2’-[1,3]dioxolan]-2-one (12b): Yield 71 %; en-1-yl)phenoxy)ethoxy)methyl-1
(Z)-5-chloro-1-(8-(4-((2-(4-(4-chloro-1,2-diphenylbut-1-
-1,2,3-trazol-1-
3
) δ 0.86-0.91 (m, yl)octyl)spiro[indoline-3,2’-[1,3]dioxolan]-2-one (12e): Yield 70 %;
H
1
Off white viscous liquid; H NMR (500 MHz, CDCl
1
4
H, 2x-CH
.93 (t, =7.4 Hz, 2H, -CH
-); 3.83 (t,
-O-); 4.29-4.34 (m, 6H, 3x-CH
; 4.72 (s, 2H, -O-CH -N-triazole); 6.57 (d,
d, =8.6 Hz, 2H, Ar-H); 6.89-6.93 (m,1H, Ar-H ); 7.02-7.03 (m,1H, triazole); 6.57 (d,
2
-); 1.64-1.66 (m, 4H, 2x-CH
; 3.43 (t, =7.5 Hz, 2H, -CH
=4.3Hz, 2H, -O-CH -); 4.01 (t,
); 4.59 (t, =6.4Hz, 2H,-CH
=8.7 Hz, 2H, Ar-H); 6.79 6H, 3x -CH
2
-); 1.86-1.89 (m, 2H,-CH
-); 3.61 (t, 6H, 3x-CH
=4.8Hz, 3.43(t, =7.6 Hz, 2H, -CH
-N- =4.4 Hz, 2H, -O-CH
2
-); off white viscous liquid; H NMR (500 MHz, CDCl
); 1.85-1.89 (m, 4H, -CH -); 2.93 (t, =7.4 Hz, 2H, -CH
-); 3.60(t, =7.2Hz, 2H, -N-CH -); 3.83(t,
=4.5 Hz, 2H, -CH -O-); 4.30-4.35 (m,
-); 4.72 (s, 2H, -O-CH -N-
=8.7 Hz, 2H, Ar-H); 6.74 (d, =8.5 Hz, 2H, Ar-H);
3
) δ 0.85-0.91 (m,
2
J
2
-
J
2
2
2
J
2
-);
J
=7.2Hz, 2H, -N-CH
2
J
2
J
J
2
J
2
2
H, -CH
2
2
J
2
J
2
-); 4.01(t,
J
2
)
(
2
J
2
); 4.56-4.60 (m, 2H, -CH
2
2
J
J
J
Ar-H ); 7.07-7.10 (m, 1H, Ar-H); 7.14-7.15 (m, 4H,Ar-H); 7.19-7.23 6.79 (d, J=8.7 Hz,1H, Ar-H ); 6.89-6.94(m, 1H, Ar-H); 7.02-7.03
(
m, 3H,Ar-H); 7.31-7.32 (m, 2H,Ar-H); 7.35-7.39 (m, 2H ,Ar-H); 7.53 (m,1H, Ar-H ); 7.17-7.23 (m, 3H,Ar-H); 7.29-7.33 (m, 3H,Ar-H); 7.35-
13
13
(s, 1H, triazole-H ) C NMR (125 MHz, CDCl ) δ 22.7, 26.3, 26.6, 7.40 (m, 2H,Ar-H); 7.53 (s, 1H, triazole-H ) C NMR (125 MHz, CDCl )
3
3
2
1
1
1
7
7.0, 29.7, 31.9,38.6, 39.7, 42.9, 50.2, 64.8, 66.0, 66.9 68.6, 68.9, δ 22.7, 26.3, 26.6, 27.0, 29.7, 30.2, 32.0, 38.6, 38.6, 39.8, 42.9, 64.9,
02.1, 108.9, 113.5, 114.3, 123. 1, 124.1, 124.9, 126.5, 126.9, 127.4, 65.4, 66.0, 67.0, 68.8, 113.5, 114.7, 117.8, 125.5, 126.6, 127.0,
28.2, 128.3, 129.3, 129.5, 130.5, 131.6, 135.0, 135.2, 140.9, 141.7, 127.5, 128.1, 128.3, 128.4, 129.4, 129.6, 130.6, 130.7, 131.5, 131.7,
+
42.8, 144.1, 156.9, 173.3 HRMS Calcd for C45
H
49ClN
4
O
5
[M]
135.1, 135.3, 137.5, 141.0, 141.7, 142.9, 156.7, 173.2 HRMS Calcd
+
+
+
60.3391 and [M+2] 762.3362, found 760.3379 and 762.3349.
