Synthesis of pyridine derivatives as potential antagonists of chemokine receptor type 4

Article abstract of DOI:10.1515/hc-2014-0041

A series of pyridine derivatives were synthesized as potential inhibitors of chemokine receptor type 4. This chemokine receptor has been linked to various disease pathways including HIV-1 proliferation, autoimmune disorders, inflammatory diseases, and cancer metastasis. The compounds were tested for activity using an affinity binding assay and an assay that tests the ability to inhibit cell invasion. Two hit compounds (2b and 2j) have been identified for further evaluation that inhibit cell invasion by at least 50% and have an effective concentration of less than 100 nm in the binding affinity assay. The structures of the synthesized compounds were confirmed by spectral data.

Full text of DOI:10.1515/hc-2014-0041

Heterocycl. Commun. 2014; 20(3): 149–153
Preliminary Communication
SSuyaznetttehReeidsMiosoroingf*,pThyerreisda iGnaineesd, ZehornigvxiangtLiivanegsandaHsyupnsouktSehinmtial
antagonists of chemokine receptor type 4
Abstract: A series of pyridine derivatives were synthesized diseases and cancer metastasis. As a result, CXCR4 has
as potential inhibitors of chemokine receptor type 4. This been a therapeutic target for these conditions. The devel-
chemokine receptor has been linked to various disease opment of small molecule CXCR4 inhibitors may be an
pathways including HIV-1 proliferation, autoimmune dis- effective treatment for many CXCR4-related conditions
orders, inflammatory diseases, and cancer metastasis. [12, 13].
The compounds were tested for activity using an affinity
Several classes of CXCR4 small-molecule antago-
binding assay and an assay that tests the ability to inhibit nists have shown anti-RA activity [14, 15]. Others have
cell invasion. Two hit compounds (2b and 2j) have been shown anti-cancer activity by inhibiting cancer growth
identified for further evaluation that inhibit cell invasion and metastasis [16–19]. AMD3100 (Figure 1) has been
by at least 50% and have an effective concentration of less one of the most successful CXCR4 antagonists [15, 20, 21].
than 100 nm in the binding affinity assay. The structures AMD3100 is approved by the FDA as a stem cell mobilizer
of the synthesized compounds were confirmed by spectral in patients with leukemia. However, because of toxicity
data.
issues, CXCR4 is only for limited use. Currently, there are
no other small-molecule antagonists of CXCR4 approved
Keywords: anti-cancer; anti-inflammatory; CXC chemokine by the FDA. Therefore, drugs with improved toxicity pro-
receptor type 4 (CXCR4); pyridine derivatives.
files will be required for long-term clinical use.
Other derivatives of AMD3100, such as WZ811
(Figure 1), have been synthesized and are active at
nanomolar concentration as a CXCR4 antagonist [22, 23].
However, in preclinical testing, WZ811 failed to exhibit
any in vivo efficacy due to poor bioavailability. Thus far,
DOI 10.1515/hc-2014-0041
Received March 26, 2014; accepted March 31, 2014
Pyridine derivatives have been explored for their potential the central aromatic ring of WZ811 and other derivatives
as pharmaceutical agents [1, 2]. In this paper, we report has remained free from modification and other aromatic
the synthesis of a series of pyridine compounds as poten- cores have not been explored. To this end, we have synthe-
tial CXC chemokine receptor type 4 (CXCR4) antagonists. sized a new class of compounds containing a central pyri-
Chemokines and their receptors are involved in the patho- dine ring (Figure 1) with the potential to improve potency
genesis of cancer, HIV, autoimmune and inflammatory and bioavailability. To determine their effectiveness as
diseases [3, 4]. One such chemokine receptor is CXCR4. potential CXCR4 inhibitors, these compounds have been
When CXCR4 interacts with its natural ligand (CXCL12), screened using two preliminary assays.
it triggers a number of signaling pathways that result in
Synthesis of pyridine derivatives 2a–l was accom-
physiological responses, such as chemotaxis, cell survival plished by reductive animation of pyridine-2,6-dicarbalde-
and proliferation, and gene transcription [5–11]. These hyde (1) in the presence of an amine in methanol with zinc
pathways are involved in the progression of autoimmune chloride as a catalyst and sodium cyanoborohydride as
the reducing agent (Scheme 1). The 1
H NMR, 13C NMR, and
HRMS analyses are reported for all final compounds.
