Synthesis and cytotoxicity evaluation of new 3-substituted 4-(4-methyloxy phenyl)-1H-pyrrole derivatives

Article abstract of DOI:10.1002/bkcs.10653

A new series of 3-substituted 4-(4-methyloxy phenyl)-1H-pyrrole derivatives were synthesized and biologically evaluated for potential anticancer activity. Fifteen targeted compounds showed high selectivity toward normal cells and cancer cells: that is, al

Full text of DOI:10.1002/bkcs.10653

Article
DOI: 10.1002/bkcs.10653
BULLETIN OF THE
X. Zhan et al.
KOREAN CHEMICAL SOCIETY
Synthesis and Cytotoxicity Evaluation of New 3-substituted
4-(4-methyloxy phenyl)-1H-Pyrrole Derivatives
Xiaoping Zhan, Lan Lan, Yuankui Zhang, Jian Chen, Kai Zhao, Shuai Wang,
*
Yuxuan Xin, and Zhenmin Mao
School of Pharmacy, Shanghai Jiaotong University, Shanghai 200240, China. *E-mail: zmmao@sjtu.edu.cn
Received September 11, 2015, Accepted October 26, 2015, Published online January 14, 2016
A new series of 3-substituted 4-(4-methyloxy phenyl)-1H-pyrrole derivatives were synthesized and biologi-
cally evaluated for potential anticancer activity. Fifteen targeted compounds showed high selectivity toward
normal cells and cancer cells: that is, all targeted compounds hadnoobviouscytotoxicity towardnormal human
cells (HUVEC and NIH/3T3), but some compounds exhibited broad-spectrum proliferation inhibitory activity
against the screened cancer cell lines. Among these pyrrole derivatives, compounds 3b and 3o showed potent
anticancer activity against the MG-63 cell line, with IC50 values of 14.9 and 12.7 μM, respectively. Other pyr-
role derivatives also showed promising proliferation inhibitory activity, including compound 3d against
A375 (IC50 = 18.6 μM), compound 3f and 3j against MGC80-3 (IC50 = 19.9 μM), and compound 3o
against MGC80-3 (IC50 = 11.9 μM). Because the developed pyrrole derivatives showed strong anticancer
activity and high selectivity, this new series of pyrrole derivatives could be considered as promising lead com-
pounds for further development of potent and safe anticancer agents.
Keywords: Pyrrole derivatives, Anticancer activity, Synthesis, MTT assay, Structure–activity relationship
Introduction
screened normal cell lines when killing cancer cells.
Therefore, our objective is to synthesize a novel series of
3,4-disubstituted pyrrole compounds, evaluate their biologi-
cal activity, explore the structure–activity relationship, and
try to find a lead compound with high selectivity and
sensitivity.
In this paper, a novel series of 3-substituted 4-(4-methyloxy
phenyl)-1H-pyrrole compounds were prepared by the
method of Van Leusen pyrrole synthesis. The proliferation
inhibitory activity of 15 pyrrole derivatives against two nor-
mal cell lines (HUVEC and NIH/3T3) and 16 cancer
cell lines were determined by MTT (3-(4,5-dimethylthiazol-
2-yl)-2,5-diphenyltetrazoliumbromide) assay. Furthermore,
the structure–activity relationship is discussed based on the
activity data.
Pyrrole derivatives are an important class of heterocyclic com-
pounds, and are found in many natural products,1–3
pharmaceuticals,4 and biological agents.5–9 Usually, pyrrole
derivatives are used as antifungal agents,10–12 antimicrobial
agents,13–15 antiviral agents,16,17 and cyclooxygenase
inhibitors.18–20 Pyrrole derivatives used as anticancer agents
have only been rarely reported till now except for a few com-
pounds separated from plant sources, such as alkaloids.21,22 It
is well known that anticancer agents in clinical use usually
induce serious toxicity during the killing of cancer cells,
and thus design and synthesis of novel anticancer agents with
potent anticancer activity and low toxicity is a desirable
approach to cancer treatment.
A series of novel 3,4-disubstituted pyrrole compounds
have been reported by us, in which the moieties at the 3-
position of the pyrrole ring are substituted by benzoyl, nitro,
cyano, acetyl, and so on, and those at the 4-position of pyrrole
ring by 4-methylthio phenyl, and 3-chloro-4-fluorophenyl.
These reported compounds have shown the same level
in vitro anticancer activity as paclitaxel. For example, some
3,4-disubstituted pyrrole derivatives have shown strong antic-
ancer activity against the MGC80-3 cell line with IC50 values
ranging from 4.5 to 9.6 μM, and some other compounds
against A375 with IC50 values ranging from 6.1 to 8.5 μM.
Moreover, these compounds have shown broad-spectrum
anticancer activity against MGC80-3, MCF-7, CHO, CT-
26, A375, and HCT-15 cell lines.23,24
Experimental
Chemistry. All chemical reagents were purchased from com-
mercial suppliers and were of analytical grade. Flash column
chromatography was performed on a column packed with
200–300 mesh silica gel 60 or neutral aluminum oxide.
Thin-layer chromatography (TLC) was performed on silica
gel 60 F254-plate with a fluorescent indicator. 1H NMR
(400 MHz) and 13C NMR (100 MHz) spectra were recorded
on a Bruker Advanced III 400 spectrometer with DMSO-d6 as
solvent and TMS as the internal standard. High-resolution
mass spectroscopy (HRMS) data were obtained on an AB
SCIEX TripleTOF® 4600 mass spectrometer using the elec-
trospray ionization (ESI) technique. Melting points were
recorded on a microscopic melting point apparatus (SGW
More importantly, thesecompoundsexhibit highselectivity
tonormal cell lines. Theyhardly induce cytotoxic effects inthe
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X-4, Shanghai Precision & Scientific Instrument Co., Ltd.,
Shanghai, China) and were uncorrected.
