Triarylethylene-indolin-2,3-dione molecular conjugates: Design, synthesis, docking studies and anti-proliferation evaluation

Article abstract of DOI:10.1039/c9ra08776a

A series of 1H-1,2,3-triazole-linked ospemifene-isatin and O-methylated ospemifene-isatin conjugates were synthesized and assayed for their anti-proliferative activities against estrogen-responsive as well as estrogen-non-responsive cells. The non-cytotoxic conjugate 14e, with an optimal combination of bromo substituents at the C-5/C-7 positions of isatin, proved to be a promising hit with an IC₅₀ value of 31.62 μM against MCF-7 and 19.23 μM against MDA-MB-231. The observed anti-proliferative activities of active conjugates were further corroborated via docking studies carried out on estrogen receptor subtypes α and β.

Full text of DOI:10.1039/c9ra08776a

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Triarylethylene-indolin-2,3-dione molecular
conjugates: design, synthesis, docking studies and
Cite this: RSC Adv., 2019, 9, 42409
anti-proliferation evaluation†
Sumit Kumar,a Gabriella Palma,b Shanen Perumal, b Mandeep Kaur,b Ashona Singh-
a
Pillay,c Raghu Raj,d Parvesh Singhc and Vipan Kumar
*
A series of 1H-1,2,3-triazole-linked ospemifene-isatin and O-methylated ospemifene–isatin conjugates
were synthesized and assayed for their anti-proliferative activities against estrogen-responsive as well as
estrogen-non-responsive cells. The non-cytotoxic conjugate 14e, with an optimal combination of
bromo substituents at the C-5/C-7 positions of isatin, proved to be a promising hit with an IC50 value of
31.62 mM against MCF-7 and 19.23 mM against MDA-MB-231. The observed anti-proliferative activities of
active conjugates were further corroborated via docking studies carried out on estrogen receptor
subtypes a and b.
Received 25th October 2019
Accepted 7th December 2019
DOI: 10.1039/c9ra08776a
rsc.li/rsc-advances
action, as SERMs act variedly in different tissues, selectively
inhibiting or stimulating estrogen-like actions.4,5 Tamoxifene
Introduction
(TAM), toremifene (TMF) and clomifene are clinically approved
SERMs for the treatment of BC and display estrogenic effects in
bones and anti-estrogenic effects in breast and endometrium
tissues. Further side effects related to TAM have been shown to
include hot ashes, insomnia, depression and dizziness.6–8
Ospemifene, a hydroxylated TAM metabolite Y, is involved in
a metabolic pathway similar to that for TAM and is recom-
mended as a rst-line drug for moderate to severe dyspareunia
associated with vulvar and vaginal atrophy (VVA).9,10
Use of isatin (1H-indole 2,3-dione) as a pharmacophore is of
great interest and has been associated with a diverse range of
biological activities such as anti-cancer, anti-depressant, anti-
convulsant, anti-fungal, anti-HIV and anti-angiogenic activi-
ties.11–16 Inhibitions of tyrosine kinase and cyclin-dependent
kinases are some of the mechanistic pathways through which
isatin exerts its anticancer potential. Bazedoxifene (BZA), an
indole-based SERM, has been approved for the prevention and
treatment of post-menopausal osteoporosis and displays
slightly higher binding affinity to ER-a than to ER-b. Recent
studies have shown that BZA, when given in combination with
conjugated estrogens, relieves hot ashes and also improves
vulvovaginal atrophy and its symptoms.17,18 The structures of
various United States Food and Drug Administration (US-FDA)-
approved drugs displaying relatively substantial affinity for
hormonal receptors are provided in Fig. 1.
