Pyrimidine Derivatives with Terminal Pyridyl Heterocycles: Facile Synthesis and Their Antiproliferative Activities

Article abstract of DOI:10.1002/jhet.3547

Incorporation of heterocyclic pyrimidine or pyridine motifs is common in the drug design for various therapeutic applications. Herein, we describe the facile synthesis of two molecules containing both pyrimidine and pyridine scaffolds. A variety of analytical techniques (multinuclear NMR, Fourier transform infrared, and mass spectrometry analyses) confirmed the purity of these molecules. In pristine form, their potential as antitumor drugs was screened by investigating their cytotoxicity against various cell lines (cancerous and normal cells). Experimental results confirmed that the two molecules exhibited cell growth inhibition at very low concentrations. This was evident from their IC₅₀ values that are in the range of 0.45–2.20 μM.

Full text of DOI:10.1002/jhet.3547

Month 2019
Pyrimidine Derivatives with Terminal Pyridyl Heterocycles: Facile Syn-
thesis and Their Antiproliferative Activities
a
Khushwant Singh,a Achintya Jana,a Petra Lippmann,b Ingo Ott,b
and Neeladri Das
*
aDepartment of Chemistry, Indian Institute of Technology Patna, Bihta 801 106, Bihar, India
bInstitute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstraße 55,
Braunschweig 38106, Germany
*E-mail: neeladri@iitp.ac.in; neeladri2002@yahoo.co.in
Received July 17, 2018
DOI 10.1002/jhet.3547
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
Incorporation of heterocyclic pyrimidine or pyridine motifs is common in the drug design for various ther-
apeutic applications. Herein, we describe the facile synthesis of two molecules containing both pyrimidine
and pyridine scaffolds. A variety of analytical techniques (multinuclear NMR, Fourier transform infrared,
and mass spectrometry analyses) confirmed the purity of these molecules. In pristine form, their potential
as antitumor drugs was screened by investigating their cytotoxicity against various cell lines (cancerous
and normal cells). Experimental results confirmed that the two molecules exhibited cell growth inhibition
at very low concentrations. This was evident from their IC50 values that are in the range of 0.45–2.20 μM.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
motivated to design unique molecules that bear all the
three aforementioned units, namely, pyrimidine, pyridine,
and ethynyl functional groups. Thereafter, we were
curious to study their cytotoxicity with respect to various
cancer cell lines. Interestingly, these newly synthesized
molecules have shown quite strong cell growth
inhibitory effects against various cancers cell lines (HT-
29, MCF-7, and MDA-MB-231). The obtained data are
comparable or in some case much better than the data
previously reported in literature with compounds bearing
pyrimidine, pyridyl, or ethynyl units (in organic
compound or in metal–organic compound) [13].
Pyridine and pyrimidine are two popular six-membered
heterocycles that are known for more than a century and
have been investigated by numerous research groups [1–4].
Derivatives of pyridine have been used as pharmaceuticals
[5], pesticides [6], and manufacture of other products [7].
The pyrimidine moiety, on the other hand, is ubiquitous
because it is an integral part of DNA and RNA of living
organisms [8]. Furthermore, the pyrimidine motif is also
found in many natural products [8,9] (such as marine
alkaloids) and used in therapeutics [10]. Thus, there is a
considerable research interest in the development of new
molecules that contain these heterocycles, and
subsequently, these are screened for their biological
interactions, especially cytotoxicity against various
cancer cell lines [11]. The ethynyl functional group
(–C≡C–) is another important structural motif that has
been incorporated particularly in organometallic
complexes of Au(I) and Pt(II) metal ions, and the
resulting compounds have been studied as “inorganic”
therapeutics agents for anticancer drugs [12].
Considering the diverse biological activities of these
three structural motifs reported in literature, we were
RESULTS AND DISCUSSION
Synthesis and characterization of molecules containing
pyrimidine and pyridine units (2 and 3). Cross-coupling
reaction is a powerful tool to join various structural
motifs via C–C bonds. Sonogashira reaction is one such
cross-coupling reaction, and it is an efficient synthetic
protocol for introducing an ethynyl moiety on aryl
compounds [14]. In the past, this reaction was used to
synthesize bis- and tris(arylethylnyl)pyrimidine oligomers
© 2019 Wiley Periodicals, Inc.