4 5
for C45H48ClN O [M] 794.3002 and [M+2] 796.2972, found
7
94.3019 and 796.2959.
(
Z)-5-chloro-1-(3-(4-((2-(4-(4-chloro-1,2-diphenylbut-1-
en-1-yl)phenoxy)ethoxy)methyl-1 -1,2,3-trazol-1-
yl)propyl)spiro[indoline-3,2’-[1,3]dioxolan]-2-one (12c): Yield 70 %; yl)phenoxy)ethoxy)methyl-1
H
(Z)-1-(3-(4-((2-(4-(4-chloro-1,2-diphenylbut-1-en-1-
-1,2,3-trazol-1-yl)propyl)-5-
off white solid; mp76-77 C; H NMR (500 MHz, CDCl ) δ 2.29-2.33 fluorospiro[indoline-3,2’-[1,3]dioxolan]-2-one (12f): Yield 73 %off
H
0
1
3
0
1
(
m, 2H, -CH
CH -); 3.67 (t,
.01 (t, = 4.3 Hz, 2H, -CH2-O-); 4.33-4.37 (m, 4H, 2x-O-CH2-); 4.56 (t, 3.82 (t,
= 5.5 Hz, 2H, -CH -N-); 4.72 (s, 2H, -O-CH -N-triazole); 6.57 (d, =8.7 =4.4 Hz, 2H, -CH
Hz, 2H, Ar-H); 6.79 (d, =8.7 Hz, 2H, Ar-H); 6.89-6.94 (m,1H, Ar-H ); CH -N-triazole); 6.57 (d,
2
-); 2.93 (t,
J
=7.5 Hz, 2H,-CH
2
-
); 3.43 (t,
J
=7.5 Hz, 2H, - white solid, mp 91-92 C; H NMR (500 MHz, CDCl
-); 2H, -CH -); 2.81 (t, =7.3 Hz, 2H, -CH ); 3.46 (t, =7.4 Hz, 2H, -CH
=6.5 Hz, 2H, -N-CH2-); 3.87 (t, =4.5 Hz, 2H, -O-CH2-);4.11 (t,
-O-); 4.44-4.49 (m, 6H, 3x-CH ); 4.71 (s, 2H, -O-
=8.8 Hz, 2H, Ar-H); 6.79 (d, =8.7 Hz, 2H,
3
) δ 1.89-1.95 (m,
2
J
=6.8 Hz, 2H, -N-CH
2
-); 3.83 (t,
J
=4.8 Hz, 2H, -O-CH
2
2
J
2
-
J
2
-);
4
J
J
J
J
2
2
J
J
2
2
J
2
J
J
7
.01-7.03 (m,1H, Ar-H ); 7.14-7.16 (m, 3H,Ar-H); 7.19-7.23 (m, Ar-H); 6.83-6.87 (m,1H, Ar-H ); 6.99-7.02 (m,1H, Ar-H ); 7.11-7.15
H,Ar-H); 7.29-7.31 (m, 2H,Ar-H); 7.35-7.38 (m, 3H ,Ar-H); 7.72 (s, (m, 3H,Ar-H); 7.18-7.22 (m, 4H,Ar-H); 7.31-7.34 (m, 2H,Ar-H); 7.40-
3
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins

Please do not adjust margins
New Journal of Chemistry
Page 10 of 12
View Article Online
DOI: 10.1039/C7NJ04964A
COMMUNICATION
Journal Name
1
3
7
.43 (m, 2H ,Ar-H); 7.55 (s, 1H, triazole-H ) C NMR (125 MHz, dimensional (3D) structure of the test ligands. The 3D structures of
CDCl ) δ 28.2, 35.9, 38.8, 43.9, 48.3, 64.1, 65.7, 67.5, 68.9, 101.9, the ligands were further optimized using the force field, MMFF94s
3
1
1
1
10.3, 113.6, 115.1, 122.6, 124.2, 125.3, 126.4, 127.3, 1278, 128.1, in the Avogadro package (V 1.2.0). AutoDock Tools (V 1.5.6) was
28.8, 129.2, 129.9, 131.3, 133.3, 135.2, 135.4, 140.9, 141.5, 142.1 used to establish grid box parameters. All non-polar hydrogens
+
45.6, 156.7, 173.3 HRMS Calcd for C40
H
38ClFN
4
O
5
[M] 708.2515 were merged, Gasteiger partial atomic charges added, and
rotatable bonds assigned. The grid box of the receptor had a grid
spacing of 0.375 Å, the size of the box and grid points are given in
Table 4 (see supporting information). Autodock Vina was used to
+
and [M+2] 710.2485, found 708.2527 and 710.2467.
Material and Methods
3
4
The cytotoxicity of conjugates viz. 11a-l and 12a-f were tested on
two different breast cancer cell lines, namely; estrogen receptor
positive (ER+) MCF-7 cells and triple negative MDA-MB-231 (ER-)
using MTT (3-(4,5-Dimethylthiazol-z-yl)-2,5-diphenyltetrazolium
perform the docking of ligands into the receptors, in triplicate.
The docking systems were validated by docking the native ligand of
the protein crystal structure into the respective binding site. The
Protein-Ligand Interaction Profiler (PLIP) was used to analyse the
non-polar interactions between the protein and ligand in
3
1
bromide) assay.
3
5
complex.
Cell culturing
MCF-7 cells were cultured in complete Dulbecco’s media Eagle’s
medium (DMEM) media with 5% FBS and 1% penicillin-streptomycin
and MDA-MB-231 cells were cultured in 3:1 DMEM and Ham’s F12
with 10% FBS and 1% penicillin-streptomycin, both cell-lines were
incubated at 37°C and 5% carbon dioxide.
Conflicts of interest
The authors declare no conflict of interest
Acknowledgements:
Biological testing
The authors thank the Centre for High Computing Performance
Cells were seeded in 96-well plates at a density of 5000 cells per
well in triplicate in media as described above. After 24 hours, the
test compounds (dissolved in DMSO), were diluted in DMEM and
added to each well. Cells were treated with a range of different
concentrations of drug (1, 5, 10, 20, 50, 100µM) and incubated for
(
CHPC) based in Cape Town (South Africa) for access and use of
computational resources. Further thanks are made to the National
Research Foundation (NRF) South Africa for their financial support
toward our research efforts, (UID: 99563). Funds provided by
University of the Witwatersrand for biological activity are also
acknowledged.
24-hours. This was followed by 24-hour incubation. A further
incubation of 2 hours was performed with the addition of sterile 5
mg/mL, MTT (Sigma-Aldrich) dissolved in PBS to each well
containing cells and test compound. A solubilisation solution (10%
SDS, 10mM HCl) of equal volume to the wells was then added to
Abbreviations Used:
each well, and incubated with cells for 16 hours at 37 °C. The optical BC, Breast Cancer; ER, Estrogen Receptor; IC50, 50% Inhibitory
Concentration; DMEM,Dulbecco’s media Eagle’s medium; LBD,
Ligand binding domain; TPSA, total polar surface area; SERMs,
Selective Estrogen Receptor Modulators; SAR, Structure
Activity Relationship
density of each well was determined at a wavelength of 570 nm
TM
using a microtiter plate reader (Tecan Sunrise Microplate Reader,
Magellan software).
Statistical analysis
®
The statistical analyses were performed using Excel and IC50values
Notes and references
were estimated using Graphpad Prism5 software (Hearne Scientific
Software). The experiments were performed in duplicate and the
statistical significance was calculated using the student’s t-test. A p-
value of less than 0.05 was used to estimate the significance of the
observations. A Z-factor was calculated for each 96-well plate and
assays having Z-factors above 0.5 were included in the statistical
1
2
3
B. Su, S. Landini, D. D. Davis, W. R. Brueggemeier, J. Med.
Chem., 2007, 50, 1635.
C. Girish, P. Vijayalakshmi, R. Mentham, B. C. Rao, S. Nama,
Pharmaceutical Sci., 2014, 4, 47.
American Cancer Society. Cancer facts and figures 2017.
https://www.cancer.org/research/cancer-facts-statistics/all-
cancer-facts-figures/cancer-facts-figures-2017.html
3
2
analysis.
4
C. Davies, H. Pan, J. Godwin, R. Gray, R. Arriagada, V. Raina,
M. Abraham, V. H. M. Alencar, A. Badran, X. Bonfill, J.
Bradbury, M. Clarke, R. Collins, S. R. Davis, A. Delmestri, J. F.
Forbes, P. Haddad, M. F. Hou, M. Inbar, H. Khaled, J.
Kielanowska, W. H. Kwan, B. S. Mathew, I. Mittra, B. Müller,
A. Nicolucci, O. Peralta, F. Pernas, L. Petruzelka, T.
Pienkowski, R. Radhika, B. Rajan, M. T. Rubach, S. Tort, G.
Urrútia, M. Valentini, Y. Wang, R. Peto, ATLAS, a randomised
trial, 2013, 381, 805.
Molecular Docking
The x-ray crystal structure of the alpha-ER (PDB ID: 3ERT) was
obtained
http://www.rcsb.org/pdb/home/home.do).
Chimera package the ligand and receptor complex was prepared for
from
the
RCSB
Protein
Data
Bank
(
Using the UCSF
3
3
docking.
Chem3D Ultra was used to construct a three-
1
0 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 11 of 12
Pl Ne ae swe Jd oo u nr no at l aod fj Cu sh te mm ai sr tgr iyn s
View Article Online
DOI: 10.1039/C7NJ04964A
Journal Name
COMMUNICATION
5
W. Yue, J. P. Wang, Y. Li, W. P. Bocchinfuso, K. S. Korach, P.
D. Devanesan, E. Rogan, E. Cavalieri, R. J. Santen, Clin. Cancer
Res., 2005, 11, 925.
W. L. McGuire, Semin. Oncol., 1978, 5, 428.
W. R. Miller, J. Steroid Biochem. Mol. Biol., 1990, 37, 467.
V. C. Jordan, Pharmacol. Rev., 1984, 36, 245.
R. A. Magarian, L. B. Overacre, S. Singh, K. L. Meyer, Curr.
6
7
8
9
Med. Chem., 1994, 1, 61.
1
1
0 R. H. Lee, T. H. Kim, K. C. Choi, Lab. Anim. Res.,2012 , 28, 71.
1 K. W. Nettles, J. B. Bruning, G. Gil, E. E. O’Neill, J. Nowak, Y.
Guo, Y. Kim, E. R. De Sombre, R. Dilis, R. N. Hanson, A.
Joachimiak, G. L. Greene, EMBO Rep.,2007, 8, 563.
1
1
2 B. H. Mitlak, F. J. Cohen, Drugs, 1999, 57, 653.
3 C. Descoteaux, V. Leblanc, G. Belanger, S. Parent, E. Asselin,
G. Berube, Steroids.,2008, 73, 1077.
1
1
1
1
4 S. Adsule, S. Banerjee, F. Ahmed, S. Padhye, F. H. Sarkar,
Bioorg. Med. Chem. Lett., 2010, 20, 1247.
5 J. Ellmen, P. Hakulinen, A. Partanen, D. F. Hayes, Breast
Cancer Res. Treat.2003, 82, 103.
6 T. L. Taras, G. T. Wurz, M. W. DeGregorio, J. Steroid Biochem.
Mol. Biol., 2001, 77, 271.
7 A. De Michele, A. Bn. Troxel, J. A. Berlin, A. L. Weber, G. R.
Bunin, E. Turzo, R. Schinnar, D. Burgh, M. Berlin, S. C. Rubin,
T. R. Rebbeck, B. L. Strom, J. Clin. Oncol., 2008, 25, 4151.
8 H. S. Ibrahim, S. M.Abou-Seri, M. Tanc, M. M. Elaasser, H. A.
Abdel-Aziz, C. T. Supuran, Eur. J. Med. Chem., 2015, 103, 583.
9 R. Rohini, P. M. Reddy, K. Shanker, K. Kanthaiah, V. Ravinder,
A. Hu, Arch. Pharm. Res.,2011, 34, 1077.
0 M. Verma, S. N. Pandeya, K. N. Singh, J. P. Stables, Acta
Pharm.,2004, 54, 49.
1 S. N. Pandeya, P. Yogeeshwari, D. Sriram, G. Nath, Indian J.
Pharm. Sci., 2002, 64, 209.
1
1
2
2
2
2 P. Selvam, N. Murugesh, M. Chandramohan, Z. Debyser, M.
Witvrouw, Indian J. Pharm. Sci., 2008, 70, 779.
2
2
3 S. K. Sridhar, A. Ramesh, Biol. Pharm. Bull., 2001, 24, 1149.
4 G. J. Roth, A. Heckel, F. Colbatzky, S. Handschuh, J. Kley, T.
Lehmann-Lintz, R. Lotz, U. Tontsch-Grunt, R. Walter, F.
Hilberg, J. Med. Chem., 2009, 52,4466.
2
2
5 C. L. Tourneau, E. Raymond, S. Faivre, Clin Risk Manag.,2007,
2, 341.
6 R. J. Motzer, M. D. Michaelson, B. G. Redman, G. R. Hudes, G.
Wilding, R. A. Figlin, M. S. Ginsberg, S. T. Kim, C.M. Baum, S.
E. DePrimo, J. Z. Li, C. L. Bello, C. P. Theuer, D. J. George, B. I.
Rini, J. Clin. Oncol. 2006, 24,16.
2
2
2
3
3
3
3
7 K. Kumar, S. Sagar, L. Esau, M. Kaur, V. Kumar, Eur. J. Med.
Chem., 2012, 58, 153.
8 P. Singh, P. Sharma, A. Anand, P. M. S. Bedi, T. Kaur, A. K.
Saxena, V. Kumar, Eur. J. Med. Chem.2012, 55, 455.
9 K. Kumar, S. C. Kremer, L. Kremer, Y. Guérardel, C. Biot, V.
Kumar,Organometallics, 2013, 32, 5713.
0 G. Wolber, A. A. Dornhofer, T. Langer, J. Comput. Aided Mol.
Des., 2006, 20, 773.
1 S. Sagar, L. Esau, B. Moosa, N. M. Khashab, V. B. Bajic, M.
Kaur, Anti-Cancer Agents in Med. Chem.,2014, 14, 170.
2 J. H. Zhang, T. D. Chung, K. R. Oldenburg, J. Biomol. Screen,
1
3 E. F. Pettersen, T. D. Goddard, C. C. Huang, G. S. Couch, D. M.
999, 4, 67.
Greenblatt, E. C. Meng, T. E. Ferrin, J. Comput. Chem., 2004,
25, 1605.
3
3
4 O. Trott, A. J. Olson, J. Comput. Chem., 2010, 31, 455.
5 S. Salentin, S. Schreiber, V. J. Haupt, M. F. Adasme,
M. Schroeder, Nucl. Acids Res., 2015, 43, 443.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 11
Please do not adjust margins

New Journal of Chemistry
Page 12 of 12
View Article Online
DOI: 10.1039/C7NJ04964A
Design, synthesis, anti-proliferative evaluation and docking studies of 1H-1,2,3-triazole
tethered Ospemifene-isatin conjugates as Selective Estrogen Receptor Modulators
a
b
b
b
c
Sumit Kumar , Liang Gu , Gabriella Palma , Mandeep Kaur* , Ashona Singh-Pillay , Parvesh
c
a
Singh* and Vipan Kumar*
aDepartment of Chemistry, Guru Nanak Dev University, Amritsar-143005, India
b
School of Molecular and Cell Biology, University of the Witwatersrand, Private Bag 3, Wits-2050, Johannesburg,
South Africa
School of Chemistry and Physics, University of KwaZulu Natal, P/Bag X54001, Westville, Durban 4000, South
Africa
c