Breast cancer (BC) is the second-leading cancer worldwide, and
shows a high incidence of morbidity and mortality. The major
risk factor for BC is being of the female sex since a high level of
estrogen in females not only fuels the division of breast cells but
also escalates the damage to DNA. BC is more prevalent in the
age groups 14–30 (younger cells more prone to carcinogens) and
above 40 (lifestyle and menopause).1,2 The low rate of breast
feeding in nations with high resources is also considered to be
a contributing factor for the disease, rendering BC a classical
cancer of these nations. The Global Cancer Observatory (GLO-
BOCAN) estimated that 2 088 849 new cases of BC with 626 679
deaths occurred worldwide in 2018, with India accounting for
17% of the world's population that suffer from this disease.3
Triarylethylenes constitute a well-known pharmacophore
with non-steroidal and non-hormonal properties. The core is
present in non-steroidal architecturally varied collections of
compounds called selective estrogen receptor modulators
(SERMs) that function by binding estrogen receptors. These
compounds are different from pure anti-estrogens in their
aDepartment of Chemistry, Guru Nanak Dev University, Amritsar-143005, India. Tel:
+91 183 2258802-09 ext. 3320. Fax: +91 183 2258819-20. E-mail: vipan_org@
yahoo.com
bSchool of Molecular and Cell Biology, University of the Witswatersrand, Private Bag 3,
Wits-2050, Johannesburg, South Africa
cSchool of Chemistry and Physics, University of KwaZulu Natal, P/Bag X54001,
Westvile, Durban 4000, South Africa
Recent reports from our laboratory have disclosed the
synthesis and anti-proliferative activities of ospemifene–isatin
conjugates with promising results against MCF-7 cells, in
contrast to the results against MDA-MB-231 cells, with the most
active conjugate of the series exhibiting an IC50 value of 1.56
mM.22 The currently described work was a continuation and
dDepartment of Chemistry, DAV College, Amritsar-143001, India
† Electronic supplementary information (ESI) available: 1H and 13C NMR data of
all the synthesized conjugates along with scanned (1H, 13C, DEPT, D2O) NMR
spectra for representative compounds viz. 13a, 13b, 14a, 14b, 14c, 14e, 15c, 15d.
See DOI: 10.1039/c9ra08776a
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Fig. 1 US-FDA-approved active SERMs (TAM, TMF, BZD and OSP) and
estrogen synthesis inhibitors (ANSTZ and LTZ).
Scheme 1 Synthesis of ospemifene and the O-methoxy derivative of
ospemifene. Reagents and conditions: (a) Zn/TiCl4, anhydrous THF, rt
to reflux, 6 h. (b) NaN3, DMF, 60 ꢀC, 4 h.
logical extension of our interests19–21 and involved the use of
a 1H-1,2,3-triazole core to link C-5-functionalized isatin to the
alkyl side chain of ospemifene and methylated ospemifene. The
use of triazole as a linker was further supported by its presence
in anastrazole, an aromatase inhibitor used in BC chemo-
therapy.23 The present series of compounds was designed based
on these literature rationales, and this design is depicted in
Fig. 2.
The second precursors, viz. N-propargylated isatin 10 and N-
propargylated isatin-spiroketal 11, were obtained by deploying
a previously reported methodology25,26 as shown in Scheme 2.
Results and discussion
Synthetic chemistry
The methodology for the synthesis of the click chemistry
precursors (Z)-2-(4-(4-azido-1,2-diphenylbut-1-en-1-yl)phenoxy)
ethan-1-ol 7 and its derivative (Z)-(4-azido-1-(4-methoxyphenyl)
but-1-ene-1,2-diyl)dibenzene 6 involved an initial McMurry
reaction between 3-chloro-1-phenylpropan-1-one 1 with (4-
methoxyphenyl)(phenyl)methanone 2 or (4-(2-hydroxyethoxy)
phenyl)(phenyl)methanone 3 under reuxing conditions in
a nitrogen atmosphere using Zn/TiCl4 in anhydrous tetrahy-
drofuran (THF) to afford 4 and 5, in a Z/E ratio of >98%.24
Sodium azide promoted nucleophilic substitution of 4 and 5 in
anhydrous dimethylformamide (DMF) and gave the desired
precursors 6 and 7, respectively (Scheme 1).
Scheme 2 Syntheses of N-propargylated C-5-substituted isatin 10
and spiroketal-N-propargylated C-5-substituted isatin 11. Reagents
and conditions: (a) 2-bromoethan-1-ol, NaH, DMF, 80 ꢀC, 6 h. (b)
Propargyl bromide, NaH, DMF, 80 ꢀC, 6 h.
Fig. 2 Design of the targeted 1H-1,2,3-triazole-linked ospemifene–isatin and O-methylated ospemifene–isatin conjugates.