K. Singh, A. Jana, P. Lippmann, I. Ott, and N. Das
Vol 000
Scheme 1. Synthesis of 2,4-diethynylpyrimidine.
[15]. In the present work, 2,4-diethynylpyrimidine was
obtained from 2,4-dichloropyrimidine via the formation
of 2,4-diidopyrimidine (Scheme 1), because the yield of
S1), the two chemically inequivalent protons of the
pyrimidine ring appear as doublets in the range 8.83–8.82
and 7.52–7.50 ppm. The two pendant pyridine rings are
chemically inequivalent. Therefore, two sets of signals
are observed for α-pyridyl and β-pyridyl protons in 2 in
the range of 8.70–8.67 and 7.51–7.47 ppm (Fig. 1).
Similarly, in case of 3, signals corresponding to the two
protons of pyrimidine ring appear as doublets, while the
four chemically nonequivalent protons present in each
pendant pyridine appear as distinctly different set of
signals (Fig. S3). The 13C{1H} NMR spectrum of both 2
and 3 exhibited all the characteristic peaks corresponding
to pyrimidine, pyridine, and ethynyl units in expected
region (Figs S2 and S4, respectively). Further, formation
and purity of 2 and 3 were also confirmed from its mass
spectrometric analysis (Figs. S7 and S8, respectively).
The absorbance maximum of compound 2 is centered at
275 nm, whereas a slightly red-shifted absorbance peak
was observed for 3 with a maximum at 295 nm in
dichloromethane (conc. = 10À5 M) at 298 K (Fig. 2). The
difference in λmax values of these compounds can be
attributed to the difference in the position of pyridine N
atom in these two molecules.
Sonogashira
coupling
reaction
between
2,4-
dichloropyrimidine and trimethylsilylacetylene was low
(25%). The reaction between 2,4-diidopyrimidine and
trimethylsilylacetylene was
a more efficient cross-
coupling reaction (yield >85%). Therefore, 2,4-
dichloropyrimidine was first converted into its diiodo
derivative, and this was subsequently reacted with
ethynyltrimethylsilane to yield 2,4-diethynylpyrimidine
(1) as shown in Scheme 1.
To obtain the desired molecules (bearing both
pyrimidine and pyridine motifs), 1 was subjected to
another Sonogashira cross-coupling reaction (Scheme 2)
with either 4-iodopyridine or 3-iodopyridine in the
presence of Pd(II) catalyst and Cu(I) as co-catalyst. These
reactions yielded 2 and 3 respectively in reasonably high
yields (>80%). Compounds 2 and 3 were obtained as
white solids that are stable in air/moisture and have high
solubility in common organic solvents such as acetone,
halogenated solvents, methanol, and tetrahydrofuran.
Spectroscopic properties of 2 and 3. These molecules (2
and 3) were characterized by FT-IR and NMR (1H and
13C) spectroscopy, mass spectrometry, and elemental
analyses. FT-IR spectra of 2 and 3 show presence of a
strong band at 2216 and 2221 cmÀ1 (ʋC≡C str.),
respectively, indicating the presence of the ethynyl
functional group in the final product (Figs. S5 and S6,
X-ray crystallographic analysis of 2. Single crystals of
2, suitable for X-ray diffraction, were obtained by slow
evaporation of its methanol solution at ambient
temperature. Compound
2
crystallizes in the
orthorhombic space group Pnn2. Crystallographic data
and refinement parameters for 2 are listed in Table 1. The
molecular structure with the numbering scheme is shown
1
respectively). In the H NMR spectrum of 2 (Figs. 1 and
Scheme 2. Synthesis of pyrimidine-based organic molecules 2 and 3.
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Figure 1. 1H NMR spectrum of 2. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 2. UV absorbance spectra of 2 and 3 recorded in DCM (conc. = 10À5 M) at 298 K. [Color figure can be viewed at wileyonlinelibrary.com]
in Fig. 3. The two pendent 4-ethynylpyridine moieties are
not in the same molecular plane that contains the central
pyrimidine ring, as evident from Fig. 3b.
Crystallographic analysis reveals that all three nitrogen
atoms (N1, N2, and N3) have intermolecular interactions
with the neighboring molecules via “hydrogen bridges.”