The synthesized analogs were subjected to two pre-
liminary screening assays. The compounds were initially
screened using a binding affinity assay [16, 24]. This assay
involves competition of a potent CXCR4 peptidic antago-
nist, TN140, with the synthesized compounds. In this
assay, MDA-MB-231 (breast cancer cells) are preincubated
*Corresponding author: Suazette Reid Mooring, Department of
Chemistry, Georgia State University, Atlanta, GA 30303, USA,
e-mail: smooring@gsu.edu
Theresa Gaines: Department of Chemistry, Georgia State University,
Atlanta, GA 30303, USA
Zhongxing Liang and Hyunsuk Shim: Department of Radiology and
Imaging Science, Emory University School of Medicine, Atlanta, GA
30322, USA
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150ꢀ
ꢀS.R. Mooring et al.: Potential antagonists of chemokine receptor type 4
NH HN
NH
N
N
HN
NH HN
AMD 3100
N
N
H
H
N
H
N
H
N
R
N
R
N
WZ811
Figure 1ꢂRationale for design of a new class of pyridine analogs.
Figure 2ꢂResults from the binding assay for two selected analogs.
Compound 2b shows EC of 10 nm and compound 2k shows EC of
1000 nm (PC, positive control; NC, negative control).
a
H
N
H
N
O
O
N
R
N
R
1
2a-l
Eight of the 12 synthesized compounds exhibit moder-
ate to good activity in the binding affinity assay (ꢀꢀ≤ ꢀꢀ100 nm)
(Table 1). Derivatives 2b (3-fluorophenyl) and 2j (4-ethyl-
phenyl) show consistently good potency in both assays.
Compound 2b has an EC of 10 nm and inhibits invasion by
50% and compound 2j has an EC value of 1 nm and inhib-
its invasion by 64%. For comparison, WZ811 (Figure 1)
displays the EC value of 10 nm in the binding affinity
assay and inhibits invasion by 90%. Interestingly, the
2-pyridyl derivative 2l is structurally similar to WZ811 (also
a 2-pyridyl derivative) but has low activity in both assays.
2a: R = Ph
2g: R = 3-trifluoromethyl
2h: R = 3-nitrophenyl
2i: R = 4-nitrophenyl
2j: R = 4-ethylphenyl
2k: R = 2-methoxyphenyl
2l: R = 2-pyridyl
2b: R = 3-fluorophenyl
2c: R = 4-fluorophenyl
2d: R = 4-methoxyphenyl
2e: R = 3-chlorophenyl
2f: R = 4-chlorophenyl
Scheme 1ꢂReagents and conditions: (a) RNH2, ZnCl2, NaBH3CN, dry
MeOH, rt, 12 h.
with analogs at concentrations of 1, 10, 100, and 1000 nm,
and then incubated with biotinylated TN140 that has
been conjugated to the red fluorescent dye rhodamine.
The binding efficiency of the new analogs to the CXCL12
binding domain of CXCR4 can be determined. The effective
concentration (EC) is defined as the lowest concentration
at which a significant reduction in the rhodamine fluo-
rescent color (red) is observed as compared to the control
reflecting the competitive displacement by the peptide,
TN140 (Figure 2). This assay is a semi-quantitative, pre-
liminary measure of the level of activity and should not be
confused with EC50.
Table 1ꢂPreliminary results of the binding affinity assay and the
Matrigel invasion assay for compounds 2a–l, compared with the
results of a potent CXCR4 antagonist, WZ811 [22].