42410 | RSC Adv., 2019, 9, 42409–42414
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A Cu(I)-promoted azide–alkyne 1,3-dipolar cycloaddition reac- determined and the results are provided in Fig. S1–S4 (see ESI†),
tion of appropriate precursors, namely 6 with 10 and 11, afforded while the IC50 data are listed in Table 1.
the targeted 1H-1,2,3-triazole-linked O-methylated ospemifene–
Analysis of these data revealed an interesting structure
isatin/spiroisatins 12 and 13, while similar cycloaddition reac- activity relationship (SAR), one depending on the nature of the
tions of 7 with 10 and 11 gave ospemifen–isatin/spiroisatin substituents at the C-5/C-7 positions as well as the nature of the
conjugates 14 and 15 (Scheme 3).
functional group at the C-3 position of the isatin ring. Of the O-
The synthesized conjugates were puried via column chro- methylated ospemifene–isatin conjugates, 12a and 12b were
matography using an ethylacetate : hexane (70 : 30) mixture as selective against MDA-MB-231 cells while 12c, having bromo
the eluent. The structure to the synthesized compounds was substituents at the C-5 and C-7 positions of the isatin ring,
assigned on the basis of spectral data and analytical evidence. displayed IC50 values of 13.06 and 14.79 mM against estrogen-
Compound 14b, for example, exhibited a molecular ion peak at responsive and estrogen-non-responsive cells, respectively.
m/z 604.1881 (M+) in its high-resolution mass spectrum The replacement of the keto-carbonyl with a spiroketal at the C-
(HRMS). Its 1H NMR spectrum included the characteristic 3 position of the isatin core in conjugates 13a–c proved to be
signals at d 2.97 (t, J ¼ 7.2 Hz), 3.86 (t, J ¼ 4.0 Hz), 3.94 (t, J ¼ 4.7 detrimental, except in the case of 13a, which exhibited IC50
Hz), 4.26 (t, J ¼ 7.4 Hz) and 4.94 (s), corresponding to its values of 21 and 20.39 mM against MCF-7 and MDA-MB-231
different methylenes. Characteristic absorptions at d 157.3 and cells, respectively. Among the ospemifene–isatin conjugates
182.4 in its 13C NMR spectrum, corresponding to isatin ring 14a–e, the presence of a halogen substituent at the C-5 position
carbonyls, further corroborated the assigned structure.
of the isatin ring improved the anti-proliferative activities, with
the order of preference being –Cl > –Br > –F. The replacement of
keto-carbonyl with spiroketal at the C-3 position of the isatin
ring again resulted in a deterioration of the anti-proliferative
activities, as evident by compounds 15a–d, which were inac-
tive against cells from both cell lines. Of the most active
conjugates, 14b and 14e were selective for the estrogen-
independent MDA-MB-231 cells.
Anti-proliferative activities of synthesized conjugates against
MCF-7 (ER+) and MDA-MB-231 (ERꢁ) cells
The synthesized ospemifene and O-methylated ospemifene–
isatin conjugates were evaluated for their anti-proliferative
activities against estrogen-dependent ER(+) and non-estrogen-
dependent ER(ꢁ) cells using the MTT assay with plumbagin
as a positive control. Their percentage growth inhibitions for
various concentrations viz. 1, 5, 10, 20, 40, 50 and 100 mM were
Based on the observed activity proles, a generalized SAR for
the series of synthesized ospemiphene–isatin/isatinspiroketal
and
O-methylated
ospemiphene–isatin/isatinspiroketal
compounds was derived, and this SAR is illustrated in Fig. 3.
The results indicated that the inclusion of bromo substituents
at C-5/C-7, a keto-carbonyl at the C-3 position of the isatin ring,
and O-methylation at the C-4 position of ospemifene improved
the anti-proliferative activity.