ArH), 7.79 (d, J = 16.0 Hz, 1H,
CH ), 7.60 (d,
J = 8.0 Hz, 2H, ArH), 7.38 (d, J = 16.0 Hz, 1H, CH ),
7.17 (t, J = 8.0 Hz, 2H, ArH), 6.94 (d, J = 8.0 Hz,
2H, ArH), 3.86 (s, 3H, OCH3).
General Procedure for the Synthesis of α,β-unsaturated
Carbonyl Compounds (2a–2o). Na (0.01 g, 0.4 mmol)
was cut to pieces and added into anhydrous MeOH (15 mL)
under ice bath; the fresh MeONa/MeOH solution was pre-
pared till no gas evolved. 4-Methoxybenzaldehyde (1.36 g,
10.0 mmol) was added to the fresh, cooled MeONa/MeOH
solution (15 mL), and then 10.0 mmol acetyl aromatic com-
pound was added dropwise. The mixture was stirred at room
temperature for 2–8 h (36–54 h for 2n and 2o due to the steric
hindrance of the naphthyl and biphenyl). The end of the reac-
tion was monitored by TLC. Afterward, water (20 mL) and
EtOAc (75 mL, 25 mL × 3) were added into the mixture.
The inorganic precipitate was removed, and the organic solu-
tion was washed with brine three times and dried. The crude
product was purified by silica gel column chromatography
with EtOAc/hexane as eluent to get pure α,β-unsaturated car-
bonyl compounds (2a–2o).
General Procedure for the Synthesis of 3,4-disubstituted
Pyrroles (3a–3o). One equivalent of α,β- unsaturated car-
bonyl compounds (2a–2o), 1.1 equiv TosMIC, and 1.2
equiv t-BuOK wereaddedtoananhydrousTHF (20 mL) solu-
tion, and the mixture was stirred in an ice bath for 1 h. Ice
water (50 mL) was poured into the mixture, THF was
removed under vacuum, and the solution was extracted by
EtOAc (75 mL, 25 mL × 3). The combined organic
layer solution was washed with saturated brine and dried
over anhydrous Na2SO4. The crude pyrrole product was
purified by aluminum oxide column chromatography with
EtOAc/hexane as eluent to get pure 3,4-disubstituted pyrroles
(3a-3o).
[4-(4-Methoxyphenyl)-1H-pyrrol-3-yl]
(4-fluoro-
phenyl) methanone (3b). White solid, yield 90.8%, mp
1
ꢀ
221–223 C. H NMR (300 MHz, CDCl3) δ (ppm): 8.55 (s,
1H, pyrrole–NH), 7.83 (t, J = 9.0 Hz, 2H, ArH), 7.34–7.28
(d, J = 9.0 Hz, 2H, ArH), 7.23 (s, 1H, pyrrole H), 7.04 (t,
J = 9.0 Hz, 2H, ArH), 6.88 (s, 1H, pyrrole H), 6.84 (d,
J = 9.0 Hz, 2H, ArH), 3.80 (s, 3H, OCH3); 13C NMR
(100 MHz, DMSO-d6) δ (ppm): 188.92, 163.95 (1C, JCF
=
249.0 Hz), 157.50, 136.57 (1C, JCF = 2.9 Hz), 131.58
(2C, JCF = 9.1 Hz), 129.41 (2C), 127.80, 127.53, 125.15,
120.24, 118.97, 115.01(2C, JCF = 21.7 Hz), 113.17 (2C),
54.95; ESI-HRMS m/z: calcd for C18H14FNO2 ([M + H]):
296.1088; found: 296.1003.
3-(4-Methoxyphenyl)-1-(2-chlorophenyl) propen-1-one
(2c). White solid, yield 97.8%. 1H NMR (300 MHz, CDCl3)
δ (ppm): 7.73 (d, J = 9.0 Hz, 2H, ArH), 7.62-7.42 (m, 4H,
ArH), 7.34 (d, J = 18.0 Hz, 1H,
J = 18.0 Hz, 1H, CH ), 7.68 (d, J = 9.0 Hz, 2H, ArH),
3.80 (s, 3H, OCH3).
[4-(4-Methoxyphenyl)-1H-pyrrol-3-yl]
CH ), 7.13 (d,
(2-chloro-
phenyl) methanone (3c). White solid, yield 94.1 %, mp
211–213 C. 1H NMR (300 MHz, DMSO-d6) δ (ppm):
ꢀ
11.63 (s, 1H, pyrrole–NH), 7.52–7.36 (m, 4H, ArH), 7.43
(d, J = 9.0 Hz, 2H, ArH), 6.97 (t, J = 3.0 Hz, 1H, pyrrole
H), 6.93 (dd, J1 = 3.0 Hz, J2 = 0.9 Hz, 1H, pyrrole H),
6.87 (d, J = 9.0 Hz, 2H, ArH), 3.75 (s, 3H, OCH3); 13C
NMR (100 MHz, DMSO-d6) δ (ppm): 188.34, 157.74,
140.84, 130.41, 130.25, 129.72 (2C), 129.50 (2C), 128.47,
127.13, 126.77, 124.86, 120.89, 119.95, 113.05 (2C),
54.99; ESI-HRMS m/z: calcd for C18H14ClNO2 ([M + H]):
312.0792, 314.0763; found: 312.0625, 314.0544.
3-(4-Methoxyphenyl)-1-(4-chlorophenyl) propen-1-one
(2d). White solid, yield 96.9%. 1H NMR (300 MHz, CDCl3)
δ (ppm): 8.07 (d, J = 9.0 Hz, 2H, ArH), 7.71 (d,
J = 9.0 Hz, 2H, CH ), 7.60 (d, J = 6.0 Hz, 2H, ArH),
7.38 (s, 4H, ArH), 7.06 (d, J = 9.0 Hz, 2H, ArH), 3.98 (s,
3H, OCH3).