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K. Singh, A. Jana, P. Lippmann, I. Ott, and N. Das
Vol 000
Table 1
The corresponding bond parameter for such intermolecular
interactions (N···H–C) is listed in Table 2. The N···H
distances are in the range 2.27–2.80 Å, while the C···N
distances lie in between 3.35 and 3.70 Å. Based on
literature reports, these interactions may be termed as
“weak hydrogen bonds” because in each case, an H atom
bridges two atoms of relatively low electronegativity
[16]. In one of the instances, the linear geometry of the
three atoms (C–H···N) supports this interaction to be
termed as a weak hydrogen interaction with more
certainty than the other two. These weak H-bonding
interactions, present in the crystal lattice of 2, are shown
in Figure S9. In addition to such electrostatic
interactions involving H bridges, there are evidences of
π–π interactions between neighboring molecules of 2.
The term “π–π interactions” has been applied in event of
stacking of aromatic rings having their respective
Crystallographic data and refinement parameters for 2.
2
Formula
C18H9N4
Mw (gmolÀ1
Temp (K)
)
281.29
100 (2)
0.71073
Orthorhombic
Pnn2
30.395 (12)
3.8049 (15)
6.058 (2)
90
λ (Mo Kα) (Å)
Crystal system
Space group
a (Å)
b (Å)
c (Å)
α (°)
β (°)
90
90
700.6 (5)
4
1.333
γ (°)
V (Å3)
Z
Dcalc (g/cm3)
μ (mmÀ1
F(000)
)
0.083
290.0
Collected reflections
Unique reflections
Max and min trans
Goodness of fit on F2
R1 [I > 2σ(I)]a
9552
1556
Table 3
0.7404, 0.5566
1.040
0.0431
0.1107
1565950
Cytotoxicity as IC50 values (μM) in several cell lines with standard errors
as superscripts.
wR2 (all data)b
HT-29
MCF-7
MDA-MB-231
RC-124
CCDC number
0.10
0.08
0.19
0.08
2
3
0.80
0.56
1.37
0.62
1.27
0.44
aR1 = ∑││Fo│ À │Fc││ / ∑│Fo│.
0.21
0.22
0.39
0.38
2.12
1.27
bwR2 = {∑[w(Fo2 À Fc2)2] / ∑[w(F2o)2]}1/2
.
Figure 3. (a) ORTEP presentation of 2 (30% thermal ellipsoid), (b) viewing along the plane containing the central pyrimidine ring. [Color figure can be
viewed at wileyonlinelibrary.com]
Table 2
Selected weak H-bond parameters observed in 2.
D–H···A
D–H (Å)
H···A (Å)
D···A (Å)
<D–H–A (°)
Symmetry
C2–H2···N3
C5–H5···N2
C9–H9···N1
1.080
1.080
1.080
2.800
2.486
2.270
3.697
3.392
3.350
140.39
140.79
180.00
x,+y + 1,+z À 1
Àx + 1/2 + 1,+y À 1/2,+z + 1/2
x,+y,+z + 1
Figure 4. Packing view of 2 along c-axis. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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molecular planes separated by 3.3–3.8 Å [17]. In the
present case, the pyridine rings of neighboring molecules
have interplanar separation of 3.80 Å. The packing view
of 2 is shown in Fig. 4.
<2.2 μM) against the tested colon and breast carcinoma
cells. Our studies also show that the molecule with 4-
pyridyl pendant groups is more active (IC50 values
<0.9 μM) against all three carcinoma cell lines suggesting
a
strong structure–activity relationship. This work
Cytotoxicity of pyrimidine–pyridine mixed molecules 2 and
3. The cell growth inhibitory effects have been studied in
three different types of cancer cell lines, namely, HT-29
motivates others and us to study pharmacology of these
and similar heterocyclic compounds in detail in near future.
(colon carcinoma cells), MCF-7, and MDA-MB-231
(breast cancer cells). Results (Table 3) were compared
with the effect on non-cancerous RC-124 kidney cell line
that was used as a reference to check for possible tumor
selectivity. Both compounds (2 and 3) have demonstrated
good cytotoxicity (0.50- to 2.20-μM range) against all
three cancer cell lines. Comparison between 2 and 3
indicates a certain trend. The former (2) is more effective
against cancer cell proliferation having lower IC50 values
(in the range of 0.56–0.80 μM) than the latter (3). This
result indicates that a subtle change in the structure
causes a marked change in the activity of the molecule
against carcinoma cell lines. In addition to the observed
antiproliferative effects with respect to cancer cell lines,
the two compounds (2 and 3) also triggered IC50 value in
similar concentration range for non-tumor (RC-124
human kidney) cell lines. This implies that 2 and 3 do
not show any selectivity for the carcinoma cells in the
same doses/concentration range. Nevertheless, the
cytotoxicity of these pyridine/pyrimidine-based molecules
against these carcinoma cell lines is superior in
comparison with several organic ligands as well as their
metal complexes such as N-heterocyclic carbenes and
their organometallic Au(I) [18], Ru(II), Rh(I), and Cu(I)
[19] N-heterocyclic carbenes complexes.