Compoundꢁ
Binding affinityꢁ
Matrigel invasion assay
(% inhibition of invasion)b
assay, EC (nm)a
WZ811
2a
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
10ꢃ
100ꢃ
90
0
2b
10ꢃ
50
4.5
4.5
34
20
15
40
9
2c
100ꢃ
The compounds were also screened using the Matrigel 2d
100ꢃ
2e
100ꢃ
invasion assay [25]. This assay was employed as a second-
2f
100ꢃ
ary functional assay to test whether the compounds can
2g
1000ꢃ
100ꢃ
block CXCR4/CXCL12-mediated chemotaxis and invasion
2h
at 100 nm. The compound and cells are added on the
upper chamber of a vessel and ligand (CXCL12) is added
in the lower chamber as a chemoattractant. A Matrigel
membrane separates the upper and lower chambers. For
potent compounds, very few cells will move through the
Matrigel membrane; that is, invasion of cells is inhibited.
2i
2j
2k
2l
ꢀ> ꢀ1000ꢃ
1ꢃ
1000ꢃ
ꢀ> ꢀ1000ꢃ
64
0
5
aCompounds were tested at 1, 10, 100, and 1000 nm only. bCom-
pounds were tested for inhibition of invasion at 100 nm.
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ꢂ151
7.12 (d, J ꢀ= ꢀ 7.6 Hz, 2 H), 7.49 (t, J ꢀ= ꢀ 7.6 Hz, 1 H); 13C NMR: δ 158.4, 152.2,
142.2, 137.2, 119.9, 114.9, 114.4, 55.8, 50.2. HRMS. Calcd for C21H24N3O2
([M + H]+): m/z 350.1869. Found: m/z 350.1865.
These 2,6-disubstituted pyridine derivatives repre-
sent a new generation of CXCR4 antagonists that warrants
further exploration. Our goal is to continue the synthesis
of additional analogs to improve the potency and biop-
harmaceutical properties of this class of compounds.
2,6-Bis(3-chloroanilinomethyl)pyridine (2e) This product was
1
obtained in 14% yield as a yellow semi-solid; H NMR: δ 4.36 (s, 4
Additional analogs with pyrazine and thiophene moieties H), 6.46 (dd, J ꢀ= ꢀ 8.0 and 1.0 Hz, 2 H), 6.58 (s, 2 H) 6.61 (d, J ꢀ= ꢀ 7.7 Hz,
2 H), 7.01 (t, J ꢀ= ꢀ 8.0 Hz, 2 H), 7.12 (d, J ꢀ= ꢀ 7.7 Hz, 2 H), 7.54 (t, J ꢀ= ꢀ 7.7 Hz,
are being synthesized. A comprehensive structure-activ-
1 H); 13C NMR: δ 157.4, 149.0, 137.5, 135.1, 130.3, 120.1, 117.5, 112.7, 111.4,
ity relationship (SAR) study of these compounds will be
48.9. HRMS. Calcd for C19H18N3Cl2 ([M + H]+): m/z 358.0872. Found: m/z
conducted.
358.0864.
2,6-Bis(4-chloroanilinomethyl)pyridine (2f) This product was
obtained in 15% yield as a yellow solid; mp 116–118°C; 1H NMR: δ 4.36
Experimental details
(br, s, 4H), 6.51 (d, J ꢀ= ꢀ 8.3 Hz, 4H), 7.06 (d, J ꢀ= ꢀ 8.3 Hz, 4H), 7.12 (d, J ꢀ= ꢀ
7.6 Hz, 2H), 7.54 (t, J ꢀ= ꢀ 7.6 Hz, 1H); 13C NMR: δ 157.6, 146.4, 137.4, 129.1,
122.3, 120.0, 114.2, 49.2. HRMS. Calcd for C19H18N3Cl2 ([M + H]+): m/z
Chemistry
358.0872. Found: m/z 358.0864.
Melting points were recorded using a Stuart SMP40 apparatus and
2,6-Bis[(3-trifluoromethyl)anilinomethyl)]pyridine (2g) This
are uncorrected. The 1H NMR (400 MHz) and 13C NMR (100 MHz) spec-
tra were recorded on a Bruker Ac 400 FT NMR spectrometer in CDCl3.
Mass spectra were recorded on a JEOL spectrometer. The syntheses
were carried out under nitrogen in dry glassware.
