Paper
NJC
Further studies indicated that 7g, 7i, and 7q showed admirable 3.3. Structure–activity relationship (SAR) of the title
À1
activities with the IC50 of 10.38, 13.90, and 11.50 mmol L
,
compounds against tumour cells
respectively. Notably, compound 7n bearing a 2-fluorobenzoyl
As indicated in Tables 1 and 2, the antitumour effects of the
target compounds were greatly affected by structural variations.
Some structure–activity relationship (SAR) analyses are discussed
pattern showed the highest inhibitory activity with the IC of
5
0
À1
7
.73 mmol L . These data were better or close to positive agents,
namely gefinitinib and 5-fluorouracil, suggesting that highly active
compounds were found by the rational modification of the core
framework.
2
below. The presence of 7g (3-F), 7i (3-Br), 7n (2-F), and 7q (2,4-F )
groups at the R position greatly increased the activities of
the target compounds against A549. For instance, the target
compounds 7a (4-CN), 7b (4-NO ), 7m (3,4-F ), 2,4-F , and 7q
Anti-tumor drugs generally have poor selectivity. They kill
tumor cells as well as normal cells, particularly the fast-growing
cell tissues in the body. Toxicity and selectivity issues, which
frequently result in the clinical chemotherapy failure, have
recently led to little improvement in the long-term cancer
therapy in the past few decades. Therefore, it is important to
develop new highly effective and low toxicity antiproliferative
agents. A type of nontumorigenic cell line NRK-52E was
used to test the selectivity of some high-activity compounds
towards cancer cells and normal cells. As shown in Table 3,
those compounds had no apparent toxicity towards NRK-52E
cells. The most potent compounds 7n and 7q were screened
against the NRK-52E nontumorigenic cell line to determine
their selectivity and relative safety towards normal cells. The
compounds showed a low cytotoxic effect with the IC50 of 21.33
and 27.97 mM against the NRK-52E cell line. Measuring the
selectivity index indicates that compounds 7n and 7q showed
more selectivity towards A549 than PC-3 cell lines than
positive drugs.
2
2
2
2
(2,4-F ) showed important antitumour activities against PC-3,
with the IC50 values of 9.11, 8.86, 8.24, 7.42 and 7.36 mM,
respectively. When F groups were at the R position, the protective
activities of the relevant compounds 7g, 7m, 7n and 7q, respectively,
were superior to other substituent groups.
3.4. 3D-QSAR study
A 3D-QSAR model was built to give more precise information of
the structure–activity relationship based on the title compounds
2
7–29
pIC50 values against PC-3.
The comparative molecular
field analysis (CoMFA) model was established via the Sybyl-X2.0
software from Tripos Inc. (St. Louis, MO, USA) (Table 4).
The computation results are illustrated in Table 2. The cross-
2
2
validation coefficient q , the correlation coefficients r , standard
errors of estimate, and the F-value of the CoMFA model are 0.547,
0
.980, 0.042, and 49.634, respectively, indicating that the optimal
30
3D-QSAR model was obtained.
The contribution of the steric field and the electrostatic
The results showed that compounds 7g, 7n and 7q
have good cytotoxicity, particularly 7n and 7q are higher than
the positive control drug gefitinib and close to the positive
control drug 5-fluorouracil towards A549 and PC-3 cells.
Based on these findings, it can be concluded that compounds
fields are 44.8% and 55.2%, suggesting that the steric and
electrostatic fields almost gave a similar influence. The predicted
pEC50 values of title compounds showed the same trend with the
experimental pEC50 values listed in Table 2. Moreover, a linear
relationship between the predicted and the experimental pIC50
7n and 7q have potential for further development as
2
was described in Fig. 2. The correlation coefficient R of the
anticancer drugs.
CoMFA model is 0.927 close to the calculated value, indicating
that the model is accurate and has a good prediction ability
3
1
(Fig. 2).
The CoMFA contour maps are illustrated in Fig. 3. As shown
Table 3 The selectivity index of some compounds 7–9 towards the
tested cell lines
in the steric contour map (Fig. 3A), the green contours (80%)
and the yellow contours (20%) represent favorable areas for
steric-bulk and steric-disfavored positions. A green pattern
located the 3-position of the phenyl ring suggested that a bulky
group would improve the antitumour activity. On the contrary,
the yellow part indicated that a bigger substituent in 4-position
would reduce the bioactivity. The pharmaceutical effects of
compounds are in the order: 7e (4-F) 4 7f (4-Cl) 4 7c (4-Br),
Selectivity index (SI)
À1
IC50 (mmol L
NRK-52E
)
Compd
A549
PC-3
7
7
7
7
7
7
7
7
7
7
7
8
8
9
9
9
9
a
b
e
g
i
k
m
n
q
r
26.90 Æ 8.76
30.05 Æ 2.43
27.13 Æ 2.38
35.42 Æ 5.10
38.17 Æ 1.58
40.69 Æ 7.83
48.42 Æ 2.43
21.33 Æ 5.00
29.77 Æ 3.54
57.55 Æ 6.66
21.04 Æ 4.13
33.27 Æ 8.08
47.42 Æ 0.21
27.73 Æ 2.38
37.56 Æ 2.70
27.74 Æ 7.41
51.09 Æ 7.57
20.07 Æ 6.31
13.89 Æ 2.85
2.95
3.39
0.54
1.25
0.92
1.27
5.88
2.87
4.04
3.56
0.53
1.44
1.93
1.68
0.99
2.02
2.11
2.06
3.19
1.84
1.98
1.26
3.41
2.75
0.99
2.10
2.76
2.59
3.36
0.87
1.57
2.74
0.76
2.17
1.27
2.52
2.18
2.14
7
a (4-CN) 4 7b (4-NO ) 4 9d (4-OCH ), 9b (3-F, 4-H) 4 9a (3,4-
2 3
F ), 7i (3-Br) 4 7h (3-Cl), 7l (3,4-Cl ) 4 7m (3,4-F ) and 9e (3-Cl,
2
2
2
4-CF ) 4 7s (3-H, 4-CF ). The blue contours (80% contribution)
3
3
and the red contours (20% contribution) in the electrostatic
s
a
b
a
b
e
f
Table 4 Summary of CoMFA analysis
Contribution (%)
2
2
q
r
s
F
Steric
0.448
Electrostatic
0.552
Gefitinib
5
-Fluorouracil
CoMFA
0.547
0.980
0.042
49.634
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2021
New J. Chem., 2021, 45, 4626À4631 | 4629