3-(4-Methoxyphenyl)-1-(2-fluorophenyl) propen-1-one
(2a). Yellow solid, yield 98.4%. 1H NMR (300 MHz, CDCl3)
δ (ppm): 7.81 (t, J = 6.0 Hz, 1H, ArH), 7.73 (d, J = 18.0 Hz,
1H, CH ), 7.59 (d, J = 9.0 Hz, 2H, ArH), 7.52 (m, 1H,
ArH), 7.51 (m, 2H, ArH), 7.33–7.12 (m, 1H, CH ), 6.94
(d, J = 9.0 Hz, 2H, ArH), 3.86 (s, 3H, OCH3).
[4-(4-Methoxyphenyl)-1H-pyrrol-3-yl]
(2-fluoro-
phenyl) methanone (3a). White solid, yield 77.7 %, mp
195–197 C. 1H NMR (300 MHz, DMSO-d6) δ (ppm):
ꢀ
11.63 (s, 1H, pyrrole–NH), 7.55–7.42 (m, 2H, ArH), 7.38
(d, J = 9.0 Hz, 2H, ArH), 7.26 (d, J = 9.0 Hz, 1H, ArH),
7.22 (dd, J1 = 3.0 Hz, J2 = 0.9 Hz, 1H, ArH), 7.09 (dd,
J1 = 3.0 Hz, J2 = 0.9 Hz, 1H, pyrrole H), 6.96 (t,
J = 3.0 Hz, 1H, pyrrole H), 6.85 (d, J = 9.0 Hz, 2H, ArH),
3.74 (s, 3H, −OCH3); 13C NMR (100 MHz, DMSO-d6) δ
(ppm): 186.45, 158.74 (1C, JCF = 248.5 Hz), 157.70,
131.70 (1C, JCF = 8.1 Hz), 129.79, 129.74 (2C), 129.70
(1C, JCF = 3.6 Hz), 129.60, 127.19, 124.88, 124.10 (1C,
JCF = 3.3 Hz), 121.42, 119.70, 115.83(1C, JCF = 21.7 Hz),
113.04 (2C), 54.97; ESI-HRMS m/z: calcd for C18H14FNO2
([M + H]): 296.1088; found: 296.0980.
[4-(4-methoxyphenyl)-1H-pyrrol-3-yl]
(4-chloro-
phenyl) methanone (3d). White solid, yield 88.1%, mp
230–232 C. 1H NMR (300 MHz, DMSO-d6) δ (ppm):
ꢀ
11.62 (s, 1H, pyrrole-NH), 7.73 (d, J = 9.0 Hz, 2H, ArH),
7.52 (d, J = 9.0 Hz, 2H, ArH), 7.30 (d, J = 9.0 Hz, 2H,
ArH), 7.23 (dd, J1 = 3.0 Hz, J2 = 1.2 Hz, 1H, pyrrole H),
7.00 (t, J = 3.0 Hz, 1H, pyrrole H), 6.84 (d, J = 9.0 Hz,
2H, ArH), 3.73 (s, 3H, OCH3); 13C NMR (100 MHz,
DMSO-d6) δ (ppm): 189.04, 157.55, 138.76, 136.15,
130.71 (2C), 129.46 (2C), 128.30–128.10 (1C), 128.17
(2C), 127.46, 125.18, 120.11, 119.12, 113.17 (2C), 54.95;
ESI-HRMS m/z: calcd for C18H14ClNO2 ([M + H]):
312.0792, 314.0763; found: 312.0695, 314.0658.
3-(4-Methoxyphenyl)-1-(4-fluorophenyl) propen-1-one
1
(2b). Pale yellow solid, yield 92.1%. H NMR (400 MHz,
3-(4-Methoxyphenyl)-1-(3-bromophenyl) propen-1-one
1
CDCl3) δ (ppm): 8.05 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 2H,
(2e). Pale yellow solid, yield 93.5%. H NMR (300 MHz,
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CDCl3) δ (ppm): 8.34–8.04 (m, 2H, ArH + CH ), 7.88 (d,
J = 9.0 Hz, 2H, ArH), 7.87–7.68 (m, 3H, ArH + CH ),
7.64–7.47 (m, 1H, ArH), 7.01 (d, J = 9.0 Hz, 2H, ArH),
3.82 (s, 3H, OCH3).
(m, 2H, ArH + CH ), 7.15–7.97 (m, 3H, ArH + CH ),
6.92 (d, J = 8.0 Hz, 2H, ArH), 3.85 (s, 3H, OCH3), 2.44 (s,
3H, PhCH3), 2.38 (s, 3H, PhCH3).
[4-(4-Methoxyphenyl)-1H-pyrrol-3-yl] (2, 4-dimethyl-
phenyl) methanone (3h). White solid, yield 93.9 %, mp
[4-(4-Methoxyphenyl)-1H-pyrrol-3-yl]
(3-bromo-
203–205 C. 1H NMR (300 MHz, DMSO-d6) δ (ppm):
ꢀ
phenyl) methanone (3e). White solid, yield 81.7 %, mp
215–217 C. 1H NMR (300 MHz, DMSO-d6) δ (ppm):
11.51 (s, 1H, pyrrole-NH), 7.40 (d, J = 9.0 Hz, 2H, ArH),
7.24 (d, J = 9.0 Hz, 1H, ArH), 7.06 (s, 1H, ArH), 7.02 (dd,
J1 = 9.0 Hz, J2 = 3.0 Hz, 1H, ArH), 6.95 (t, J = 3.0 Hz,
1H, pyrrole H), 6.89 (t, J = 3.0 Hz, 1H, pyrrole H), 6.85 (d,
J = 9.0 Hz, 2H, ArH), 3.75 (s, 3H, OCH3), 2.30 (s,
3H, PhCH3), 2.22 (s, 3H, PhCH3); 13C NMR (100 MHz,
DMSO d6) δ (ppm): 192.14, 157.59, 138.59, 138.57,
135.14, 131.08, 129.63 (2C), 129.23, 127.88, 127.54,
125.44, 124.88, 121.87, 119.41, 113.02 (2C), 54.97, 20.79,
19.33; ESI-HRMS m/z: calcd for C20H19NO2 ([M + H]):
306.1495; found: 306.1259.