1
product was obtained in 18% yield as a light brown semi-solid; H
NMR: δ 4.40 (br s, 4H), 6.71 (d, J ꢀ= ꢀ 7.7 Hz, 2H), 6.80 (br s, 2H), 6.88 (d,
J ꢀ= ꢀ 7.7 Hz, 2H), 7.13 (d, J ꢀ= ꢀ 7.6 Hz, 2H), 7.17 (d, J ꢀ= ꢀ 7.6 Hz, 2H), 7.55 (t, J ꢀ= ꢀ
7.7 Hz, 1H); 13C NMR: δ 157.3, 148.0, 137.5, 129.7, 125.7, 123.0, 120.2, 116.0,
114.1, 109.3, 48.8. HRMS. Calcd for C21H17F6N3 ([M + H]+): m/z 426.1405.
Found: m/z 426.1403.
General procedure for the synthesis of
pyridine analogs 2a–l
2,6-Bis(3-nitroanilinomethyl)pyridine (2h) This product was
1
obtained in 34% yield as a yellow-orange solid; mp 147–149°C; H
NMR: δ 4.54 (d, J ꢀ= ꢀ 5.0 Hz, 4H), 6.96 (d, J ꢀ= ꢀ 8.1 Hz, 2H), 7.24 (br s, 2H),
7.31 (t, J ꢀ= ꢀ 8.1 Hz, 2H), 7.49 (br s, 2 H), 7.56 (d, J ꢀ= ꢀ 8.1 Hz, 2H), 7.65–7.71
(m, 1H); 13C NMR: δ 156.8, 148.6, 137.7, 129.8, 120.4, 119.2, 112.4, 106.6,
48.7. HRMS. Calcd for C19H17N5O4 ([M + H]+): m/z 380.1359. Found: m/z
380.1358.
To a solution of pyridine-2,6-dicarbaldehyde (50 mg, 0.37 mmol) in
methanol (4 mL) was added an aniline (0.81 mmol) and ZnCl2 (100
mg, 0.74 mmol). The solution was stirred for 2 h at room temperature,
then treated with NaBH3CN (46.5 mg, 0.81 mmol). The solution was
then stirred overnight. The crude product was purified by column
chromatography.
2,6-Bis(4-nitroanilinomethyl)pyridine (2i) This product was
1
obtained in 10% yield as a yellow semi-solid; H NMR: δ 4.51 (d, J ꢀ= ꢀ
2,6-Bis(anilinomethyl)pyridine (2a) This product was obtained
1
5.1 Hz, 4H), 6.56 (d, J ꢀ= ꢀ 9.1 Hz, 4H), 7.17 (d, J ꢀ= ꢀ 7.8 Hz, 2H), 7.64 (t, J ꢀ= ꢀ
7.8 Hz, 1H), 8.05 (d, J ꢀ= ꢀ 9.1 Hz, 2H); 13C NMR: δ 156.1, 152.7, 137.9, 126.4,
120.5, 111.6, 48.9. HRMS. Calcd for C19H18N5O4 ([M + H]+): m/z 380.1359.
Found: m/z 380.1359.
in 37% yield as an off-white semi-solid; H NMR: δ 4.38 (s, 4H), 6.59
(d, J ꢀ= ꢀ 7.8 Hz, 4H), 6.65 (t, J ꢀ= ꢀ 7.2 Hz, 2H), 7.06–7.15 (m, 6 H), 7.49 (t,
J ꢀ= ꢀ 7.8 Hz, 1H); 13C NMR: δ 158.1, 148.0, 137.3, 129.3, 119.9, 117.7, 113.1,
49.3. HRMS. Calcd for C19H20N3 ([M + H]+): m/z 290.1657. Found: m/z
290.1657.
