Novel 1,3,5-triazine derivatives exert potent anti-cervical cancer effects by modulating Bax, Bcl2 and Caspases expression

Article abstract of DOI:10.1111/cbdd.13133

This study aimed to develop novel 1,3,5-triazine derivatives as potent anti-cervical cancer agents. The compounds were synthesized in short steps with an excellent yield and characterized via various spectroscopic and analytical methods. A structure–activity relationship study suggested that electron-withdrawing substituents showed greater anticancer activity than electron-donating groups. Compound 7p (p-fluoro) showed the highest activity against cervical cancer cells. In a nude mouse xenograft model inoculated with HeLa cells, 7p showed dose-dependent inhibition of cervical tumour growth. Histopathological examination of excised tumour-bearing tissues showed that 7p improved the microstructure in a dose-dependent manner. Compound 7p also increased the proportions of HeLa cells in G0/G1 and S-phase and significantly decreased that of G2/M-phase. The effects of 7p on C-caspase-3, C-caspase-9, Bcl-2 and Bax expression in HeLa cells were also determined.

Full text of DOI:10.1111/cbdd.13133

DR WEI ZHANG (Orcid ID : 0000-0002-0811-9773)
Article type : Research Article
Novel 1,3,5-Triazine Derivatives Exert Potent Anti-cervical Cancer Effects
by Modulating Bax, Bcl2, and Caspases Expression
Xiwen Wang1, Yuexiong Yi1, Qiongying Lv1, Juan Zhang2, Kejia Wu1, Wanrong Wu2, Wei
Zhang1*
1Department of obstetrics and gynecology, Zhongnan Hospital of Wuhan University,
Wuhan, 430071, China
2Department of obstetrics and gynecology, Renmin Hospital of Wuhan University,
Wuhan, 430071 China
*Corresponding author:
Wei Zhang
Department of obstetrics and gynecology,
Zhongnan Hospital of Wuhan University, China
Tel/Fax: 0086-027-67813142
Email: Warde.Amantea5523@hotmail.com
Running title: Anti-cervical cancer activity of 1,3,5-triazine derivatives
Abstract
The present study aimed to develop novel 1,3,5-triazine derivatives as potent anti-cervical
cancer agents. The compounds were synthesised in short steps with an excellent yield and
characterised via various spectroscopic and analytical methods. A structure–activity
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been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/cbdd.13133
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relationship study suggested that electron-withdrawing substituents showed greater anticancer
activity than electron-donating groups. Compound 7p (p-fluoro) showed the highest activity
against cervical cancer cells. In a nude mouse xenograft model inoculated with HeLa cells,
7p showed dose-dependent inhibition of cervical tumour growth. Histopathological
examination of excised tumour-bearing tissues showed that 7p improved the microstructure
in a dose-dependent manner. Compound 7p also increased the proportions of HeLa cells in
G0/G1 and S-phase and significantly decreased that of G2/M-phase. The effects of 7p on C-
caspase-3, C-caspase-9, Bcl-2, and Bax expression in HeLa cells were also determined.
Keywords: 1,3,5-triazine, anti-cervical cancer, HeLa cells, C-caspase-3
1. Introduction
Cancer is the second-leading cause of morbidity and mortality globally, after cardiovascular
disease [1,2]. It has been estimated that by 2025, there will be 19.3 million new cases of
cancer annually [3]. Recent advances in diagnostics and therapeutics have enhanced our
understanding of cancer, which has resulted in development of targeted therapeutics [4].
After breast cancer, cervical cancer is the most frequent type of cancer in women, with an
annual incidence of 528,000 new cases in developed countries [5,6]. Current treatments for
cervical cancer have numerous disadvantages, such as loss of efficacy, resistance to drugs,
pharmacokinetic tolerability, and side effects [7,8]. Thus, development of novel drugs
effective against cervical cancer is essential [9].
