Substrate-controlled chemoselective synthesis and potent cytotoxic activity of novel 5,6,7-triarylpyrido[2,3-d]pyrimidin-4-one derivatives

Article abstract of DOI:10.1016/j.bmcl.2010.09.114

The substrate-controlled chemoselective synthesis of novel 5,6,7-triarylpyrido[2,3-d]pyrimidin-4-one derivatives has been successfully achieved via microwave-assisted three-component reactions of 2,6-diaminopyrimidin-4(3H)-one, aromatic aldehydes and 1,2-

Full text of DOI:10.1016/j.bmcl.2010.09.114

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1554–1558
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Substrate-controlled chemoselective synthesis and potent cytotoxic activity
of novel 5,6,7-triarylpyrido[2,3-d]pyrimidin-4-one derivatives
Feng Shi a,b, Jie Ding b, Shu Zhang c, Wen-Juan Hao b, Chuang Cheng b, Shujiang Tu a,b,
⇑
a College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215000, PR China
b School of Chemistry and Chemical Engineering, Key Laboratory of Biotechnology for Medicinal Plant, Xuzhou Normal University, Xuzhou, Jiangsu 221116, PR China
c Clinical Research Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 July 2010
Revised 21 September 2010
Accepted 24 September 2010
Available online 29 September 2010
The substrate-controlled chemoselective synthesis of novel 5,6,7-triarylpyrido[2,3-d]pyrimidin-4-one
derivatives has been successfully achieved via microwave-assisted three-component reactions of 2,6-
diaminopyrimidin-4(3H)-one, aromatic aldehydes and 1,2-diphenylethanone. This approach has the
prominent features of chemoselectivity, diasteroselectivity, atom economy, short reaction time, high
yield as well as operational simplicity. Moreover, these novel compounds were subject to the test of
in vitro cytotoxicity to carcinoma SW1116 and SGC7901 cells. Most of the tested compounds showed sig-
nificant cytotoxicity to SW1116 cells and compound 4b exhibited more potent and efficacious cytotox-
icity to SGC7901 cells than doxorubicin hydrochloride as positive control.
Keywords:
Pyridopyrimidinone
Chemoselective synthesis
Multi-component reaction
Cytotoxicity
Ó 2011 Published by Elsevier Ltd.
It is known to all that cancer is a leading cause of death. Apart
form the use of surgical treatment and irradiation, chemotherapy
still remains an important option for the treatment of cancer. In
this context, the search for novel chemotherapeutic agents and ap-
proaches to cancer treatment is an active research field stimulated
by the discovery of new biological targets and by the possibility of
obtaining new drugs with less undesirable side effects.
Among potential chemotherapeutic agents, heterocyclic com-
pounds represent an outstanding type of anti-cancer drug candi-
date. Pyrido[2,3-d]pyrimidin-4-one derivatives, containing two
fused heterocyclic scaffolds in one molecule, exhibit significant
biological properties such as antitumor1 and antifungal activities.2
In spite of the much attention paid to the synthesis of this class of
poly-functionalized compounds from organic and medicinal chem-
ists,2,3 a survey of the literature reveals no report on the synthesis
and bioactivity evaluation of 5,6,7-triarylpyrido[2,3-d]pyrimidin-
4-one derivatives (Fig. 1), which have high steric hindrance
resulted from the three adjacent aromatic rings. Therefore,
developing an efficient approach to the synthesis of this novel class
of heterocycles as well as evaluation on their cytotoxic activity is
very important for the sake of discovering new anticancer drug
candidates.
3,4-dihydropyridine are easy to change into each other by tauto-
merizm, in which the equilibrium tends toward the 1,4-dihydro
form in most cases.4 This fact resulted in our observations of either
exclusive formation of the 1,4-dihydro derivative or a mixture
where it predominated over the 3,4-dihydro form. Can 3,4-dihy-
dropyridines be exclusively synthesized? Compared with the vast
attentions and numerous synthetic approaches to 1,4-dihydropyri-
dines, the investigations on the synthesis of 3,4-dihydropyridines
are rather rare.5
In view of the prominent merits of microwave-assisted multi-
component reactions6 and as a continuation of our efforts on
chemoselective synthesis of heterocyclic compounds with poten-
tial bioactivities,7 we investigated the three-component reactions
of 2,6-diaminopyrimidin-4(3H)-one 1, aromatic aldehydes 2 and
1,2-diphenylethanone
3 under microwave irradiation (MW)
(Scheme 1). To our delight, the chemoselective synthesis of 5,6,7-
triarylpyrido[2,3-d]pyrimidin-4(3H,5H,8H)-ones 4 and trans-5,6-
dihydro-5,6,7-triarylpyrido[2,3-d]pyrimidin-4(3H)-ones 5 as single
diastereoisomers, which include the units of 1,4-dihydropyridine
and 3,4-dihydropyridine respectively, were achieved by the control
of different substrates 2.
On the other hand, in the skeleton of 5,6,7-triarylpyrido-
[2,3-d]pyrimidin-4-one derivatives, a unit of 1,4-dihydropyridine
is embedded. It is well known that 1,4-dihydropyridine and
Ar1
O
Ar2
Ar3
HN
H2N
N
N
H
⇑
Corresponding author. Tel./fax: +86 516 83500365.
E-mail address: laotu2001@263.net (S. Tu).
Fig. 1. Structure of 5,6,7-triarylpyrido[2,3-d]pyrimidin-4-one derivatives.
0960-894X/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2010.09.114