EXPERIMENTAL
General details. All chemicals and anhydrous solvents
used in the present work were purchased from commercial
sources and used without further purification. 2,4-
Diethynylpyrimidine
was
prepared
following
experimental protocol reported literature [15]. FTIR
spectra were recorded in a PerkinElmer spectrum 400 FT-
IR spectrophotometer. 1H and 13C{1H} NMR spectra
were recorded on a Bruker 400-MHz spectrometer.
Elemental analyses were carried out using an Elementar
vario Micro Cube elemental analyzer. HRMS (ESI-MS)
analysis was performed using a Bruker Impact ESI-Q-
TOF system.
Synthesis of 2 and 3. 2,4-Diethynylpyrimidine (50 mg,
0.390 mmol), iodopyridine (159.90 mg, 0.78 mmol)
(4-idopyridine for 2 and 3-idopyridine for 3), Cu(I)
(7.4 mg, 0.03 mmol), and bis(triphenylphosphine)
palladium(II) dichloride (27.37 mg, 0.03 mmol) were
charged in a 50-mL Schlenk flask in the glove box.
Subsequently, 10-mL dry THF and freshly distilled
triethylamine (0.5 mL, 1.56 mmol) were added under
nitrogen. The reaction mixture was stirred overnight at
room temperature. Subsequently, the dark brown reaction
mixture was filtered through a bed of celite. The filtrate
CONCLUSION
obtained was evaporated to dryness on
a rotary
evaporator to yield the crude product that was purified by
column chromatography on neutral alumina by eluting
with 35% ethyl acetate in hexane to isolate the desired
products (2 and 3) as off-white solids.
Herein, we have reported the synthesis of two new
molecules having the unique feature of possessing three
motifs that are reported to have a wide spectrum of
biological activities. The three motifs are pyridine,
pyrimidine, and ethynyl. Compounds have been obtained
in reasonable high yields using metal-catalyzed
Sonogashira cross-coupling reactions. These nitrogen-rich
molecules (2 and 3) were thoroughly characterized by FT-
IR, multinuclear NMR spectroscopy, ESI-TOF-MS
spectrometry, and elemental analyses. Compound 2 was
also structurally characterized by single-crystal X-ray
diffraction. Considering the anticancer potencies of
pyridine-based or pyrimidine-based molecules, it was our
curiosity to investigate the anticancer activity of the two
newly synthesized molecules. Consequently, 2 and 3 were
tested against three different cancer cell lines (HT-29,
MCF-7, and MDA-MB-231). The cytotoxic activity
results revealed that both are active (IC50 values
2,4-Bis-pyridin-4-ylethynyl-pyrimidine
(2).
Yield:
0.095 g, 86%; mp 153–158°C; 1H NMR (400 MHz,
CDCl3): δ 8.83–8.82 (d, 1H, J = 4 Hz Ar–H), 7.52–7.51
(d, 1H, J = 4 Hz, Ar–H), 8.70–8.66 (m, 4H, Ar–H),
7.50–7.46 (m, 4H, Ar–H). 13C{1H} NMR (CDCl3,
100 MHz): δ 157.9, 152.8, 150.5, 150.1, 150.0, 129.2,
128.9, 126.0, 125.8, 122.5, 91.8, 90.8, 89.3, 84.9, IR
(ATR): 3024, 2920, 2851, 2216, 1734, 1586, 1401, 1383,
1309, 1187, 1112, 996, 951, 869, 811 cmÀ1. Anal. Calcd
for C18H10N4C, 76.58; H, 3.57; N, 19.85. Found: C,
76.71; H, 3.66; N, 19.92. HRMS (ESI, m/z): calculated
for C18H10N4 ([M + H]+): 283.10; found: 283.10. CCDC
1565950.
2,4-Bis-pyridin-3-ylethynyl-pyrimidine
(3).