The discovery of anticancer drugs has been enhanced by protein kinase (PK) inhibitors due to
their important role in tumour cell proliferation and survival [10]. To date, more than 40
inhibitors of approximately 30 distinct kinases have reached phase I clinical trials. Kinases
are overexpressed in various cell types. The PI3K/AKT pathway is altered in tumours from
patients with a positive post-therapy [18F]-fluoro-deoxy-glucose-positron emission
tomography (FDG-PET). Moreover, p-AKT expression was found to be higher in pre-
treatment biopsy samples, and patients whose tumours expressed high levels of p-AKT had
decreased survival and an increased prevalence of metastatic disease after standard
chemoradiation [11]. Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase
(RTK), is involved in cervical cancer progression [12,13]. Moreover, its stimulation activates
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the PI3K/AKT/mTOR pathway, resulting in protein synthesis activated by translation factor.
and degradation of the tumour-suppressor transcription factor FOXO3 [14].
Synthetic molecules are used to develop kinase inhibitor anticancer agents that attenuate
cellular proliferation [15,16]. In this regard, derivatives of 1,3,5-triazine have received
considerable attention [17,18]. 1,3,5-Triazines have various pharmacological activities, such
as antibacterial [19-22], antifungal [23], antimalarial [24-26], antidiabetic [27,28], and anti-
cystic fibrosis [29] effects. Moreover, 1,3,5-triazine exerts anticancer effects by inhibiting
PI3K/mTOR [30], Rad6 ubiquitin conjugating enzyme [31], and human epidermal growth
factor receptor-tyrosine kinases (EGFR-TKs) [32, 33].
Therefore, in the present study, we developed a novel series of 1,3,5-triazines containing
substituted phenylthiazole derivatives as potent anti-cervical cancer agents.
2. Materials and Methods
2.1. Chemistry
1
The chemicals used in the present study were procured from Sigma Aldrich (USA). H and
13C nuclear magnetic resonance (NMR) spectra were recorded on Bruker Avance 400 and
Bruker Avance 100 spectrophotometers, respectively. Chemical shifts are expressed in parts
per million (ppm), and coupling constants are expressed in Hertz (Hz). Low-resolution mass
spectra (MS) were recorded on a Waters ZQ LC/MS single quadrupole system equipped with
an electrospray ionisation (ESI) source. Elemental analysis of the final derivatives was
performed using a Vario Elemental analyser. Thin-layer chromatography was performed on
0.25-mm Merck silica gel plates (60F-254) and visualised under ultraviolet light.
2.1.1. Synthesis of 2-chloro-4,6-bis(2-phenylhydrazinyl)-1,3,5-triazine (3)
2,4,6-Tri chloro-s-triazine (1) (0.1 mol) was dissolved in 25 mL acetone at 40–45C.
Phenylhydrazine (2) (0.2 mol) was added, the solution was stirred for 3 h, and NaHCO3
(0.1 mol) was added dropwise while maintaining a pH > 7.0. The product was filtered,
washed with cold water, and recrystallised with ethanol to afford pure products (3).
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2.1.2. General procedure for synthesis of 4-(4-subsituted phenyl)thiazole-2-Yl)amine 6
(a-p)
Various substituted phenyl thiazoles were synthesised as reported previously [34].
2.1.3. General procedure for synthesis of title compounds 7 (a-p)
2-Chloro-4,6-bis(2-phenylhydrazinyl)-1,3,5-triazine (3) (0.1 mol) and various substituted
phenyl thiazole 6 (a-p) and K2CO3 (0.1mol) were added to 60 mL of 1,4-dioxane and
refluxed at 120–125C for 12 h. The product was filtered, washed with cold water, and
recrystallised with ethanol to afford the title compounds 7a–p.
2.1.3.1.
