The synthesis and evaluation of thymoquinone analogues as anti-ovarian cancer and antimalarial agents

Article abstract of DOI:10.1016/j.bmcl.2018.02.051

Thymoquinone (TQ), 2-isopropyl-5-methyl-1,4-benzoquinone, a natural product isolated from Nigella sativa L., has previously been demonstrated to exhibit antiproliferative activity in vitro against a range of cancers as well as the human malarial parasite Plasmodium falciparum. We describe here the synthesis of a series of analogues of TQ that explore the potential for nitrogen-substitution to this scaffold, or reduction to a hydroquinone scaffold, in increasing the potency of this antiproliferative activity against ovarian cancer cell lines and P. falciparum. In addition, alkyl or halogen-substituted analogues were commercially sourced and tested in parallel. Several TQ analogues with improved potency against ovarian cancer cells and P. falciparum were found, although this increase is suggested to be moderate. Key aspects of the structure activity relationship that could be further explored are highlighted.

Full text of DOI:10.1016/j.bmcl.2018.02.051

Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The synthesis and evaluation of thymoquinone analogues as anti-ovarian
cancer and antimalarial agents
Okiemute Rosa Johnson-Ajinwo a,b, Imran Ullah a, Haddijatou Mbye a, Alan Richardson a,
Paul Horrocks a, Wen-Wu Li a,
⇑
a Institute for Science and Technology in Medicine, Keele University, Staffordshire, United Kingdom
b Faculty of Pharmaceutical Sciences, University of Port Harcourt, Nigeria
a r t i c l e i n f o
a b s t r a c t
Article history:
Thymoquinone (TQ), 2-isopropyl-5-methyl-1,4-benzoquinone, a natural product isolated from Nigella
sativa L., has previously been demonstrated to exhibit antiproliferative activity in vitro against a range
of cancers as well as the human malarial parasite Plasmodium falciparum. We describe here the synthesis
of a series of analogues of TQ that explore the potential for nitrogen-substitution to this scaffold, or
reduction to a hydroquinone scaffold, in increasing the potency of this antiproliferative activity against
ovarian cancer cell lines and P. falciparum. In addition, alkyl or halogen-substituted analogues were com-
mercially sourced and tested in parallel. Several TQ analogues with improved potency against ovarian
cancer cells and P. falciparum were found, although this increase is suggested to be moderate. Key aspects
of the structure activity relationship that could be further explored are highlighted.
Received 5 December 2017
Revised 14 February 2018
Accepted 26 February 2018
Available online xxxx
Keywords:
Thymoquinone
Ovarian cancer
Malaria
Ó 2018 Elsevier Ltd. All rights reserved.
Synthesis
The seeds of Nigella sativa L., belonging to the Ranunculaceae
family, are commonly known as ‘black cumin’ or ‘black onion’. As
well as a common spice, these seeds have been widely used as a
traditional medicine in the treatment of a range of diseases such
as cancer, diabetes, hypertension, fever, arthritis, inflammation,
and gastro-intestinal disturbances.1 Studies that have explored
the anti-inflammatory, antidiabetic, antimicrobial, antioxidant,
immunomodulatory and antitumor activities of the essential oil
from these seeds have identified thymoquinone (TQ, 1), 2-iso-
propyl-5-methyl-1,4-benzoquinone (Fig. 1) as a key bioactive com-
ponent.2–5 Further, studies specifically investigating the cytotoxic
activity of TQ have shown this compound to inhibit proliferation
of several cancer cell lines, including ovarian, prostate, colon,
breast, pancreatic cancers, leukaemia and osteosarcoma.2,4,6
Recently, TQ has been shown to block substrate recognition by
the Polo-Box domain of Polo-like-kinase 1 (Plk1), a mitotic regula-
tor that when overexpressed causes cancer.7 TQ-based inhibitors of
Plk1, such as poloxin, have been developed and validate the poten-
tial of targeting Plk1 using non-peptide inhibitors of protein-
protein interactions at the Polo-Box domain.8 Further modifica-
tions to TQ, including; TQ-fatty acid9 and -terpene10 conjugates,
6-alkyl thymoquinone,11 2,5-bis (alkyl/aryl-amino) 1,4-benzo-
quinone,12 TQ-gallate conjugate,13 and TQ-artesunic acid hybrid14
have similarly demonstrated the utility of TQ-analogues as