ꢀ
11.64 (s, 1H, pyrrole–NH), 7.80–7.55 (m, 3H, ArH),
7.51–7.37 (m, 1H, ArH), 7.28 (d, J = 9.0 Hz, 2H, ArH),
7.25 (dd, J1 = 3.0 Hz, J2 = 0.9 Hz, 1H, pyrrole H), 7.00 (t,
J = 3.0 Hz, 1H, pyrrole H), 6.83 (d, J = 9.0 Hz, 2H, ArH),
3.73 (s, 3H, OCH3); 13C NMR (100 MHz, DMSO-d6) δ
(ppm): 118.61, 157.57, 142.24, 133.93, 131.27, 130.34,
129.50 (2C), 128.43, 127.82, 127.39, 125.23, 121.44,
120.00, 119.23, 113.17 (2C), 54.96; ESI-HRMS m/z: calcd
for C18H14BrNO2 ([M + H]): 356.0287, 358.0266; found:
356.0163, 358.0192.
3-(4-Methoxyphenyl)-1-(4-bromophenyl) propen-1-one
(2f ). Pale yellow solid, yield 93.5%. 1H NMR
(300 MHz, CDCl3) δ (ppm): 8.07 (d, J = 9.0 Hz, 2H, ArH),
7.85 (d, J = 9.0 Hz, 2H, CH ), 7.75 (d, J = 6.0 Hz, 4H,
ArH), 6.99 (d, J = 9.0 Hz, 2H, ArH), 3.80 (s, 3H, OCH3).
3-(4-Methoxyphenyl)-1-(3-methoxo-phenyl) propen-1-
one (2i). Pale yellow solid, yield 96.5%. 1H
NMR (300 MHz, CDCl3) δ (ppm): 7.81 (d, J = 15.0 Hz,
1H, CH ), 7.62 (d, J = 9.0 Hz, 2H, ArH), 7.60–7.50 (m,
2H, ArH + CH ), 7.46–7.35 (m, 2H, ArH), 7.13 (dd,
J1 = 9.0 Hz, J2 = 3.0 Hz, 1H, ArH), 6.95 (d, J = 9.0 Hz,
2H, ArH), 3.90 (s, 3H, OCH3), 3.87 (s, 3H, OCH3).
[4-(4-Methoxyphenyl)-1H-pyrrol-3-yl]
(4-bromo-
phenyl) methanone (3f ). White solid, yield 93.9 %, mp
250–252 C. 1H NMR (300 MHz, DMSO-d6) δ (ppm):
[4-(4-Methoxyphenyl)-1H-pyrrol-3-yl]
(3-methoxo-
ꢀ
11.62 (s, 1H, pyrrole–NH), 7.63 (s, 4H, ArH), 7.28 (d,
J = 9.0 Hz, 2H, ArH), 7.21 (dd, J1 = 3.0 Hz, J2 = 0.9 Hz,
1H, pyrrole H), 6.99 (t, J = 3.0 Hz, 1H, pyrrole H), 6.82 (d,
J = 9.0 Hz, 2H, ArH), 3.72 (s, 3H, OCH3); 13C NMR
(100 MHz, DMSO-d6) δ (ppm): 189.16, 157.55, 139.11,
131.11 (2C), 130.89 (2C), 129.46 (2C), 128.23, 127.45,
125.18, 125.13, 120.06, 119.13, 113.17 (2C), 54.96; ESI-
HRMS m/z: calcd for C18H14BrNO2 ([M + H]): 356.0287,
358.0266; found: 356.0203, 358.0199.
phenyl) methanone (3i). Pale yellow solid, yield 93.4 %,
1
ꢀ
mp 193–195 C. H NMR (300 MHz, DMSO-d6) δ (ppm):
11.56 (s, 1H, pyrrole–NH), 7.41–7.29 (m, 3H, ArH), 7.30
(d, J = 9.0 Hz, 2H, ArH), 7.32–7.26 (m, 2H, 1 pyrrole H
+1 ArH), 7.12 (m, 1H, ArH), 6.99 (t, J = 3.0 Hz, 1H, pyrrole
H), 6.82 (d, J = 9.0 Hz, 2H, ArH), 3.77 (s, 3H, OCH3), 3.73
(s, 3H, OCH3); 13C NMR (100 MHz, DMSO-d6) δ (ppm):
189.92, 158.86, 157.50, 141.51, 129.43 (2C), 129.20,
128.01, 127.62, 125.16, 121.36, 120.32, 118.99, 117.37,
113.57, 113.14 (2C), 55.12, 54.95; ESI-HRMS m/z: calcd
for C19H17NO3 ([M + H]): 308.1287; found: 308.1203.
3-(4-Methoxyphenyl)-1-(4-methoxo-phenyl) propen-1-
one (2j). Pale yellow solid, yield 94.2%. 1H NMR
(300 MHz, CDCl3) δ (ppm): 8.16 (d, J = 9.0 Hz, 2H, ArH),
7.83 (d, J = 18.0 Hz, 1H, CH ), 7.82 (d, J = 9.0 Hz, 2H,
3-(4-Methoxyphenyl)-1-(4-methylphenyl)
propen-1-
1
one (2g). White solid, yield 94.7%. H NMR (400 MHz,
CDCl3) δ (ppm): 7.93 (d, J = 8.0 Hz, 2H, ArH), 7.78 (d,
J = 16.0 Hz, 1H, CH ), 7.50 9 (d, J = 9.0 Hz, 2H, ArH),
7.42 (d, J = 16.0 Hz, 1H, CH ), 7.30 (d, J = 8.0 Hz, 2H,
ArH), 6.94 (d, J = 8.0 Hz, 2H, ArH), 3.86 (s, 3H, OCH3),
2.44 (s, 3H, PhCH3).
ArH), 7.68 (d, J = 18.0 Hz, 1H,
CH ), 7.09 (d,
[4-(4-Methoxyphenyl)-1H-pyrrol-3-yl]
(4-methyl-
J = 9.0 Hz, 2H, ArH), 7.02 (d, J = 9.0 Hz, 2H, ArH), 3.87
phenyl) methanone (3g). White solid, yield 81.3 %, mp
(s, 3H, OCH3), 3.82 (s, 3H, OCH3).
[4-(4-Methoxyphenyl)-1H-pyrrol-3-yl]
215–217 C. 1H NMR (300 MHz, DMSO-d6) δ (ppm):
(4-methoxo-
ꢀ
11.52 (s, 1H, pyrrole-NH), 7.65 (d, J = 9.0 Hz, 2H, ArH),
7.27 (t, J = 6.0 Hz, 4H, ArH), 7.16 (dd, J1 = 3.0 Hz,
J2 = 1.2 Hz, 1H, pyrrole H), 6.98 (t, J = 3.0 Hz, 1H, pyrrole
H), 6.83 (d, J = 9.0 Hz, 2H, ArH), 3.73 (s, 3H, OCH3), 2.36
(s, 3H, PhCH3); 13C NMR (100 MHz, DMSO-d6) δ (ppm):
190.03, 157.46, 141.48, 129.35 (2C), 129.11 (2C), 128.65
(2C), 127,70, 127.51, 125.08, 120.46, 118.81, 113.17 (2C),
54.94, 21.01; ESI-HRMS m/z: calcd for C19H17NO2
([M + H]): 292.1338; found: 292.1012.
phenyl) methanone (3j). White solid, yield 93.3 %, mp
203–205 C. 1H NMR (300 MHz, DMSO-d6) δ (ppm):
ꢀ
11.50 (s, 1H, pyrrole–NH), 7.75 (d, J = 9.0 Hz, 2H, ArH),
7.27 (d, J = 9.0 Hz, 2H, ArH), 7.17 (dd, J1 = 3.0 Hz,
J2 = 0.9 Hz, 1H, pyrrole H), 6.99 (dd, J1 = 3.0 Hz,
J2 = 0.9 Hz, 1H, pyrrole H), 7.00–6.98 (m, 1H, pyrrole H),
6.82 (d, J = 9.0 Hz, 2H, ArH), 3.82 (s, 3H, OCH3), 3.73
(s, 3H, OCH3); 13C NMR (100 MHz, DMSO-d6) δ (ppm):
189.26, 162.00, 157.40, 132.42, 131.24 (2C), 129.23 (2C),
127.75, 126.72, 124.98, 120.55, 118.55, 113.35 (2C),
113.20 (2C), 55.33, 54.93; ESI-HRMS m/z: calcd for
C19H17NO3 ([M + H]): 308.1287; found: 308.1212.
3-(4-Methoxyphenyl)-1-(2, 4-dimethyl phenyl) propen-
1
1-one (2h). White solid, yield 91.8%. H NMR (300 MHz,
CDCl3) δ (ppm): 7.52 (d, J = 9.0 Hz, 2H, ArH), 7.50–7.39
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3-(4-Methoxyphenyl)-1-(2-pyridyl) propen-1-one (2k).
White solid, yield 30.6%. H NMR (300 MHz, CDCl3) δ
(ppm): 8.79 (d, J = 3.0 Hz, 1H, ArH), 8.20–7.98 (m, 3H,
ArH + CH ), 7.88–7.75 (m, 3H, ArH + CH ), 7.69
(m, 1H, ArH), 7.03 (d, J = 9.0 Hz, 2H, ArH), 3.83 (s,
3H, OCH3).
1H, thiophenyl H), 7.01 (t, J = 3.0 Hz, 1H, pyrrole H), 6.85
(d, J = 9.0 Hz, 2H, ArH), 3.74 (s, 3H, OCH3); 13C NMR
(100 MHz, DMSO-d6) δ (ppm): 181.85, 157.51, 145.71,
133.16, 132.87, 129.26 (2C), 128.18, 127.50, 126.51,
124.80, 120.11, 118.91, 113.27 (2C), 54.95; ESI-HRMS m/
z: calcd for C16H13NO2S ([M + H]): 284.0746; found:
284.0547.
1
[4-(4-Methoxyphenyl)-1H-pyrrol-3-yl]
(2-pyridyl)
methanone (3k). White solid, yield 92.5 %, mp
3-(4-Methoxyphenyl)-1-(1-naphthyl)
propen-1-one
1
139–141 C. 1H NMR (300 MHz, DMSO-d6) δ (ppm):
(2n). Pale yellow solid, yield 82.9%. H NMR (300 MHz,
CDCl3) δ (ppm): 8.28 (m, 1H, ArH), 8.13 (d, J = 9.0 Hz,
1H, ArH), 8.04 (m, 1H, ArH), 7.93 (dd, J1 = 3.0 Hz,
J2 = 0.9 Hz, 1H, ArH), 7.76 (d, J = 9.0 Hz, 2H, ArH),
7.77–7.75 (m, 4H, ArH + CH ), 7.43 (d, J = 15.0 Hz,
1H, CH ), 6.99 (d, J = 9.0 Hz, 2H, ArH), 3.80 (s,
3H, OCH3).
ꢀ
11.58 (s, 1H, pyrrole–NH), 8.65 (d, J = 6.0 Hz, 1H, pyridine
H), 7.96 (dt, J1 = 9.0 Hz, J2 = 3.0 Hz, 1H, pyridine H), 7.72
(dd, J1 = 3.0 Hz, J2 = 0.9 Hz, 1H, pyrrole H), 7.81 (d,
J = 9.0 Hz, 1H, ArH), 7.55 (m, 1H, pyridine H), 7.34 (d,
J = 9.0 Hz, 2H, ArH), 6.93 (t, J = 3.0 Hz, 1H, pyrrole H),
6.86 (d, J = 9.0 Hz, 2H, ArH), 3.76 (s, 3H, OCH3); 13C
NMR (100 MHz, DMSO-d6) δ (ppm): 187.36, 157.57,
156.87, 148.23, 137.09, 130.55, 129.76 (2C), 127.90,
125.75, 125.65, 122.99, 118.90, 118.84, 112.99 (2C),
54.96; ESI-HRMS m/z: calcd for C17H14N2O2 ([M + H]):
279.1134; found: 279.0886.
3-(4-Methoxyphenyl)-1-(3-pyridyl) propen-1-one (2l).
Pale yellow solid, yield 47.3%. 1H NMR (400 MHz, CDCl3)
δ (ppm): 9.29 (t, J = 4.0 Hz, 1H, ArH), 8.80 (m, 1H, ArH),
8.43 (m, 1H, ArH), 7.86 (d, J = 12.0 Hz, 2H, ArH), 7.79
(d, J = 12.0 Hz, 2H, CH ), 7.59 (m, 1H, ArH), 7.01 (dd,
J1 = 12.0 Hz, J2 = 4.0 Hz, 2H, ArH), 3.81 (s, 3H, OCH3).
[4-(4-Methoxyphenyl)-1H-pyrrol-3-yl]
(1-naphthyl)
methanone (3n). White solid, yield 86.0 %, mp
209–211 C. 1H NMR (300 MHz, DMSO-d6) δ (ppm):
ꢀ
11.56 (s, 1H, pyrrole-NH), 8.06-7.94 (m, 3H, ArH), 7.65-
7.59 (m, 1H, ArH), 7.58–7.49 (m, 3H, ArH), 7.47 (d,
J = 9.0 Hz, 2H, ArH), 6.99 (t, J = 3.0 Hz, 1H, pyrrole H),
6.95 (dd, J1 = 3.0 Hz, J2 = 0.9 Hz, 1H, pyrrole H), 6.87 (d,
J = 9.0 Hz, 2H, ArH), 3.76 (s, 3H, OCH3); 13C NMR
(100 MHz, DMSO-d6) δ (ppm): 191.43, 157.68, 139.02,
133.14, 130.14, 129.98, 129.77 (2C), 129.61, 128.21,
127.49, 126.63, 126.10, 125.88, 125.33, 125.18, 124.67,
122.24, 119.67, 113.04 (2C), 54.98; ESI-HRMS m/z: calcd
for C22H17NO2 ([M + H]): 328.1338; found: 328.1064.
3-(4-Methoxyphenyl)-1-(4-biphenyl) propen-1-one(2o).
[4-(4-Methoxyphenyl)-1H-pyrrol-3-yl]
(3-pyridyl)
methanone (3l). White solid, yield 58.2 %, mp
202–204 C. 1H NMR (400 MHz, DMSO-d6) δ (ppm):
ꢀ
1
11.69 (s, 1H, pyrrole-NH), 8.82 (dd, J1 = 4.0 Hz,
J2 = 1.2 Hz, 1H, pyridine H), 8.70 (dd, J1 = 8.0 Hz,
J2 = 4.0 Hz, 1H, pyridine H), 8.05 (dt, J1 = 12.0 Hz,
J2 = 4.0 Hz, 1H, pyridine H), 7.48 (ddd, J1 = 12.0 Hz,
J2 = 4.0 Hz, J3 = 1.2 Hz, 1H, pyridine H), 7.32 (d,
J = 12.0 Hz, 2H, ArH), 7.30-7.28 (m, 1H, pyrrole H), 7.02
(t, J = 4.0 Hz, 1H, pyrrole H), 6.84 (d, J = 12.0 Hz, 2H,
ArH), 3.74 (s, 3H, OCH3); 13C NMR (100 MHz, DMSO-
d6) δ (ppm): 188.56, 157.59, 151.70, 149.38, 136.20,
135.58, 129.61 (2C), 128.81, 127.32, 125.19, 123.33,
120.26, 119.39, 113.16 (2C), 54.95; ESI-HRMS m/z: calcd
for C17H14N2O2 ([M + H]): 279.1134; found: 279.1043.
3-(4-Methoxyphenyl)-1-(2-thienyl) propen-1-one (2m).
Yellow solid, yield 79.7%. H NMR (300 MHz, CDCl3)
δ (ppm): 8.12 (d, J = 9.0 Hz, 2H, ArH), 7.9-7.55 (m, 6H,
ArH + CH ), 7.55–7.35 (m, 3H, ArH + CH ), 7.27 (s,
2H, ArH), 6.96 (d, J = 9.0 Hz, 2H, ArH), 3.88 (s,
3H, OCH3).