2-(4,6-bis(2-phenylhydrazinyl)-1,3,5-triazin-2-yl)-4-(2-fluorophenyl)thiazole
(7n)
Yield: 77%; MP: 194–195C; MW: 470.52; Rf: 0.68; FT-IR (νmax; cm−1 KBr): 3395 (N–H str,
–NH), 3128 (Ar C-H str), 1623 (C=C str), 1138 (aromatic C-Cstr), 1535, 1502 (N–H bend,
NH), 1208 (Ar-F), 1043 (C–N str), 639 (C–S str) cm−1; 1H-NMR (400 MHz, DMSO, TMS) δ
ppm: 8.06 (s, 1H, thiazole-H), 7,64 (d, 1H, J = 3.5 Hz, Ar-H), 7,49 (d, 1H, J = 1.5 Hz, Ar-H),
7.42 (d, 1H, J = 7.4 Hz, Ar-H), 7.24 (d, 4H, J = 8.2 Hz, ArH), 7.21 (d, 1H, J = 3.2 Hz, ArH),
7.04 (d, 4H, J = 3.2 Hz, ArH), 6.94 (d, 2H, J = 1.2 Hz, ArH), 3.93 (s, 4H, NHx4); 13C-NMR
(100 MHz, CDCl3) δ, ppm: 179.2, 176.5, 161.4, 158.3, 152.3, 148.8, 130.4, 129.3, 129.1,
124.9, 123.5, 122.8, 114.8, 113.2, 110.8; mass: 471.58 (M+1); elemental analysis of
C24H19FN8S: calculated: C, 61.26; H, 4.07; N, 23.81; found: C, 61.34; H, 4.02; N, 23.86.
2.1.3.2.
2-(4,6-bis(2-phenylhydrazinyl)-1,3,5-triazin-2-yl)-4-(3-fluorophenyl)thiazole
(7o)
Yield: 73%; MP: 198–199C; MW: 470.52; Rf: 0.71; FT-IR (νmax; cm−1 KBr): 3398 (N–H str,
–NH), 3126 (Ar C-H str), 1625 (C=C str), 1132 (aromatic C-Cstr), 1535, 1502 (N–H bend,
NH), 1206 (Ar-F), 1045 (C–N str), 634 (C–S str) cm−1; 1H-NMR (400 MHz, DMSO, TMS) δ
ppm: 8.09 (s, 1H, thiazole-H), 7,65 (d, 1H, J = 1.5 Hz, Ar-H), 7.54 (d, 1H, J = 1.2 Hz, Ar-H),
7.52 (d, 1H, J = 8.1 Hz, Ar-H), 7.26 (d, 4H, J = 1.3 Hz, ArH), 7.22 (d, 1H, J = 8.2 Hz, ArH),
13
7.05 (d, 4H, J = 3.2 Hz, ArH), 6.92 (d, 2H, J = 1.2 Hz, ArH), 3.95 (s, 4H, NHx4); C-NMR
(100 MHz, CDCl3) δ ppm: 178.8, 176.4, 162.2, 161.3, 152.4, 148.9, 134.6, 129.3, 127.5,
123.1, 122.8, 115.9, 115.4, 113.2, 110.8; mass: 471.55 (M+1); elemental analysis of
C24H19FN8S: calculated: C, 61.26; H, 4.07; N, 23.81; found: C, 61.28; H, 4.09; N, 23.84.
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2.1.3.3.
2-(4,6-bis(2-phenylhydrazinyl)-1,3,5-triazin-2-yl)-4-(4-fluorophenyl)thiazole
(7p)
Yield: 83%; MP: 205–206C; MW: 470.52; Rf: 0.69; FT-IR (νmax; cm−1 KBr): 3397 (N–H str,
–NH), 3128 (Ar C-H str), 1629 (C=C str), 1135 (aromatic C-Cstr), 1536, 1504 (N–H bend,
NH), 1208 (Ar-F), 1047 (C–N str), 635 (C–S str) cm−1; 1H-NMR (400 MHz, DMSO, TMS) δ
ppm: 7.97 (s, 1H, thiazole-H), 7,83 (d, 2H, J = 3.2 Hz, Ar-H), 7.23 (d, 4H, J = 8.2 Hz, ArH),
7.16 (d, 2H, J = 8.5 Hz, ArH), 7.04 (d, 4H, J = 3.1 Hz, ArH), 6.90 (d, 2H, J = 1.2 Hz, ArH),
13
3.97 (s, 4H, NHx4); C-NMR (100 MHz, CDCl3) δ ppm: 178.9, 176.5, 162.8, 161.4, 152.3,
148.9, 130.7, 129.2, 128.7, 122.8, 116.1, 113.3, 110.8; mass: 471.63 (M+1); elemental
analysis of C24H19FN8S: calculated: C, 61.26; H, 4.07; N, 23.81; found: C, 61.23; H, 4.08; N,
23.79.