antiproliferatives in cancer cell lines. In addition to the anticancer
potential of TQ, it has also been shown to have in vitro anti-plas-
modial activity with an IC50 of 0.2 mg/ml (1.2 mM).15 P. falciparum
lacks polo-like kinases, although a number of mitotic kinases have
been described.16,17
Whilst TQ and TQ-analogues appear relatively safe, efforts have
been focussed on improvement of the antiproliferative activity and
increased solubility to enhance its bioavailability.18 For example,
only a preliminary structure-activity relationship (SAR) of TQ ana-
logues against pancreatic cancer cell lines explored the potential of
amino-substituted 2-methyl-naphthoquinone and 1,4-benzo-
quinone.12 Thymoquinone has been demonstrated to be effective
against ovarian cancer cells in vitro and in vivo.19–22 In particular,
treatment of syngeneic mice of ovarian cancer by TQ alone resulted
in a 2-fold increase in ascites volume after 60 days compared to
vehicle-treated mice. A further combination of TQ and cisplatin
caused increased reduction in peritoneal implants and mesenteric
tumors compared to either drug alone.19 TQ has been shown to
induce apoptosis by regulation of Bcl-2 and Bax21 and increase of
reactive oxygen species in ovarian cancer cells.20 However, there
is no SAR study on TQ against ovarian cancer and plasmodial par-
asites. In particular, the effect of the two alkyl substitution groups
(methyl and 2-isopropyl groups) on the quinone ring, the addi-
tional substitution of the quinone ring of TQ by amine or halogen
groups, and the reduction of quinones to quinol forms on the
⇑
Corresponding author.
E-mail address: w.li@keele.ac.uk (W.-W. Li).
https://doi.org/10.1016/j.bmcl.2018.02.051
0960-894X/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Johnson-Ajinwo O.R., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.02.051

2
O.R. Johnson-Ajinwo et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Fig. 1. Structure and schemes for the synthesis of TQ analogues.
in vitro anti-ovarian cancer and antiplasmodial activities has not
been investigated.
showed potent cytotoxicity in OVCAR-8 and CIS-A2780 (cisplatin
resistant) cancer cell lines with the former one being more resis-
tant. Compound 10 with a tert-butyl group (an additional methyl
group to the isopropyl group of TQ) and a methyl group on the qui-
none ring does not increase its cytotoxicity, however its SI
increased from 2.3 of TQ to 7.5. Further increase of the bulkiness
and hydrophobicity of the side chains either at the 5-methyl or
2-isopropyl group significantly decreases their cytotoxicity as seen
for compounds (8, 13, 16, and 17). These findings are consistent
with loss of cytotoxicity in pancreatic cancer cell lines of the syn-
thetic TQ analogues with bulkier substitution groups via amino
addition as previously reported.12
This study aims to discover potent cytotoxic/antiplasmodial
analogues of TQ. Eleven TQ analogues including six nitrogen-sub-
stituted TQ analogues (2–4, 6–8) and five reduced hydroquinones
(18–22) were synthesized (Supporting information), and ten others
(5, 9–17) with different substituted groups (e.g. variation of length
of alkyl chains and halogen atoms) were procured (Fig. 1). Both the
synthetic and procured TQ analogues were investigated for their
growth inhibition in three human ovarian cancer cell lines and
immortalized human ovarian epithelial cell line (HOE) by deter-
mining their IC50 values using sulforhodamine B (SRB) cytotoxicity
assay23,24 (Table 1). Eleven TQ analogues (6, 9, 10–12, 14, 18–22)
showed IC50 less than 10 mM as TQ in A2780 cell line; they also
Substitution of CH of isopropyl group of TQ by a single nitrogen
atom in 6 results in a 2-fold increase in cytotoxicity against the
Please cite this article in press as: Johnson-Ajinwo O.R., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.02.051

O.R. Johnson-Ajinwo et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
3
Table 1
Evaluation of inhibition of cell growth in ovarian cancer cell lines, HOE, and P. falciparum (Dd2 strain), selectivity index (SI), and ClogP values of the TQ analogues. The SI values are
calculated by comparing the activity against the non-cancer HOE cell line with that against A2780 ovarian cancer cells. The results are expressed as mean SEM, n = 3.