F. Shi et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1554–1558
1555
Table 2
Ar
O
N
Chemoselective synthesis of 4 and 5 under MWa
Ph
Ph
HN
H2N
4
Entry
2
4 or 5 Ar
Time (min) Yieldb (%)
N
H
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
4a
4b
4c
4d
4e
4f
4-FC6H4
4-BrC6H4
4-ClC6H4
4-CH3OC6H4
10
9
82
89
85
86
83
81
80
83
84
81
82
Ar = 4-FC6H4, 4-BrC6H4,
O
4-ClC6H4, 4-OMeC6H4,
4-(Dimethylamino)phenyl,
3,4-OCH2OC6H3, Thiophen-2-yl
Ph
O
K2CO3/glycol
MW, 110oC
Ar
HN
H2N
+
+
12
10
CHO
2
Ph
N
NH2
Ar
O
4-(Dimethylamino)phenyl 12
1
3
Ph
3,4-OCH2OC6H3
Thiophen-2-yl
2-CH3OC6H4
12
14
10
12
14
11
HN
H2N
5
_
(+)
2g
2h 5a
4g
N
N
Ph
Ar = 2-OMeC6H4, 3,4-(OMe)2C6H3,
3,4,5-(OMe)3C6H2, 2-ClC6H4
2i
2j
2k
5b
5c
5d
3,4-(CH3O)2C6H3
3,4,5-(CH3O)3C6H2
2-ClC6H4
10
11
Scheme 1. Chemoselective synthesis of heterocycles 4 and 5.
a
All the reactions were carried out with 1 mmol of 1, 1 mmol of 2 and 1 mmol of
3 in 2 mL of glycol with the presence of K2CO3 (0.1 mmol) at 110 °C under MW at
the initial/maximum power of 100 W/250 W.
b
It goes without saying that chemoselectivity is a key issue to be
controlled in the fields of organic and medicinal syntheses. In re-
cent years, many studies have focused on the chemoselectivity of
reactions controlled by metal catalysts and solvents.8 In spite of
these achievements, the investigations on substrate-controlled
chemoselective reactions are not well documented. Therefore,
these chemoselective syntheses of 5,6,7-triarylpyrido[2,3-d]pyrim-
idine-4-one derivatives 4 and 5 provide good examples of sub-
strate-controlled chemoselective reactions.
In this paper, we report this efficient substrate-controlled
chemoselective synthesis of novel 5,6,7-triarylpyrido[2,3-d]pyrim-
idin-4-one derivatives via microwave-assisted three-component
reactions and the evaluation of their cytotoxic activity, leading to
the discovery of some new heterocycles with potent cytotoxicity
higher than or similar to doxorubicin hydrochloride, a powerful
anticancer drug.
Isolated yields.
suitable reaction temperature (Table 1, entry 6) in view of the
highest yield of 4b.
Under the optimized reaction conditions, various aromatic alde-
hydes 2 bearing electron-withdrawing or electron-donating groups
on the aromatic ring were reacted with 2,6-diaminopyrimidin-
4(3H)-one 1 and 1,2-diphenylethanone 3 (Table 2). Surprisingly,
aside from the expected products 4 (Table 2, entries 1–7) in their
1,4-dihydropyridine forms, several undesired products 5 (Table 2,
entries 8–11) in the 3,4-dihydropyridine forms were generated
when using different substrates 2.
The results indicate that the Ar group in dihydropyridine skele-
tons of 4 and 5 serves as a convenient tautomeric ‘switch’. It seems
that the selectivity of this reaction has no necessary relationship
with the electronic nature of the substituents since compounds 4
and 5 can be prepared not only by aromatic aldehydes with elec-
tron-donating groups (Table 2, entries 4–6 and 8–10), but also by
those with electron-withdrawing groups (Table 2, entries 1–3
and 11). Obviously, the aromatic group in the undesired products
5 is ortho-substituted or poly-substituted with either electron-
donating (Table 2, entries 8–10) or electron-withdrawing groups
(Table 2, entry 11). Thus, 4 exists exclusively in the 1,4-dihydro
form, while 5 is entirely in the 3,4-dihydro form, presumably due
to a steric effect.4c,4d
Initially, the reaction of 2,6-diaminopyrimidin-4(3H)-one 1
(1 mmol), 4-bromobenzaldehyde 2b (1 mmol) and 1,2-diphenyl-
ethanone 3 (1 mmol) was employed to optimize the reaction con-
ditions. As illustrated in Table 1, K2CO3/glycol was preferred as the
optimal catalyst/solvent system and 110 °C was chosen as the most
Table 1
Reaction condition optimization for the synthesis of 4ba
Br
Ar
N
Ar
N
Br
O
N
O
N
O
Ph
Ph
O
Ph
HN
H2N
HN
H2N
Ph
Ph
HN
H2N
MW
_
(+)
_
(+)
+
+
HN
H2N
N
NH2
Ph
O
Ph
Ph
N
N
H
cis-5
trans-5
trans-5:cis-5 >100:1
CHO
1
2b
3
4b
Fig. 2. Configurations of compound 5.
Entry
Catalyst/solvent
T (°C)
Time (min)
Yieldb (%)
Ph
3
O
Ar
1
2
3
4
5
6
7
8
9
Glycol
95%EtOH
Water
DMF
AcOH
K2CO3/glycol
Et3N/Glycol
NaHCO3/glycol
K2CO3/glycol
K2CO3/glycol
K2CO3/glycol
110
110
110
110
110
110
110
110
90
12
18
24
15
14
9
15
12
16
12
9
77
58
Trace
64
72
89
81
83
79
84
+
Ph
2
CHO
K2CO3
Ar
Ar
Ar
O
O
N
O
N
Ph
Ph
Ph
Ph
Ph
HN
H2N
HN
H2N
HN
+
Ph
N
NH2
O
NH
O
H2N
NH2
O
O
6
1
7
Ar
10
11
100
120
Ar
N
Ar
O
N
O
N
Ph
87
Ph
Ph
HN
H2N
-H2O
HN
HN
_
(+)
a
All the reactions were carried out with 1 mmol of 1, 1 mmol of 2b and 1 mmol
of 3 in 2 mL of solvent without or with the presence of catalyst (0.1 mmol) under
Ph
OH
N
N
H
H2N
H2N
N
H
Ph
Ph
4
5
MW at the initial/maximum power of 100 W/250 W.
b
Isolated yields.
Scheme 2. Supposed mechanism of this reaction.

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F. Shi et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1554–1558
Table 3
Cytotoxicity of new compounds 4 and 5
Entry
Compound
Inhibition rate on SW1116a (%)
IC50 to SGC7901b
(lg/mL)
0.1
lg/mL
1
l
g/mL
10 lg/mL
F
O
N
Ph
Ph
1
31.55 7.79
19.78 2.61
14.88 1.72
43.01 1.28
17.60 3.91
19.27 7.35
25.14 5.63
29.12 8.44
50.29 7.33
11.96 2.68
25.54 1.16
42.84 5.39
13.035
HN
H2N
N
H
4a
Br
O
N
Ph
Ph
2
3
4
0.074
0.104
0.341
HN
H2N
N
H
4b
Cl
O
N
Ph
Ph
HN
H2N
N
H
4c
OCH3
O
N
Ph
HN
H2N
N
Ph
H
4d
N
O
N
Ph
Ph
5
6
20.54 2.03
27.89 7.55
13.99 2.58
0.790
0.090
HN
H2N
N
H
4e
O
O
O
N
Ph
Ph
15.12 4.63
34.63 0.74
20.55 8.17
HN
H2N
N
H
4f
S
O
Ph
Ph
HN
H2N
7
8
22.39 1.20
22.35 4.32
37.24 0.64
48.32 0.67
31.55 4.23
0.108
0.359
N
N
H
4g
OCH3
Ph
_
(+)
O
HN
H2N
6.47 2.57
N
N
Ph
5a
OCH3
OCH3
O
9
Ph
_
(+)
2.24 0.19
13.81 1.23
23.90 1.75
0.606
2.979
HN
H2N
N
N
Ph
5b
OCH3
H3CO
OCH3
O
10
21.82 0.88
16.69 1.83
36.89 3.13
Ph
HN
H2N
_
(+)
N
N
Ph
5c