2.2. Cancer cell proliferation assay
The in vitro activities of the compounds against the human cancer cell lines MDA-MB-231
(breast), HeLa (cervical), KG1a (acute myelogenous leukaemia), Jurkat (T-cell leukaemia)
cells, as well as MCF 12A normal breast epithelial cells; and the cervical cancer cell lines
SiHa, CasKi and DoTc2, were evaluated. Target tumour cells were grown to logarithmic
phase in DMEM supplemented with 10% foetal bovine serum. After reaching 1 × 105 cells
mL−1, 100 μL of cell suspension was added to each well of 96-well culture plates.
Subsequently, incubation was performed at 37°C in a 5% CO2 atmosphere for 48 h. Samples
at pre-set concentrations were added to six-well plates; erlotinib was used as the positive
control. After incubation for 72 h, 25 L of PBS containing 2.5 mg mL−1 MTT were added to
each well. After 4 h, the medium was replaced with 150 L DMSO to dissolve purple
formazan crystals. The absorbance at 570 nm of each well was measured using an ELISA
plate reader. The data are means of three independent experiments ± standard deviation (SD).
The IC50 value was defined as the concentration at which 50% of cells survived [35].
2.3. Selectivity index
The selectivity indexes of compounds 7n, 7o, and 7p against MCF 12A cells were calculated
using the following formula: SI = 50% inhibitory concentration (IC50) of the pure compound
in MCF 12A cells  IC50 in SiHa cells.
2.4. Nude mouse xenograft model
The in vivo antitumour activity of compound 7p was evaluated in nude mice inoculated with
HeLa cells, as described previously [36]. Briefly, BALB/C nude mice were randomly
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classified into four groups of five mice each – group 1: control group (0.5% dimethyl
sulfoxide [DMSO], 0.1 ml/10 g); group 2: 2 mg/kg/d compound 7p, intraperitoneally (i.p.);
group 3: 5 mg/kg/d compound 7p, i.p.; and group 4: 10 mg/kg/d compound 7p, i.p.. The mice
(18–22 g) were then injected subcutaneously (s.c.) in the right flank with HeLa cells (2.0 ×
106/mouse). When the tumour diameter reached approximately 2–3 mm, mice were treated
i.p. with various concentrations of compound 7p or an equal volume of solvent control (0.5%
DMSO, i.p.). Treatment continued for 15 days, and tumour sizes (width and length) were
measured at 0, 5, 8, 12, and 15 days. Tumour volumes were determined using the formula:
volume = (width2 × length)  2, and the body weight of the mice. Tumour tissue was fixed in
10% neutral-buffered formalin, embedded in paraffin, sectioned, and processed for
haematoxylin and eosin (HE) staining (magnification, 100).
2.5. Western blotting
HeLa cells (1  106/flask) were seeded in T-25 flasks and treated with 10, 20, or 30 μg/mL
compound 7p. After incubation for 24 h, cells were harvested and total proteins extracted
with cell lysis buffer. The protein concentration was determined using a BCA protein assay
kit. Equal amounts of total protein (40 μg) were separated by sodium dodecyl sulphate-
polyacrylamide gel electrophoresis (SDS-PAGE). Proteins were transferred to polyvinylidene
difluoride (PVDF) membranes and probed with monoclonal antibodies against caspase-3,
caspase-9, Bax, Bcl-2 and β-actin. After incubation for 12 h at 4°C, a horseradish peroxidase
(HRP)-labelled secondary antibody was added, and incubated for 2 h at 37°C. Protein bands
were detected using a Beyo ECL Plus kit. To normalise protein loading, Bio-Rad Quantity
One software was used to quantify band densities, and protein levels were expressed relative
to that of β-actin.
2.6. Statistical analysis
Values are expressed as means ± SD and were evaluated by Student’s t-test or one-way
analysis of variance (ANOVA). All statistical analyses were performed using SPSS 17.0
software; a value of P < 0.05 was considered to indicate significance.
3. Results and Discussion
3.1. Chemistry
The target derivatives were synthesised with excellent yields via a facile synthetic route
(Scheme 1). Initially, 2-chloro-4,6-bis(2-phenylhydrazinyl)-1,3,5-triazine (3) was obtained by
reaction of 1,3,5-triazine (1) with phenylhydrazine (2) using NaHCO3 in acetone. At the
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second stage, various substituted phenyl thiazoles 6(a-p) were obtained by reaction of
substituted phenyl acetone 4(a-p) with thiourea (5). Finally, the title derivatives 7(a-p) were
obtained by the reaction of phenyl thiazole derivatives 6(a-p) with 2-chloro-4,6-bis(2-
phenylhydrazinyl)-1,3,5-triazine (3) in DMSO using K2CO3 as a base. The structures of the
1
12
synthesised derivatives were ascertained by determining their mass, and by H-NMR, C-
NMR, FT-IR, and elemental analyses. The FT-IR spectra of all synthesised derivatives 7(a-p)
were characterised by the appearance of strong bands at 3398–3395 cm−1, attributed to
stretching vibrations of secondary amine groups. Furthermore, the strong band at 3126–3128
cm−1 was due to aromatic ring C-H groups. The aromatic F group appeared at 1206–1208
cm−1. The strong bond at 636–634 cm−1 was attributed to stretching vibrations of C–S groups
1
in thiazole rings. The H NMR spectra of derivatives 7(a-p) exhibited a doublet
corresponding to aromatic rings at 7.22–7.04 ppm. The phenyl thiazole ring appears at 8.08–
798 ppm as a single peak. Furthermore, the resonance at 7.81–7.54 ppm confirmed the
presence of a methylene proton with a doublet peak of fluoro phenyl thiazole rings. The
phenyl thiazole side-chain NH proton appeared at 3.95–3.93 as a singlet peak. The structures
of all synthesised derivatives were confirmed by mass spectroscopy and elemental analysis.
<Scheme 1>
3.2. Biological activity
3.2.1. Anticancer activity
The activities of the synthesised compounds against MDA-MB-231 (breast), HeLa (cervical),
KG1a (acute myelogenous leukaemia), and Jurkat (T-cell leukaemia) cancer cells were
evaluated using erlotinib as a control (Table 1). All of the compounds, with the exception of
compounds 7a and 7b, showed considerable inhibition of all of the cell lines. Compound 7a,
which has intact phenyls in the thiazole ring substituted on a 1,3,5-triazine core scaffold
showed negligible activity (Table 1). Compound 7b, which has an o-methyl substitution in
the phenyl ring of thiazole, showed a similar pattern of inhibition. Alteration of the methyl
position from ortho to meta (7c) markedly increased the activity of the compounds against
MDA-MB-231, KG1a, Jurkat, and HeLa cells. A shift of the methyl to the para position
significantly increased the activity of the resulting compound (7d) against the cancer cell
lines. Next, the methyl was replaced by methoxy on the phenyl ring (7e, 7f, and 7g); this also
increased the activity of the compounds. There was no significant difference in the activities
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of compounds 7f and 7g, which contain meta- and para-methoxy groups, respectively. The
ortho-methoxy substituted compound (7e) showed the lowest activity. The compounds with
ortho- (7h) and meta-hydroxy (7i) as substituents exhibited similar effects on MD-MB-231,
HeLa, and KG1a cells, but not Jurkat cells. In contrast, 7j (para-) showed excellent inhibitory
activity against all cell lines, including HeLa cells (IC50 24.05 ± 2.33 µg/mL).
Halogen-containing compounds showed considerable activity against all cell lines.
Compounds 7k, 7l, and 7m (chloro-) showed moderate inhibitory activity against the cancer
cell lines, suggesting para-chloro to be more potent than ortho- and meta-. Compounds 7n,
7o, and 7p (fluoro-) exhibited the greatest activity against all of the cell lines.
The compounds exerted potent effects against HeLa cells but lesser effects against Jurkat
cells. A structure–activity relationship study suggested that the halogen-containing
compounds (F and Cl) had higher activity than non-halogen (OH, OCH3, and CH3)
compounds. Moreover, the pattern of substitution influenced the activity of the compounds
(Scheme 1[B]). The para substituted compound found to be more active than ortho-
substituted congener (Figure 1).
<Table 1>
<Figure 1>
We next analysed the inhibitory activity of compounds 7n, 7o, and 7p against SiHa, CasKi,
and DoTc2 cervical cancer cells (Table 2). Compound 7p showed the highest activity against
SiHa (IC50 1.34 ± 0.12 µg/mL), DoTc2 (IC50 2.15 ± 0.18 µg/mL), and CasKi (IC50
4.56 ± 0.35 µg/mL) cells. Compounds 7o and 7n showed similar inhibitory effects, and
compound 7n showed high activity against all cervical cancer cell lines. The selectivity of
these compounds against SiHa cells was quantified; the compounds selectively inhibited all
of the cervical cancer cell lines (Table 3).
<Table 2>
<Table 3>
The effect of compound 7p against cervical cancer was evaluated in the nude mouse
xenograft model (Figure 2). Compound 7p exerted a dose-dependent inhibitory effect on
tumour growth, as evidenced by the reduction in tumour volume. The control group showed a
normal cellular (NC) architecture (Figure 3a), whereas in the treated groups, the number of
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normal cells were less visible with increased viable tumour cells (VC) and mitotic figures. At
the highest test dose (10 mg/kg), apoptotic cells (AC) caused karyopyknosis and cellular
damage. Thus, compound 7p exerts a dose-dependent effect on microstructural changes in
tumour tissues (Figure 3).
<Figure 2>
<Figure 3>
The effect of compound 7p on cell growth and cell-cycle arrest was evaluated. Pre-treatment
of HeLa cells with compound 7p (5 µM) resulted in a significant increase in the proportion of
cells in G0/G1 phase from 40.33% to 46.66% (Figure 4); the S-phase proportion also
increased considerably. Compound 7p showed a significant decrease (> 9%) in the proportion
of cells in G2/M phase compared with the control.
<Figure 4>
Apoptosis is a complex biological process that involves a series of interrelated events.
Caspases are activated via the death-receptor mediated pathway, and subsequently induce
cellular death by recruiting mediators of apoptosis. Caspase-3 is an important effector of the
extrinsic and intrinsic apoptosis pathways. The Bcl2 protein family plays a vital role in
regulating mitochondria-mediated apoptosis by exerting pro- and anti-apoptotic effects. Bax
and Bcl-2 are crucial pro- and anti-apoptotic proteins, respectively. Thus, we next elucidated
the effect of compound 7p on C-caspase-3, C-caspase-9, Bcl-2, and Bax expression in HeLa
cells. Compound 7p significantly increased C-caspase-3, C-caspase-9, and Bax expression in
a time-dependent manner (Figure 5). In contrast, compound 7p significantly decreased Bcl-2
expression in a concentration-dependent manner, suggesting a role in modulation of apoptosis
during cancer progression.
<Figure 5>
Conclusion
The synthesised 1,3,5-triazine derivatives exerted considerable anti-cervical cancer effects by
increasing the fraction of G0/G1-phase cells and decreasing that of G2/M-phase cells.
Compound 7p exhibited the highest activity, together with favourable toxicity and metabolite
profiles, suggesting its utility for synthesis of more-potent analogues.
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Acknowledgements
Authors are thankful to the Zhongnan Hospital of Wuhan University, Wuhan, China for
supporting the present study.