Compound
ClogP
A2780 (mM)
OVCAR-8 (mM)
CIS-A2780 (mM)
HOE (mM)
SI against A2780
P. falciparum (mM)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1.04
0.01
0.35
0.51
0.06
0.71
0.71
0.74
1.66
1.51
1.59
1.16
2.73
0.29
2.73
3.56
6.06
2.98
4.63
3.45
2.23
1.74
À0.34
2.50
7.9 0.2
14.0 0.4
12.6 0.2
19.9 0.6
12.1 0.4
6.2 0.2
16.7 2.0
15.0 0.5
4.9 0.2
7.5 1.2
4.5 0.5
5.7 0.5
34.0 5.6
3.2 0.2
24.6 0.6
36.1 0.1
44.2 0.3
3.1 0.2
3.4 0.4
6.4 1.5
3.6 0.4
5.7 0.4
16.0 1.0
0.009 0.001
0.05 0.01a26
–
11.6 0.3
12.9 0.6
16.0 0.7
35.1 0.4
13.4 2.5
5.6 0.4
35.6 6.6
32.0 3.9
3.6 0.3
13.5 1.5
6.0 0.4
10.0 0.5
51.2 0.4
5.2 0.2
37.4 1.5
54.2 1.6
56.5 0.6
8.9 0.7
11.6 0.5
12.2 0.5
8.3 0.7
6.2 0.2
10.8 1.3
0.01 0.004
7.8 0.2
7.3 0.3
9.6 0.6
19.3 1.5
11.8 0.5
4.7 0.5
20.5 3.0
21.8 0.3
5.3 0.5
7.9 2.0
4.2 0.6
4.9 1.2
42.5 1.9
2.9 0.3
31.1 4.1
48.8 5.4
51.8 3.1
9.8 0.3
4.8 0.4
11.5 0.3
3.6 0.6
4.7 0.2
>100
17.8 0.4
36.8 3.0
30.3 2.0
138.9 5.0
6.0 0.3
7.9 0.9
28.2 3.9
20.2 2.1
7.3 0.4
55.8 6.2
3.1 0.3
10.3 1.1
117.4 1.6
5.3 0.5
51.5 0.5
>200
2.3
5.0
3.1
7.1
<1
1.7
1.3
1.3
1.5
7.5
<1
1.8
3.4
1.7
2.1
>5
>4.6
4.5
3.2
13.4
2.1
1.1
1.0
–
25.0 5.3
52.7 10.8
11.1 1.3
19.3 0.8
–
9.9 1.4
191.1 32.3
100.3 22.5
30.0 5.1
19.7 2.8
16.2 1.1
15.6 1.8
4.2 0.9
10.4 1.9
29.5 2.7
78.8 0.8
116.3 15.8
15.9 2.4
25.6 1.1
17.9 1.0
15.4 0.8
133.7 23.3
12.025
17
18
19
20
21
22
>200
14.0 2.4
11.0 2.1
85.6 5.2
7.8 1.6
6.3 0.7
15.2 3.0
–
Carboplatin
Paclitaxel
–
–
0.003–0.00427
0.03 0.01a26
–
0.6
–
0.003–0.00628
0.17 0.02
Chloroquine
5.00
–
a
The IC50 reported was determined using the MTT method.26
cancer cell lines although its SI is similar to that of TQ (1). Addition
of a free amine group (4) or an alkylamino (methylamine (2) or
ethylamino (3)) group slightly reduces their activity. Substitution
of TQ (1) and compound 10 with bromine and chlorine, respec-
tively, shows a similar potency as TQ. Reduction of five quinones
(1, 9, 10, 14 and 5) to their reduced hydroquinones (18–21)29,30
generally increases their potency and selectivity (Table 1). The
therapeutic or selectivity index (SIs) of TQ (1) and most of their
synthetic analogues are slightly better than that of the clinically
used carboplatin for the treatment of ovarian cancer with a similar
potency in cytotoxicity as TQ (Table 1). They are also better than
that of the extremely cytotoxic paclitaxel (IC50 1–50 nM) which
show little difference here in selectivity between A2780 and HOE
cell lines.26
The IC50s of TQ analogues against human malarial parasite
P. falciparum Dd2 using Sybr Green l fluorescence assay were deter-
mined (Table 1). TQ shows a moderate anti-plasmodial activity
with IC50 of 25.0 5.3 mM being greater than that previously
reported.15 Ten compounds (3, 6, 10–14, 18, 20, and 21) show more
potent antiplasmodial activity than TQ itself, particularly com-
pounds 6 and 13 showed their IC50 values less than 10 mM. Prelim-
inary structure antimalarial activity relationship of TQ analogues is
drawn as follows. Compound 10 with a single tert-butyl substitu-
tion and a methyl group slightly increases its antiplasmodial
activity compared to TQ (1). Compound 12 with single tert-butyl
substitution group without a methyl group is also active, and com-
pound 13 with two tert-butyl groups at 2 and 5 positions of qui-
none ring shows the most potent activity with IC50 of 4.2 mM.