[4-(4-Methoxyphenyl)-1H-pyrrol-3-yl]
(4-biphenyl)
methanone (3o). Yellow solid, yield 40.2 %, mp
252–254 C. 1H NMR (300 MHz, DMSO-d6) δ (ppm):
ꢀ
11.59 (s, 1H, pyrrole-NH), 7.90–7.65 (m, 6H, ArH), 7.50 (t,
J = 6.0 Hz, 2H, ArH), 7.41 (t, J = 6.0 Hz, 1H, ArH), 7.33
(d, J = 9.0 Hz, 2H, ArH), 7.25 (t, J = 3.0 Hz, 1H, pyrrole
H), 7.01 (t, J = 3.0 Hz, 1H, pyrrole H), 6.85 (d, J = 9.0 Hz,
2H, ArH), 3.73 (s, 3H, OCH3); 13C NMR (100 MHz,
DMSO-d6) δ (ppm): 189.83, 157.52, 142.93, 139.19,
138.91, 129.68 (2C), 129.44 (2C), 129.03 (2C), 128.05,
127.90, 127.65, 126.83 (2C), 126.35 (2C), 125.19, 120.42,
118.99, 113.18 (2C), 54.95; ESI-HRMS m/z: calcd for
C24H19NO2 ([M + H]): 354.1495; found: 354.1321.
1
Yellow solid, yield 85.2%. H NMR (300 MHz, CDCl3) δ
(ppm): 8.30 (dd, J1 = 3.0 Hz, J2 = 0.9 Hz, 1H, ArH), 8.04
(dd, J1 = 3.0 Hz, J2 = 0.9 Hz, 1H, ArH), 7.85 (d,
J = 6.0 Hz, 2H, ArH), 7.75 (d, J = 18.0 Hz, 1H, CH=),
7.70 (d, J = 18.0 Hz, 1H, CH ), 7.31 (dd, J1 = 3.0 Hz,
J2 = 0.9 Hz, 1H, ArH), 7.03 (d, J = 6.0 Hz, 2H, ArH), 3.83
(s, 3H, OCH3).
In vitro Cytotoxicity Studies
Cell Culture. All cell lines, namely A375 (human malignant
melanoma), A549 (human lung cancer), CHO (Chinese ham-
ster ovary), CT-26 (murine colon carcinoma), DU145 (human
prostate cancer), HCT-15 (human colorectal adenocarci-
noma), HCT-116 (human colon cancer), HeLa (human cervi-
cal carcinoma), Hep G2 (human hepatoma), K-562 (human
chronic myeloid leukemia), L1210 (murine leukemia),
MCF-7 (human breast cancer), MG-63 (human
[4-(4-Methoxyphenyl)-1H-pyrrol-3-yl]
(2-thienyl)
methanone (3m). White solid, yield 67.5 %, mp
205–207 C. 1H NMR (300 MHz, DMSO-d6) δ (ppm):
ꢀ
11.59 (s, 1H, pyrrole–NH), 7.92 (dd, J1 = 3.0 Hz,
J2 = 0.9 Hz, 1H, thiophenyl H), 7.71(d, J = 3.0 Hz, 1H, thio-
phenyl H), 7.49 (t, J = 3.0 Hz, 1H, pyrrole H), 7.30 (d,
J = 9.0 Hz, 2H, ArH), 7.20 (dd, J1 = 3.0 Hz, J2 = 0.9 Hz,
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osteosarcoma), MGC80-3 (human gastric cancer), NCI-H460
(humanlargecelllungcancer), SGC-7901(humangastricade-
nocarcinoma), HUVEC (human umbilical vein endothelial),
and NIH/3T3 (murine embryonic fibroblast) were purchased
from Type Culture Collection of the Chinese Academy of Sci-
ence (Shanghai, China). The cells were cultured in RPMI-
1640 (Hyclon) orhigh glucose DMEM (Hyclon) medium with
10% heat-inactivated fetal bovine serum (Hyclon) 1%
penicillin–streptomyciꢀn (Hyclon), and incubated at standard
culture conditions (37 C, 5% CO2 in air) (Thermo Fisher Sci-
entific, Wisconsin, USA). The culture medium was refreshed
every 2 days.
MTT Assay. The logarithmic growth phase cells were col-
lected and seeded into 96-well plates at a seeding density
5000 cells/well and incubated at 37 ꢀC for 24 h. The cells were
treated with different concentrations ofdrugs, andfour parallel
wells were arranged for each concentration. The blank control
groups were prepared by the same procedure without sample
treatment. After 24 h of treatment, the treatment medium was
removed, and then 150 μL culture medium and 20 μL MTT
solution (5 mg/mL in PBS) were added to each well. After
4 h of incubation, the medium was discarded, 100 μL DMSO
was added to each well, and then the plate was shaken for
10 min for dissolving the formazan crystals. The percentage
of cell viability was determined by measuring the absorption
at 570 nm using a Multiskan MK3 microplate reader
(Thermo, USA).
Biological Evaluation. The results of the proliferation inhib-
itory activity tests are shown in Table 1. It was found that all
targeted compounds showed no obvious cytotoxicity toward
normal cell lines (HUVEC and NIH/3T3) but potent prolifer-
ation inhibitory activity against some cancer cell lines. Among
the tested derivatives, compounds 3b and 3o showed better or
similar cytotoxic effect toward MG-63 cell compared with
positive controls (paclitaxel and 5-fluorouracil) with an IC50
value of 14.9, 12.7, 20.5, and 27.8 μM, respectively. Other
compounds also showed promising anticancer activity; for
example, the IC50 value of compound 3d inhibiting against
A375 was 18.6 μM, the IC50 of compound 3f and 3j against
MGC80-3 was 19.9 μM, and the IC50 of compound 3o against
MGC80-3 was 11.9 μM.
Although paclitaxel and 5-fluorouracil showed stronger
proliferationinhibitoryactivity against cancer cells incompar-
ison with most pyrrole derivatives, they also showed medium
cytotoxicity toward normal cells. The IC50 values of paclitaxel
inhibiting against HUVEC and NIH/3T3 were 57.9 and
54.3 μM, respectively. The IC50 values of 5-fluorouracil
inhibiting against HUVEC and NIH/3T3 were 83.2 and
92.3 μM, respectively. However, the tested pyrrole deriva-
tives hardly showed cytotoxicity toward normal cells. Thus,
3,4-disubstitued pyrrole derivatives had higher selectivity
compared with other anticancer agents in clinical use.