Conflicts of Interest
The authors declare no conflict of interest.
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Figures, Tables and Schemes captions
Figure 1: Structure activity relationship (SAR) of compounds as anticancer agents.
Figure 2: Effect of compound 7p on the tumour volume of BALB/C nude mice after
inoculated subcutaneously with Hela cells. The data were expressed as mean ± SD; *p < 0.05,
**p < 0.01, compared with control mice.
Figure 3: Anti-tumour activity of compound 7p in vivo anti-tumour activity in mice models.
a: control group, b: 7p (2 mg/kg); c: 7p (5 mg/kg); d: 7p (10 mg/kg), Where, normal cells
(NC), viable tumour cells (VC), mitotic cells (MC) and apoptotic cells (AC). Mag.40x.
Figure 4: Compound 7p causes increases in the fraction of G0/G1 phase cells and decreases
the proportion of G2/M phase cells. The data were expressed as mean ± SD; *p < 0.05
compared with control mice
Figure 5: Effect of compound 7p on the expressions of Bcl-2, Bax and caspase family of
proteins.
Scheme 1: Synthesis of 1,3,5-triazine derivative. Reagents and condition (A) a) NaOH, 40–
50°C; b) Br2, reflux c) NaHCO3, 135–145 °C;
Table 1: Anticancer activity of target compounds 7 (a-p) against in human cancer cell lines
MDA-MB-231 (breast), HeLa (cervical), KG1a (acute myelogenous leukaemia) and Jurkat (T
cell leukaemia).
Table 2: Anticancer activity of compound against cervical cancer cells.
Table 3: Selectivity Index of target compounds.
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List of Tables
Table 1
Compound
IC50 (in µg/mL)#
KG1a
MDA-MB-231
>100
HeLa
>100
>100
Jurkat
7a
>100
>100
7b
>100
>100
>100
7c
78.34
41.21±5.55
36.45±4.42
32.15±3.58
28.44±4.45
27.11±5.03
26.34±4.24
26.76±2.21
24.05±2.33
21.17±2.63
15.45±2.04
14.34±2.35
11.56±1.03
6.15±0.87
2.21±0.54
0.21±0.03
67.12±6.72
51.82±4.65
41.63±6.22
35.73±3.25
35.46±4.30
31.31±3.35
31.52±4.36
29.43±3.30
28.54±1.34
16.78±1.41
18.39±1.52
15.86±1.40
8.53±1.05
6.45±0.65
0.18±0.05
91.45±11.21
73.36±6.52
62.50±5.30
58.42±4.52
57.62±4.73
56.33±5.67
52.34±3.40
45.24±3.56
41.66±3.36
39.45±2.43
37.31±4.43
31.30±3.42
27.13±2.45
28.33±2.34
22.43±1.32
7d
66.30±7.35
44.56±6.13
39.31±5.56
38.04±5.63
30.22±5.27
30.11±3.48
28.52±3.45
26.63±2.02
18.54±1.45
17.22±2.40
17.26±1.67
8.21±0.56
4.34±0.23
0.16±0.004
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
Erlotinib
#Results are expressed as triplicate testing mean values.
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Table 2
IC50 (in µg/mL)#
CasKi
Compound
SiHa
DoTc2
7n
1.99±0.03
1.56±0.05
1.34±0.12
0.25±0.06
6.13±0.60
5.03±0.55
4.56±0.35
0.34±0.02
4.51±0.73
3.40±0.45
2.15±0.18
0.28±0.04
7o
7p
Erlotinib
#Results are expressed as triplicate testing mean values.
Table 3
Compound
IC50 (in µg/mL)#
MCF 12 A
Selectivity Index##
SiHa
7n
1.99±0.03
1.56±0.05
1.34±0.12
0.25±0.06
87.13±0.60
68.03±0.55
59.56±0.35
Non-toxic
43.78
7o
43.60
7p
44.44
Erlotinib
Not determined
#Results are expressed as triplicate testing mean values.
## Selectivity index = IC50 on normal cells/IC50 of cancer cells
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This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.