However, compound 15 with also two tert-butyl groups but at 2
and 6 positions of quinone ring show decreased activities; further
increase of their hydrophobicity in the side chains in compounds 8,
16, 17 causes further decrease of their activities. These indicate
that the number of tert-butyl groups and their position on the qui-
none ring are crucial for their in vitro antiplasmodial activity. Intro-
ducing a basic nitrogen atom to TQ has also a great impact on the
antiplasmodial activity as their cytotoxicity described above. The
antiplasmodial activity of compound 6 was found to be 2-fold
more potent than 1. Compounds 3 and 4 but not 2 show a greater
antiplasmodial activity than TQ. Halogen-substituted quinones like
9 and 11 demonstrate similar activity. Hydroquinones (18–21)
show similar or slightly more potency compared to their oxidized
quinones.
Based on the calculated partition coefficient (ClogP) values of
1.04 and 0.29 for 6 and 14, respectively (Table 1), they were pre-
dicted to be more water-soluble than TQ (1). As expected, the
water solubility of compound 1, 6 and 14 were determined to be
467.8 2.2, 8320.7 0.7 and 5043.0 6.5 mg/ml in a phosphate
buffer (pH7.4) at 37 °C using high-performance liquid chromatog-
raphy, respectively (Supporting Information). Compound 6 and 14
possess 18 and 11-fold more water-soluble than TQ. The obtained
solubility of TQ is consistent with the previously documented sol-
ubility of TQ.31 This finding is significant as poor aqueous solubility
is a major deterrent to the clinical advancement of almost 50% of
potent compounds classed as new chemical entities.32 However,
the most anti-plasmodial compound 13 has a larger ClogP of
2.73 (Table 1), its water solubility was not further determined
and is expected to be less water-soluble.
Key observations of SAR of TQ are summarized as follows:
Ovarian cancer cell lines:
ꢀ Except the promising compound 6, there appears to be no real
improvement when nitrogen containing substitutions are
tested
ꢀ When halogen substitutions are used, we see an improvement
in 9 and 11
ꢀ Bulky alkyl substations, like in pancreatic cancer,12,13 are less
potent
ꢀ A reduction of TQ to produce thymoquinols generally increases
potency, and appears to be additive when halogens are included
in 19, but no improvement in selective activity
ꢀ 4 and 20 are of note, they are less active against HOE and this
increases their SI, but for 4 this is only due to lower potency
against HOE and for 20 it is improved activity against cancer cell
line and reduced toxicity against HOE
Please cite this article in press as: Johnson-Ajinwo O.R., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.02.051

4
O.R. Johnson-Ajinwo et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
9. Breyer S, Effenberger K, Schobert R. Effects of thymoquinone-fatty acid
P. falciparum:
conjugates on cancer cells. ChemMedChem. 2009;4:761–768.
10. Effenberger K, Breyer S, Schobert R. Terpene conjugates of the Nigella sativa
seed-oil constituent thymoquinone with enhanced efficacy in cancer cells.
Chem Biodivers.. 2010;7:129–139.