2,6-Bis(4-ethylanilinomethyl)pyridine (2j) This product was
1
obtained in 11% yield as an orange oil; H NMR: δ 1.18 (t, J ꢀ= ꢀ 7.7 Hz,
2,6-Bis(3-fluoroanilinomethyl)pyridine (2b) This product was
obtained in 62% yield as a brown semi-solid; 1H NMR: δ 4.34 (s, 4H),
6.21–6.40 (m, 6H), 6.95–7.06 (m, 2H), 7.10 (d, J ꢀ= ꢀ 7.8 Hz, 2H), 7.51 (t, J ꢀ= ꢀ
7.8 Hz, 1H); 13C NMR: δ 165.4, 162.9, 157.5, 149.8, 149.7, 137.4, 130.3, 120.1,
109.0, 104.2, 104.0, 99.9, 99.6, 48.9. HRMS. Calcd for C19H18N3F2 ([M +
H]+): m/z 326.1469. Found: m/z 326.1462.
6H), 2.50–2.57 (m, 4H), 4.41 (s, 4H), 6.59 (d, J ꢀ= ꢀ 8.3 Hz, 4H), 6.97 (d,
J ꢀ= ꢀ 8.3 Hz, 2H), 7.01 (d, J ꢀ= ꢀ 8.3 Hz, 4H), 7.53 (t, J ꢀ= ꢀ 7.7 Hz, 1H); 13C NMR:
δ 158.4, 146.0, 137.3, 133.6, 128.7, 119.9, 115.3, 113.3, 49.7, 28.0, 16.02.
HRMS. m/z [M + H]+ Calcd for C23H28N3 ([M + H]+): m/z 346.2283.
Found: m/z 346.2291.
2,6-Bis(2-methoxyanilinomethyl)pyridine (2k) This product was
obtained in 51% yield as a brown solid; mp 112–114°C; 1H NMR: δ 3.81
(s, 6 H), 4.43 (s, 4 H), 6.49 (d, J ꢀ= ꢀ 7.7 Hz, 2H), 6.58–6.64 (m, 2H), 6.70–
6.79 (m, 4H), 7.14 (d, J ꢀ= ꢀ 7.7 Hz, 2H), 7.48 (t, J ꢀ= ꢀ 7.7 Hz, 1H); 13C NMR: δ
158.7, 147.0, 137.9, 137.3, 121.3, 119.6, 116.7, 110.3, 109.5, 55.5, 49.4. HRMS.
Calcd for C21H23N3O2 ([M + H]+): m/z 350.1869. Found: m/z 350.1862.
2,6-Bis(4-fluoroanilinomethyl)pyridine (2c) This product was
obtained in 34% yield as a brown semi-solid; 1H NMR: δ 4.33 (s, 4H),
6.51 (dd, J ꢀ= ꢀ 8.7 and 4.2 Hz, 4H), 6.81 (t, J ꢀ= ꢀ 8.7 Hz, 4H), 7.12 (d, J ꢀ= ꢀ 7.6
Hz, 2 H), 7.52 (t, J ꢀ= ꢀ 7.6 Hz, 1H); 13C NMR: δ 158.0, 157.2, 154.8, 137.4,
137.2, 120.0,115.9, 115.7, 115.6, 115.5, 114.3, 113.5, 113.4, 49.9. HRMS. Calcd
for C19H18N3F2 ([M + H]+): m/z 326.1469. Found: m/z 326.1462.
2,6-Bis(pyridin-2-aminomethyl)pyridine (2l) This product
obtained in 14% yield as a white solid; mp 152–153°C (lit mp 153–
155°C) [26]; 1H NMR: δ 4.66 (d, J ꢀ= ꢀ 5.1 Hz, 4H), 6.47 (d, J ꢀ= ꢀ 7.7 Hz, 2H),
2,6-Bis(4-methoxyanilinomethyl)pyridine (2d) This product was
obtained in 30% yield as a brown solid; mp 63–65°C; 1H NMR: δ 3.66
(s, 6 H), 4.33 (s, 4 H), 6.55 (d, J ꢀ= ꢀ 8.8 Hz, 4 H), 6.70 (d, J ꢀ= ꢀ 8.8 Hz, 4 H),
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6.61 (d, J ꢀ= ꢀ 5.1 Hz, 2H), 7.21 (d, J ꢀ= ꢀ 7.7 Hz, 2H), 7.42 (t, J ꢀ= ꢀ 7.7 Hz, 2H), 7.60
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