Molecular docking studies
Molecular docking was performed on a set of test compounds
viz. 12c, 13a, 14b and 14e against the two estrogen receptor
subtypes a and b in order to identify the critical ligand–protein
interactions. Compound 12c was the most potent inhibitor of
the cells from both cell lines. In the docking, the binding of 12c
to the b-subtype was supported by two hydrophobic interactions
from residue Glu108 and the ligand at bond distances of 3.64
ꢀ
and 3.78 A. These interactions were accompanied by three
hydrogen bonds involving residues Glu28 and Gly109 as H-bond
donors and residue Cys106 and the oxygen moiety of the ligand
as H-bond acceptors (with bond distances of 2.33, 2.57 and 1.59
ꢀ
ꢀ
ꢀ
ꢀ
A, respectively, and bond angles of 115.58 , 127.29 and 175.71 ,
respectively). According to the dockings, compound 13a shared
a similar binding prole with 12c and also showed two hydro-
phobic interactions with residue Glu108, here with bonding
ꢀ
distances of 3.68 and 3.82 A, and a single hydrogen bond with
ꢀ
donor residue Gly109, with a bond distance of 3.11 A and bond
angle of 133.67ꢀ. Compound 14b displayed two hydrophobic
interactions with Gly108 and the ligand (with bond distances of
Scheme 3 Syntheses of 1H-1,2,3-triazole-linked ospemifene–isatin/
spiroisatin and O-methylated ospemifene–isatin/spiroisatin conjugates.
Reagent and conditions: (a) CuSO4, sodium ascorbate, ethanol : H2O
(9 : 1), rt, 6–8 h.
ꢀ
3.57 and 3.92 A). These interactions were accompanied by three
hydrogen bonds between donor residues Glu28, Gly109 and
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Table 1 IC50 values of the test compounds in MCF-7 and MDA-MB-231 cells
MDA-MB-231
MDA-MB-231
Code
Structure
MCF-7 (mM)
(mM)
Code
Structure
MCF-7 (mM)
(mM)
12a
>100
52.26
14c
70.71
70.71
>100
19.23
12b
12c
>100
75.92
14.79
14d
14e
>100
13.06
31.62
13a
13b
13c
21
20.39
>100
>100
15a
15b
>100
>100
>100
>100
>100
>100
15c
15d
>100
>100
>100
>100
14a
14b
>100
>100
OSP
TAM
Plumbagin
55
50
3.5
>100
75
4.4
33.13
18.11
Glu112 and the oxygen of the ligand (with bond distances of volume allowed for an improved interaction with the ligand in
ꢀ
ꢀ
ꢀ
2.95, 2.96 and 2.91 A and bond angles of 146.92 , 148.12 and our dockings. Here, the interaction prole of compound 12c
160.53ꢀ, respectively). Compound 14e displayed, according to comprised three distinct sets of features: six hydrophobic
the dockings, a more extensive binding interaction network: interactions, ve hydrogen bonds and a p-stacking. The
including two hydrophobic interactions with residue Glu108 at hydrophobic interactions were observed between residues
ꢀ
bonding distances of 3.47 and 3.94 A; ve hydrogen bonds Leu49, Trp78, Lys224, Val228, Pro230 and Leu234 and the
observed between residues Glu28, Ala29, Gly109 and Glu112 hydrophobic pharmacophores of the ligand (bond distances of
ꢀ
and the oxygen groups of the ligand (bond distances of 3.04, 3.90, 3.92, 3.73, 3.34, 3.92 and 3.72 A, respectively). The ve
ꢀ
ꢀ
ꢀ
3.96, 2.87/2.99 and 2.94 A, and bond angles of 136.45 , 155.75 , hydrogen bonds involved residues Gly75, Lys224 and Tyr232 as
129.58ꢀ/154.86ꢀ and 165.31ꢀ, respectively); and a single elec- donors and residue Glu75 as the acceptor (bond distances of
ꢀ
ꢀ
trostatic interaction between the bromine of the ligand and 2.44, 3.77, 3.18 and 2.44/2.50 A, and bond angles of 102.63 ,
Lys214 (bond distance of 3.43 A and bond angle of 151.48 ) 119.34ꢀ, 158.60ꢀ and 171.15/161.49ꢀ, respectively). A P-type p-
(Fig. S5, see ESI†). stacking was established between residue Trp78 and the ligand
The volume of the ligand-binding domain of ER-a has been at a distance of 4.05 A and angle of 24.79 . Compound 14e
ꢀ
ꢀ
ꢀ
ꢀ
found to be much greater than that of ER-b, and this greater displayed
42412 | RSC Adv., 2019, 9, 42409–42414
a
similar binding landscape with extensive
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3ERT) and these results are shown in Table S1 (see ESI†). Three
of the most active conjugates, namely 12c, 13a and 14e, were
selected for determining their cytotoxicity levels against the
non-tumorigenic HEK-293 cells. The percentage growth inhi-
bitions of these compounds are presented in Fig. 4 while their
IC50 values are listed in Table 2. Conjugate 14e proved to be
non-cytotoxic against the HEK-293 cells while the conjugates
12c and 13a were moderately cytotoxic.
Fig. 3 Generalized structure activity relationship of the synthesized
conjugates.
Conclusion
In conclusion, a series of ospemifene–isatin and O-methylated
ospemifene–isatin conjugates were synthesized using the Mc-
Murray reaction as the key synthetic step. The synthesized
conjugates were assayed for their anti-proliferative activities
against ER+ (MCF-7) and ERꢁ (MDA-MB-231) cells. The
replacement of the carbonyl core with a spiroketal at the C-3
position of the isatin ring resulted in the loss of anti-
proliferative activity, except in the case of 13a, which exhibited
IC50 values of 21 and 20.39 mM against MCF-7 and MDA-MB-231
cells. The most potent compound of the series, 12c, with an
optimum combination of bromo substituents at C-5/C-7 and
a keto-carbonyl at C-3 of the isatin ring linked to O-methylated
ospemiphene, displayed IC50 values of 13.06 and 14.79 mM
against MCF-7 and MDA-MB-231 cells, respectively. However 12c
was moderately cytotoxic to HEK 293 cells. On the other hand, the
non-cytotoxic conjugate 14e, with similar structural characteris-
tics of an isatin ring linked to ospemifene, was more selective
towards the ER-cells, with which it displayed an IC50 of 19.23 mM,
and can hence be regarded as a promising hit.
Fig. 4 Representative graph of the cell death percentages of HEK293
cells at selected concentrations of test compounds 14e, 12c and 13a.
Plumbagin at a concentration of 40 mM was used as a positive control.
Data are shown as mean ꢂ standard deviation S.D. (n ¼ 3), where *p #
0.05, **p # 0.01 and ***p # 0.001 each indicate the significance of the
difference with the untreated control.
hydrophobic interactions between residues Trp78, Leu220,
Tyr221 and Lys224 at bond distances of 3.56, 3.96/3.85, 3.76 and
Abbreviations
ꢀ
3.99/3.51 A. Hydrogen bond interactions were identied
BC
ER
Breast cancer
Estrogen receptor
Global cancer observatory
Selective estrogen receptor modulators
Tamoxifene
Toremifene
Vulvar and vaginal atrophy
Bazedoxifene
between donor residue Leu231 and acceptor residue Glu218
ꢀ
ꢀ
(bond distances of 4.02 and 3.00 A, and bond angles of 155.26
GLOBOCAN
SERMs
TAM
TMF
VVA
BZA
THF
DMF
SAR
DMEM
and 158.19ꢀ, respectively) (Fig. S6, see ESI†). A T and P-type p-
stacking was measured between Tyr221 andꢀ the liganꢀd
ꢀ
(distances of 5.24 and 4.17 A, and angles of 89.17 and 24.76 ,
respectively). Compounds 13a and 14b shared similar binding
proles, differing only in the presence of a hydrogen bond
network in compound 13a between residues Ala45 and Leu231
Tetrahydrofuran
ꢀ
ꢀ
(bond distances of 3.23 and 3.11 A, and bond angles of 111.57
Dimethylformamide
Structure activity relationship
Dulbecco's modied Eagle's medium
and 164.55ꢀ, respectively) and an electrostatic interaction in
compound 14b incorporating the chloride group and Arg89
ꢀ
ꢀ
(distance of 3.81 A, angle of 142.51 ). The complexes of 12c, 13a,
14b and 14e showed high binding affinities during the dockings
in the active sites of estrogen receptors (PDB ID: 3OLS/PDB ID:
Conflicts of interest
The authors declare no conict of interest.
Table 2 The IC 50 values of selected test compounds in HEK293 cells
Compound
IC50 value
Acknowledgements
12c
13a
14e
21.61
43.87
>100
Financial assistance from the Science and Engineering Research
Board (SERB) under Start-Up Research Grant Scheme No. YSS/2015/
000879/CS (RR) is gratefully acknowledged. The authors would like
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to thank the National Research Foundation of South Africa for their 12 R. Rohini, P. M. Reddy, K. Shanker, K. Kanthaiah,
support in facilitating our research (UID: 99563). We would also V. Ravinder and A. Hu, Arch. Pharmacal Res., 2011, 34, 1077.
like to thank the Centre for High Performance Computing based in 13 M. Verma, S. N. Pandeya, K. N. Singh and J. P. Stables, Acta
Cape Town for access to computational resources.
Pharm., 2004, 54, 49.
14 S. N. Pandeya, P. Yogeeshwari, D. Sriram and G. Nath, Indian
J. Pharm. Sci., 2002, 64, 209.
15 P. Selvam, N. Murugesh, M. Chandramohan, Z. Debyser and
M. Witvrouw, Indian J. Pharm. Sci., 2008, 70, 779.
16 S. K. Sridhar and A. Ramesh, Biol. Pharm. Bull., 2001, 24,
1149.
17 D. M. Biskobing, Clin. Interventions Aging, 2007, 2, 299.
18 R. Kagan, R. S. Williams, K. Pan, S. Mirkin and J. H. Pickar,
Menopause, 2010, 2, 281.
19 S. Kumar, L. Gu, G. Palma, M. Kaur, A. S. Pillay, P. Singh and
V. Kumar, New J. Chem., 2018, 42, 3703.
Notes and references
1 B. Su, S. Landini, D. D. Davis and W. R. Brueggemeier, J. Med.
Chem., 2017, 50, 1635.
2 American Cancer Society, Cancer facts and gures 2017,
https://www.cancer.org/research/cancer-facts-statistics/
allcancer-facts-gures/cancer-factsgures-2017.html.
3 F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre
and A. Jemal, Ca-Cancer J. Clin., 2018, 68, 394.
4 G. Kaur, M. P. Mahajan, M. K. Pandey, P. Singh,
S. R. Ramisetti and A. K. Sharma, Eur. J. Med. Chem., 2014,
86, 211.
20 A. Singh, S. T. Saha, S. Perumal, M. Kaur and V. Kumar, ACS
Omega, 2018, 3, 1263.
5 G. Kaur, M. P. Mahajan, M. K. Pandey, P. Singh,
S. R. Ramisetti and A. K. Sharma, Bioorg. Med. Chem. Lett.,
2016, 26, 1963.
6 J. Ellmen, P. Hakulinen, A. Partanen and D. F. Hayes, Breast
Cancer Res. Treat., 2003, 82, 103.
21 B. Sharma, A. Singh, L. Gu, S. T. Saha, A. S. Pillay, N. Cele,
P. Singh, M. Kaur and V. Kumar, RSC Adv., 2019, 9, 9809.
22 S. Kumar, S. T. Saha, L. Gu, G. Palma, S. Perumal, A. S. Pillay,
P. Singh, A. Anand, M. Kaur and V. Kumar, ACS Omega, 2018,
3, 12106.
7 T. L. Taras, G. T. Wurz and M. W. DeGregorio, J. Steroid
Biochem. Mol. Biol., 2001, 77, 271–279.
8 A. DeMichele, 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 and B. L. Strom, J. Clin. Oncol.,
2008, 26, 4151–4159.
23 A. Mojaddami, A. Sakhteman, M. Fereidoonnezhad,
Z. Faghih, A. Najdian, S. Khabnadideh, H. Sadeghpour and
Z. Rezaei, Res. Pharma. Sci., 2017, 12, 21.
24 L. Eklund and J. Nilsson, New Processes for Producing
Benzophenone Derivatives, PCT WO 2011/089385 A1, 2011.
´
25 K. Kumar, S. C. Kremer, L. Kremer, Y. Guerardel, C. Biot and
9 C. Descoteaux, V. Leblanc, G. Belanger, S. Parent, E. Asselin
and G. Berube, Steroids, 2008, 73, 1077.
V. Kumar, Organometallics, 2013, 32, 5713.
26 K. Kumar, C. Biot, S. C. Kremer, L. Kremer, Y. Guerardel,
´
10 S. Adsule, S. Banerjee, F. Ahmed, S. Padhye and F. H. Sarkar,
Bioorg. Med. Chem. Lett., 2010, 20, 1247.
P. Roussel and V. Kumar, Organometallics, 2013, 32, 7386.
11 H. S. Ibrahim, S. M. Abou-Seri, M. Tanc, M. M. Elaasser,
H. A. Abdel-Aziz and C. T. Supuran, Eur. J. Med. Chem.,
2015, 103, 583.
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