11. Effenberger-Neidnicht K, Breyer S, Mahal K, Diestel R, Sasse F, Schobert R.
Cellular localisation of antitumoral 6-alkyl thymoquinones revealed by an
alkyne-azide click reaction and the streptavidin-biotin system. ChemBioChem.
2011;12:1237–1241.
ꢀ Introduction of halogen, nitrogen and larger alkyl substitutions
in general have no effect on potency
ꢀ The same is also true for the thymoquinols
ꢀ Of note are 6 and 13 – the 2,5 arrangement may be important
based on comparisons between 6 and 7
12. Banerjee S, Azmi AS, Padhye S, et al. Structure-activity studies on therapeutic
potential of Thymoquinone analogs in pancreatic cancer. Pharm Res.. 2010;27:
1146–1158.
ꢀ SI is not appropriate here – HOE is not really an effective com-
parison to make
13. Yusufi M, Banerjee S, Mohammad M, et al. Synthesis, characterization and anti-
tumor activity of novel thymoquinone analogs against pancreatic cancer. Bioorg
Med Chem Lett.. 2013;23:3101–3104.
14. Frohlich T, Ndreshkjana B, Muenzner JK, et al. Synthesis of Novel Hybrids of
Thymoquinone and Artemisinin with High Activity and Selectivity Against
Colon Cancer. ChemMedChem. 2017;12:226–234.
15. Fujisaki R, Kamei K, Yamamura M, et al. In Vitro and in Vivo Anti-Plasmodial
Activity of Essential Oils, Including Hinokitiol. Se Asian J Trop Med.. 2012;43:
270–279.
16. Reininger L, Wilkes JM, Bourgade H, Miranda-Saavedra D, Doerig C. An essential
Aurora-related kinase transiently associates with spindle pole bodies during
Plasmodium falciparum erythrocytic schizogony. Mol Microbiol.. 2011;79:
205–221.
In summary, we have synthesized a series of TQ analogues and
evaluated their antiproliferative activities against ovarian cancer
cell lines and human malaria parasite. The TQ analogues 6 and
14 had significant inhibitory activities that doubled that of TQ.
Compound 6 and 2,5-di-tert-butyl-1,4-benzoquinone (13) show
the most potent antiplasmodial activity. Furthermore, the
improved solubility of compound 6 together with its synthetic
tractability warrants additional SAR studies of other analogues
(e.g. monoalkylamino, dialkylamino, and cyclic amino groups) in
order to find lead compounds with significantly improved antipro-
liferative activities against ovarian cancer cell lines.
17. Carvalho TG, Doerig C, Reininger L. Nima- and Aurora-related kinases of malaria
parasites. Biochim Biophys Acta.. 2013;1834:1336–1345.
18. Al Amri AM, Bamosa AO. Phase
I safety and clinical activity study of
thymoquinone in patients with advanced refractory malignant disease. Shiraz
Med J. 2009;10:107–111.
19. Wilson AJ, Saskowski J, Barham W, Yull F, Khabele D. Thymoquinone enhances
cisplatin-response through direct tumor effects in a syngeneic mouse model of
ovarian cancer. J Ovarian Res. 2015;8:46.
20. Taha MME, Sheikh BY, Salim LZA, et al. Thymoquinone induces apoptosis and
increase ROS in ovarian cancer cell line. Cell Mol Biol. 2016;62:97–101.
21. Liu XL, Dong JH, Cai WY, Pan Y, Li RL, Li B. The effect of thymoquinone on
apoptosis of SK-OV-3 ovarian cancer cell by regulation of Bcl-2 and Bax. Int J
Gynecol Cancer. 2017;27:1596–1601.
22. Li WW, Rosa JO, Siddique MR, Bajana B, Sule-Suso J, Richardson A. Anti-cancer
thymoquinone from Nigella sativa. Planta Med. 2013;79:1126.
23. Johnson-Ajinwo OR, Richardson A, Li WW. Cytotoxic effects of stem bark
extracts and pure compounds from Margaritaria discoidea on human ovarian
cancer cell lines. Phytomedicine. 2015;22:1–4.