F. Shi et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1554–1558
1557
Table 3 (continued)
Entry
Compound
Inhibition rate on SW1116a (%)
IC50 to SGC7901b
(lg/mL)
0.1
lg/mL
1
lg/mL
10 lg/mL
Cl
Ph
_
(+)
Ph
O
HN
11
31.77 7.54
27.31 2.46
38.73 2.27
28.52 1.47
1.565
0.078
H2N
N
N
5d
Doxorubicin hydrochloridec
12
a
The inhibition rate on SW1116 was represented as mean S.D.
The IC50 value to SGC7901 corresponded to the compound concentration causing 50% mortality in SGC7901 cells.
Doxorubicin hydrochloride was used as a positive control.
b
c
The structures of compounds 4 and 5 were unambiguously
by controlling the different substrates in microwave-assisted
three-component reactions. This approach has the prominent fea-
tures of chemoselectivity, diasteroselectivity, atom economy, short
reaction time, high yield as well as operational simplicity. More-
over, the in vitro cytotoxic activity of these novel 5,6,7-triarylpyr-
ido[2,3-d]pyrimidin-4-one derivatives 4 and 5 were assayed, which
resulted in the finding of compound 4b with more potent and effi-
cacious cytotoxicity than doxorubicin hydrochloride. Although
there is no obvious relationship between the structure and the
cytotoxic activity of the tested compounds, the results indicated
that this novel class of 5,6,7-triarylpyrido[2,3-d]pyrimidin-4-one
derivatives may become promising anti-cancer drug candidates
after further investigations.
characterized by IR, 1H NMR, 13C NMR and HRMS (ESI).9 It is
worth-noting that the configurations of the two adjacent tertiary
hydrogen atoms in all the products 5 were exclusively trans
(Fig. 2) and the ratios of trans-5 to cis-5 were more than 100:1,
which was determined by 1H NMR spectroscopy. The trans stereo-
chemistry of compounds 5 was established by the coupling con-
stants (J = 0 Hz) between the two adjacent methine protons,
which was reported in the literature to be 0 Hz for the trans diaste-
reoisomers of 3,4-dihydropyridine derivatives10 because of the
nearly orthogonal positions of the two protons confirmed by an
X-ray structure determination.10b
A plausible mechanism for the formation of compounds 4 and 5
is shown in Scheme 2. Firstly, 2,6-diaminopyrimidin-4(3H)-one 1
underwent Michael addition with the intermediate 6, which was
formed from Knoevenagel condensation of aromatic aldehydes 2
and 1,2-diphenylethanone 3, to give an open-chain intermediate
7. Subsequently intramolecular cyclization and dehydration affor-
ded products 4 or tautomers 5.
In order to survey the possible bioactivity of this class of novel
compounds, 5,6,7-triarylpyrido[2,3-d]pyrimidin-4-one derivatives
4 and 5 were subject to the test of in vitro cytotoxicity to colon car-
cinoma cell line SW1116 and stomach carcinoma cell line
SGC7901.9
The cytotoxic activity of compounds 4 and 5 to colon carcinoma
cell line SW1116 was assayed in three concentrations of 0.1, 1 and
10 lg/mL (Table 3). The results suggested that all the tested com-
pounds in the three concentrations inhibited proliferation of
SW1116 cells with inhibition rate (IR) from 11.96% to 50.29%. In
the three tested concentrations, most of the tested compounds
Acknowledgments
We are grateful for financial support by Natural Science Foun-
dation of China (No. 21002083 and 21072163), the Natural Science
Foundation (09KJB150011) and Qing Lan Project (08QL001) of
Jiangsu Education Committee, and the Interdisciplinary Key Item
of Xuzhou Normal University (09XKXK01).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.09.114.
References and notes
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compounds 4a (IR = 50.29%), 4d (IR = 42.84%), 4g (IR = 48.32%), 5a
(IR = 31.55%), 5c (IR = 36.89%) and 5d (IR = 38.73%) inhibited the
growth of SW1116 cells in higher rates at the same concentration
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