G Model
CCLET 3799 1–5
4
X.-D. Jia et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
Table 2
In vitro activity of selected compounds against ten cell lines.
a
Compd.
IC50
(
mmol/L)
HL60
HepG2
HCT-116
A549
PANC-1
Hela
DU145
SKOV3
MCF-7
MCF-7/DOX
10c
1.62
0.77
12.10
6.20
1.18
2.76
4.80
1.17
2.91
16.73
13.24
15.72
10.85
2.99
39.40
27.69
23.32
21.15
5.62
17.27
11.62
22.93
8.74
>50
>50
>50
>50
5.30
>50
>50
>50
>50
>50
>50
49.24
28.80
22.68
26.49
5.18
35.82
24.78
31.05
17.28
5.57
16.54
23.56
<0.5
10e
32.52
>50
10h
10i
42.08
21.72
6.25
26.50
15.41
5.52
>50
<0.5
10j
4.05
<0.5
10k
13.59
6.77
29.70
12.68
18.74
>50
16.00
5.19
44.62
15.76
41.64
25.65
34.29
33.90
44.97
19.63
12.21
14.59
16.27
1.43
10m
1a
>50
26.42
29.21
>50
3.17
22.06
48.05
6.96
18.05
Etoposide
1.97
>50
a
IC50 values were presented as the concentration of drug inhibition 50% cell growth and determined by at least three separate tests and reported.
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
Etoposide- and/or 1a – resistant ones, and is 1.3 to >100 fold more
potent than those of the two references against these cell lines,
except HL60 and HepG2.
Appendix A. Supplementary data
164
Supplementary data associated with this article can be found, in
165
166
167
According to the biological evaluation results shown in
Tables 1 and 2, the antitumor activity of the naphthyridinone
derivatives in this study depends on both of the groups at the
N-1 and C-7 positions. The relative contribution of the
heteroaromatic ring at the N-1 position to activity is as
follows: thiazol-2-yl (1a) ꢀ 1H-imidazol-2-yl (1f) >thiophen-
3-yl (1d), and the others (1b, 1c, 1e, 1g–i) have no activity
(Table 1).
On the other hand, 1-(thiazol-2-yl)naphthyridinones 10a–n
generally exhibit in vitro activity (Table 1), which indicates that a
nitrogen heterocycle with an oxime group is permitted at the C-7
position. Although a simple SAR is difficult to explore, the sizes of
the heterocycle and the oxime group are important for the activity.
For example, the activity imparted to the 7-(3-aminomethyl-3-
methylpyrrolidin-1-yl)naphthyridinone ring by the alkyl group of
the oxime moiety is as follows: benzyl > ethyl > methyl (10j vs 10i
vs 10h), which suggests that simply increasing the lipophilicity
could improve the activity (Table 2). Above all, thiazol-2-yl and 3-
aminomethyl-4-benzyl oxyimino-3-methylpyrrolidin-1-yl groups
are the most active at the N-1 and C-7 positions of naphthyridinone
core, respectively.
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4. Conclusion
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In summary, structural modifications of compound 1a (a
precursor of Voreloxin) at the N-1 position (various heteroaro-
matic rings instead of the thiazol-2-yl) and C-7 position (four-/
five-/six-membered nitrogen heterocyclic amine moieties with an
oxime group instead of 3-aminopyrrolidin-1-yl one), respectively,
were made in this study. Our results reveal that thiazol-2-yl and 3-
aminomethyl-4-benzyloxyimino-3-methylpyrrolidin-1-yl
groups are optimal at the N-1 and C-7 positions of naphthyr-
idinone core, respectively. The most active compound 10j shows
considerable broad-spectrum antitumor activity (IC50: <0.5–
6.25
mmol/L) against all of the tested cell lines including Etopo-
side- and/or 1a-resistant ones and is 1.3 to >100 fold more potent
than those of the two references against these cell lines, except
HL60 and HepG2.
158
159
Acknowledgment
This work was supported by National Key Research and
160 Q2 Development Program (2016YFA0201500), the National S&T
161
162
163
Major Special Project on Major New Drug Innovations (Nos.
2014ZX09507009-003, 2015ZX09102007) and NSFC (Nos.
81373267, 21502237).
Please cite this article in press as: X.-D. Jia, et al., Synthesis and in vitro antitumor activity of novel naphthyridinone derivatives, Chin.