Acknowledgments
Okiemute Rosa Johnson-Ajinwo is funded by the Education Tax
Fund (ETF), Nigeria for a PhD studentship. Imran Ullah was sup-
ported by a Keele University (UK) ACORN PhD award and the
Charles Wallace Pakistan Trust (UK). We also thank Dr. Johannes
Reynisson for advice.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.bmcl.2018.02.051.
24. Uche FI, Drijfhout FP, McCullagh J, Richardson A, Li WW. Cytotoxicity effects
and apoptosis induction by bisbenzylisoquinoline alkaloids from Triclisia
subcordata. Phytother Res. 2016;30:1533–1539.
25. Murray V, Campbell HM, Gero AM. Plasmodium falciparum: the potential of the
cancer chemotherapeutic agent cisplatin and its analogues as anti-malarials.
Exp Parasitol. 2012;132:440–443.
26. Yang YI, Lee KT, Park HJ, et al. Tectorigenin sensitizes paclitaxel-resistant
human ovarian cancer cells through downregulation of the Akt and NFkappaB
pathway. Carcinogenesis. 2012;33:2488–2498.
27. Januchowski R, Sterzynska K, Zaorska K, et al. Analysis of MDR genes expression
and cross-resistance in eight drug resistant ovarian cancer cell lines. J Ovarian
Res. 2016;9:65.
References
1. Majdalawieh AF, Fayyad MW. Immunomodulatory and anti-inflammatory
action of Nigella sativa and thymoquinone:
Immunopharmacol. 2015;28:295–304.
2. Schneider-Stock R, Fakhoury IH, Zaki AM, El-Baba CO, Gali-Muhtasib HU.
Thymoquinone: fifty years of success in the battle against cancer models. Drug
Discov Today. 2014;19:18–30.
3. Gali-Muhtasib H, Roessner A, Schneider-Stock R. Thymoquinone: a promising
anti-cancer drug from natural sources. Int
a comprehensive review. Int
28. Schrevel J, Sinou V, Grellier P, Frappier F, Guenard D, Potier P. Interactions
J Biochem Cell Biol. 2006;38:
between
docetaxel
(taxotere)
and
plasmodium-falciparum-infected
1249–1253.
erythrocytes. Proc Natl Acad Sci USA. 1994;91:8472–8476.
29. Johnson-Ajinwo OR, Li WW. Stable isotope dilution gas chromatography–mass
spectrometry for quantification of thymoquinone in black cumin seed oil. J
Agric Food Chem. 2014;62:5466–5471.
30. Lu S, Li WW, Rotem D, Mikhailova E, Bayley H. A primary hydrogen-deuterium
isotope effect observed at the single-molecule level. Nat Chem. 2010;2:
921–928.
31. Salmani JM, Asghar S, Lv H, Zhou J. Aqueous solubility and degradation kinetics
of the phytochemical anticancer thymoquinone; probing the effects of solvents,
pH and light. Molecules. 2014;19:5925–5939.
32. Savjani KT, Gajjar AK, Savjani JK. Drug solubility: importance and enhancement
techniques. ISRN Pharm. 2012;2012:195727.
4. Woo CC, Kumar AP, Sethi G, Tan KH. Thymoquinone: potential cure for
inflammatory disorders and cancer. Biochem Pharmacol. 2012;83:443–451.
5. Padhye S, Banerjee S, Ahmad A, Mohammad R, Sarkar FH. From here to eternity
- the secret of Pharaohs: Therapeutic potential of black cumin seeds and
beyond. Cancer Ther. 2008;6:495–510.
6. Khan MA, Tania M, Fu S, Fu J. Thymoquinone, as an anticancer molecule: from
basic research to clinical investigation. Oncotarget. 2017;8:51907–51919.
7. Yin Z, Song YL, Rehse PH. Thymoquinone Blocks pSer/pThr Recognition by Plk1
Polo-Box Domain As a Phosphate Mimic. Acs Chem Biol.. 2013;8:303–308.
8. Yuan J, Sanhaji M, Kramer A, et al. Polo-box domain inhibitor poloxin activates
the spindle assembly checkpoint and inhibits tumor growth in vivo. Am J
Pathol.. 2011;179:2091–2099.
Please cite this article in press as: Johnson-Ajinwo O.R., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.02.051