Based on the activity data in Table 1 and the results of the
previously reported compounds,23,24 some preliminary
structure–activity relationship of 3,4-disubstituted pyrrole
compounds could be summarized as follows: (i) When substi-
tuted groups were benzoyl analogs at the 3-position of the pyr-
role ring, the type of substituents on the benzoyl ring affected
the anticancer activity. The structure–activity relationship was
usually in the order: methoxy > bromo > chloro > fluoro >
methyl, such as compounds 3j, 3f, 3d, 3b, and 3g.
(ii) When the substituents on the benzoyl ring were the same,
the position of the substituents on the benzoyl ring also
affected the anticancer activity. The structure–activity rela-
tionship was in the order: para- > (meta-, ortho-), such as in
compounds 3j and 3i, compounds 3b and 3a, compounds 3f
and 3e. (iii) When the benzene ring on the benzoyl was
replaced by pyridine ring, the anticancer activity of com-
pounds decreased, such as compounds 3k and 3l.
Results and Discussion
Chemistry. The target compounds, namely 3-substituted-4-
(4-methyloxy phenyl)-1H-pyrrole derivatives 3a–3o,
were synthesized according to the methods described in
Scheme 1.
As shown in Scheme 1, a simple synthetic route of 3,4-
disubstituted pyrroles includes a two-step reactions: (1) α,β-
unsaturated carbonyl compounds (2a–3o) synthesized
by Aldol condensation reaction under base-catalyzed condi-
tions, and (2) 3,4-disubstituted pyrroles (3a–3o) synthesized
by Van Leusen pyrrole methodology under ice-bath
conditions.
Scheme 1. Synthetic route of 3-substituted-4-(4-methyloxy phenyl)-1H-pyrrole 3a–3o. Reagents and conditions: (1) CH3ONa, CH3OH;
(2) 1.1 equiv TosMIC, 1.2 equiv t-BuOK, THF, or DMSO, ice bath.
Bull. Korean Chem. Soc. 2016, Vol. 37, 200–206
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Table 1. The IC50 of the targeted compounds
Compound
IC50 (μmol/L)
A375
>100
56.9
—
A549
—
CHO
76.3
78.3
—
CT-26
>100
57.6
>100
27.9
>100
25.3
>100
>100
—
DU-145
>100
>100
—
HCT-15
>100
41.7
>100
60.4
87.6
38.8
>100
54.8
—
HCT-116
>100
—
Hela
67.8
20.8
—
Hep G2
—
a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
>100
—
>100
—
—
18.6
>100
25
>100
>100
—
>100
—
40.1
>100
24.2
78
>100
>100
24.2
>100
>100
94.3
82.6
34.6
3.4
>100
>100
>100
>100
>100
—
>100
—
26
>100
—
>100
>100
>100
>100
>100
>100
>100
>100
74.9
>100
>100
1.7
>100
>100
—
20.5
—
61
91.1
>100
—
—
—
—
25.1
>100
>100
43.5
56.9
—
>100
—
25.3
>100
—
>100
—
38.8
—
20.2
>100
>100
45.6
>100
>100
16.5
13.6
61
—
—
—
—
—
>100
—
35.7
27.2
22.9
6.7
>100
—
86.6
57.8
23.5
5.5
>100
56
77.3
13.8
10.4
—
—
Paclitaxel
5-Fluorouracil
5.6
13.7
3.8
8.2
7.8
8.3
11.4
7.6
10.1
9.3
Compound
IC50 (μmol/L)
K-562
>100
94.7
—
L1210
MCF-7
>100
>100
—
MG-63
>100
14.9
—
MGC80-3
22
NCI-H460
>100
23.4
—
SGC-7901
>100
40
NIHn3 T3
—
HUVEC
3a
3b
3c
>100
24.4
—
—
>100
—
26.4
—
>100
—
—
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
65.2
>100
>100
90
>100
>100
>100
—
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
7.9
>100
>100
>100
>100
—
31.8
>100
30.6
>100
59.7
—
22.2
22.5
19.9
28.9
62.6
69.7
19.9
—
25
>100
>100
>100
—
—
>100
—
>100
25.8
67.7
>100
—
—
—
>100
—
—
>100
—
—
>100
—
—
—
>100
—
30.6
—
25.8
—
>100
—
—
>100
—
—
—
—
—
—
—
—
—
—
—
—
>100
96.3
12.7
20.5
27.8
45.9
43.4
11.9
4.2
64.7
56.9
>100
6.9
>100
—
—
>100
—
—
—
—
>100
5.1
10.3
>100
5.6
10.2
—
—
—
Paclitaxel
5-Fluorouracil
a
15.1
10.2
54.3
83.2
57.9
92.3
23.2
14.7
28.7
When IC50 > 300 μmol/L, the compound is considered to have no cytotoxicity.
Conclusion
Acknowledgments. Publication cost of this article was sup-
ported by the Korean Chemical Society.
A series of novel 3,4-disubstituted pyrrole derivatives (3a–3o)
were synthesized and their in vitro anticancer activities eval-
uated. These pyrrole derivatives exhibited broad-spectrum
anticancer activity against the screened cancer cell lines; espe-
cially, compounds 3b and 3o showed stronger cytotoxicity
toward MG-63 than positive controls. Structure–activity stud-
ies revealed that the type and position of the substituents on the
benzoyl ring at the 3-position of the pyrrole ring seriously
affected their proliferation inhibitory activities. These results
contributed to the design and development of lead compounds
with potent anticancer activity and high selectivity.
SupportingInformation. Additionalsupportinginformation
is available in the online version of this article.
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