Yield:
0.097 g, 88%; mp 165–170°C; 1H NMR (400 MHz,
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K. Singh, A. Jana, P. Lippmann, I. Ott, and N. Das
Vol 000
CDCl3): δ 8.91–8.90 (m, 1H, Ar–H), 8.86–8.86 (m, 1H,
Ar–H), 8.80–8.79 (d, J = 4 Hz, 1H, Ar–H), 8.66–8.63
(m, 2H, Ar–H), 7.97–7.90 (m, 2H, Ar–H), 7.44–7.43 (d,
J = 4 Hz, 1H, Ar–H), 7.37–7.32 (m, 2H, Ar–H). 13C{1H}
NMR (CDCl3, 100 MHz): δ 157.7, 153.1, 153.0, 152.9,
150.8, 150.3, 150.0, 139.5, 139.3, 123.2, 123.1, 122.0,
118.5, 118.2, 91.1, 90.5, 89.0, 84.8. IR (ATR): 3030,
2920, 2857, 2221, 1545, 1470, 1412, 1320, 1187, 1187,
1124, 1019, 945, 846, 800, 702 cmÀ1. Anal. Calcd for
C18H10N4: C, 76.58; H, 3.57; N, 19.85. Found: C, 76.83;
H, 3.76; N, 19.98. HRMS (ESI, m/z): calculated for
C18H10N4 ([M + H]+): 283.10; found: 283.10.
was replaced by different concentrations of the compound
in cell culture medium (six wells for each concentration).
Twelve wells of each plate were treated with a solution of
0.1% DMF in cell culture medium (untreated control).
Subsequently, the plates were incubated at 5% CO2 and
37°C for 72 h (HT-29) or 96 h (MDA-MB-231). After
exposure to the 2 and 3, the medium was removed, and the
cells were treated with 100 μL of a 10% glutaraldehyde
solution. Afterwards, the cells of all plates were washed
with 180-μL PBS and stained with 100 μL of a 0.02%
crystal violet solution for 30 min. The crystal violet
solution was removed, and the plates were washed with
water and dried. A volume of 180 μL of ethanol 70% was
added to each well, and after 3–4 h of gentle shaking, the
absorbance was measured at 595 nm in a microplate reader
(Victor X4, PerkinElmer). The mean absorbance value of
the t0 plate was subtracted from the absorbance values of
all other absorbance values. The IC50 values were
calculated as the concentrations reducing the cellular
proliferation in comparison with the untreated control by
50% and are given as the means and errors of three
independent experiments.
Single-crystal structure determination.
A suitable
single crystal of 2 was carefully selected under a
polarizing microscope and mounted on crystal
a
mounting loop after coating with paratone oil. Single-
crystal data were collected on a Bruker D8 Quest
diffractometer equipped with an Oxford Cryostream low-
temperature device and a fine-focus sealed-tube X-ray
source (Mo-Kα radiation, λ = 0.71073 Å, graphite
monochromated) operating at 50 kV and 30 mA. The
unit cell measurement, data collection (φ and ω scan),
integration, scaling, and absorption corrections for the
crystal were performed using Bruker Apex II software
[20]. The structure was solved using direct method
followed by full matrix least square refinements against
F2 (all data HKLF 4 format) using SHELXTL [21]. A
multiscan absorption correction, based on equivalent
reflections, was applied to the data. Anisotropic
refinement was used for all non-hydrogen atoms.
Hydrogen atoms were placed in appropriate calculated
positions.
Acknowledgments. N. D. thanks Indian Institute of Technology
(IIT) Patna for laboratory facility and DAAD [for
a
“Forschungsaufenthalt” award Research Stays for University
Academics and Scientists, 2018 (57378441)]. K. S. and A. J.
thank UGC, New Delhi, India, for a Research Fellowship. The
authors acknowledge SAIF-Panjab University for providing
NMR spectroscopy facilities. The authors also acknowledge
SAIF-IIT Patna for providing ESI-MS and XRD facilities.
Cell culture and cytotoxicity assay.
HT-29 colon
carcinoma cells, MDA-MB-231 breast cancer cells,
MCF-7 breast carcinoma cells were maintained in
Dulbecco’s Modified Eagle Medium (4.5 g/L (D)-
glucose, L-glutamine, pyruvate), which was supplemented
with gentamycin (50mg/L)and fetal bovine serum superior,
standardized (Biochrom GmbH, Berlin) (10% v/v), and
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet