Synthesis of 3,4-diaryl- and 4-acyl-3-arylpyrroles and study of their antimitotic activity

Article abstract of DOI:10.1007/s11172-018-2150-3

The Barton–Zard reaction of nitro substituted stilbenes and chalcones with ethyl isocyanoacetate afforded 3,4-diaryl- and 4-acyl-3-arylpyrroles, respectively. 3-Arylpyrrole-2,4- dicarboxylates and 4-arylisoxazoline N-oxides were side reaction products. An

Full text of DOI:10.1007/s11172-018-2150-3

Russian Chemical Bulletin, International Edition, Vol. 67, No. 5, pp. 858—865, May, 2018
858
Synthesis of 3,4-diaryl- and 4-acyl-3-arylpyrroles
and study of their antimitotic activity
A. V. Samet,а E. A. Sil´yanova,а,b V. I. Ushkarov,а M. N. Semenova,c and V. V. Semenova
аN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
E-mail: sametav@ioc.ac.ru
bD. I. Mendeleev University of Chemical Technology of Russia,
9 Miusskaya pl., 125047 Moscow, Russian Federation
cN. K. Kol´tsov Institute of Developmental Biology, Russian Academy of Sciences,
26 ul. Vavilova, 119334 Moscow, Russian Federation
The Barton—Zard reaction of nitro substituted stilbenes and chalcones with ethyl isocyano-
acetate afforded 3,4-diaryl- and 4-acyl-3-arylpyrroles, respectively. 3-Arylpyrrole-2,4-
dicarboxylates and 4-arylisoxazoline N-oxides were side reaction products. Antimitotic activ-
ity of target 3,4-disubstituted pyrroles was studied on a sea urchin embryo model. Pyrroles
unsubstituted at positions 2 and 5 were the most active. The activity increased with the number
of methoxy groups in the Ar substituent.
Key words: antimitotic activity, combretastatin, nitrostilbenes, nitrochalcones, ethyl iso-
cyanoacetate, Barton—Zard reaction, 3,4-diarylpyrroles, 4-acyl-3-arylpyrroles, sea urchin
embryo.
A number of modern studies in medicinal chemistry
are devoted to the development of new synthetic analogs
of natural antimitotic combretastatin A-4 (CA4, 1), featur-
ing steric stability, strong antiproliferative activity with
minimum side effects and the ability to overcome multi-
drug resistance.1,2
Methods for their synthesis are reported in a number of
reviews.1,3 Combretastatin derivatives CA4P (fosbretabulin),
AVE8062, and ZD6186 are at 2/3 stages of clinical trials as
anticancer drugs. Their mechanism of action involves inhi-
bition of intracellular protein tubulin resulting in micro-
tubule destabilization and tumor blood vessel destruction.4
For optimal binding to tubulin and high antimitotic
activity, molecules of combretastatins should have cis-con-
figuration.1,5,6 Five-membered heterocycles are considered
as nonisomerizable and metabolically stable bioisosteric
replacement of the double bond in combretastatins, fixing
rings A and B in cis-position.
Results and Discussion
Earlier, diaryl-substituted pyrazole,7,8 1,3,4-oxadi-
azole,9,10 isoxazole,11—13 triazole,14 tetrazole,8,13,15,16 imid-
azole,8,17 and thiazole8 derivatives have already been
studied. In the present work, we consider 3,4-diarylpyrrole
derivatives.
Ethyl pyrrole-2-carboxylates were obtained by the
Barton—Zard reaction19 from diarylethylenes 4a—d and
1,3-diaryl-2-nitroprop-2-en-1-ones 5a,b (Scheme 1, Table 1).
In the 1Н NMR spectra of target compounds 6 and 7, the
signal for pyrrole NH proton was found at δH 11.87—12.21
and 12.33—12.50, respectively.
The yields of target product are quite moderate (which
is consistent with the literature data19—21) due to the for-
mation of by-products. As far as we know, by-products in
the Barton-Zard reaction were not yet objects of study; in
A linker binding two aromatic rings may also include
three carbon atoms; in particular, some chalcones (e.g.,
pedicin (2) or derricin (3)18) exhibit cytostatic activity.
Such compounds, in which the C = C bond is replaced by
the pyrrole ring, were also studied in this work.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 0858—0865, May, 2018.
1066-5285/18/6705-0858 © 2018 Springer Science+Business Media, Inc.

Synthesis of 3,4-diaryl- and 4-acyl-3-arylpyrroles
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 5, May, 2018
859
Scheme 1
Reagents and conditions: DBU, THF, 20 °C, 12 h.
Table 1. The yields of compounds 6 and 7
the present work we succeeded in establishing the struc-
tures of some of them.
For the reactions with nitrochalcones 5, the 1Н NMR
spectra showed that α-nitrochalcones decomposed to the
starting compounds, p-methoxybenzoylnitromethane (8)
and aldehyde, which under the reaction conditions under-
went oxidation to acid 9 (no such products were detected
for the reactions with nitrostilbenes 4).
Compound
R
Yield (%)
6a
6b
6c
6d
7a
7b
4-MeO
4-Cl
3,5-(MeO)2
4-NO2
4-MeO
4-Cl
39
43
37
34
37
41
dicarboxylates 10 (Scheme 2) resulting from elimination
of hydrogen cyanide from the intermediate compound 11,
which, in turn, was formed from isocyanide 12 in the reac-
tion with ethyl isocyanoacetate. In the 1Н NMR spectra, the
admixture of 10 can be distinguished from compounds 6
In the reactions of both nitrostilbenes 4 and nitrochal-
cones 5, we observed the formation of diethyl pyrrole-2,4-
Scheme 2
X = 4-MeOC6H4, 4-MeOC6H4CO

860
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 5, May, 2018
Samet et al.
and 7 by the shift of the NH proton, which was found in
lower field at δH 12.35—12.60.
Pure compounds 10b, 10c, and 10d were isolated by
chromatographic separation.
In the reactions with nitrostilbenes 4, isoxazoline
N-oxides 13 were detected as side products (Scheme 3),
1
which in the Н NMR spectra have indicative doublets
with J = 4.3—4.6 Hz and chemical shifts at δH 5.11—5.30
(H(4)) and δH 5.41—5.52 (H(5)). Apparently, they are
formed by the addition of p-methoxyphenylnitromethane
to nitrostilbenes 4 and subsequent cyclization of the in-
termediate adducts 14.
Pure isoxazoline oxide 13b was isolated in the course
of synthesis.
Formation of similar isoxazoline N-oxides was not
detected in the reactions involving nitrochalcones 5.
Alkaline hydrolysis of esters 6 and 7 gave the corre-
sponding acids 15 and 16, while their subsequent de-
carboxylation resulted in pyrroles 17 and 18 (Scheme 4,
Table 2).
Scheme 3
There is an example19 of one-pot synthesis of 3,4-di-
arylpyrroles by reflux of pyrrole-2-carboxylates 6 and 7
with alkali in ethylene glycol. However, in our experiments
the higher yields were obtained in the two-step procedure
including heating with NaOH in aqueous ethanol (with
subsequent acidification) and decarboxylation of thus
isolated acid.
Notably, the impurity of isoxazoline N-oxides 13 in
esters 6 (of which it is not always easy to get rid by recrys-
tallization or chromatography) does not prevent the
X = 4-MeOC6H4
Scheme 4

Synthesis of 3,4-diaryl- and 4-acyl-3-arylpyrroles
Table 2. The yields of compounds 15—18
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 5, May, 2018
861
Table 3. Effects of 3,4-diaryl- and 3-aryl-4-benzoylpyrroles on
sea urchin embryos Paracentrotus lividus
Compound
R
Yield (%)
Com-
pound
ECа/μmol L–1
15a
15b
15c
15d
16a
16b
17a
17b
17c
17d
18a
18b
4-MeO
4-Cl
80
57
80
85
83
83
68
46
46
67
66
67
Cleavage
alteration
Cleavage
arrest
Embryo
spinning
3,5-(MeO)2
4-NO2
4-MeO
4-Cl
6а
6b
6c
7a
>4
>4
1
>4
>4
4b
>4
>4
>4
>4
>4
1
>4
>4
>4
>4
>4
>4
>4
>4
5
4-MeO
4-Cl
>4
>4
>4
>4
4
3,5-(MeO)2
4-NO2
4-MeO
4-Cl
7b
15c
16a
17b
17c
17d
18a
СА4d
0.5
4c
>4
>4
0.01
>4
>4
0.05
isolation of pure hydrolysis products, pyrrole-2-carboxylic
acids 15. The alkaline hydrolysis gives water-soluble so-
dium salts of the acids, while isoxazoline N-oxides 13
through recyclization and elimination of water are con-
verted to water-insoluble isoxazoles 19 (Scheme 5).22
Thus, the impurity can be removed by simple filtration of
the reaction mixture.
>4
0.002
а ЕС is the threshold concentration causing the effect.
b Arrested eggs acquired tuberculate shape typical of microtubule
destabilizers.
c Developmental delay without visible morphological abnor-
malities.
This procedure was used to isolate pure isoxazole 19a.
d Combretastatin А-4 (СА4) was used as a positive control.
Biоlogical activity of 3,4-diaryl- and 3-aryl-4-benzo-
ylpyrroles was studied in sea urchin Paracentrotus lividus
embryos according to the published procedure.23 This
phenotypic assay does not require complicated and ex-
pensive equipment and provides quick identification of
antimitotic compounds that alter fertilized egg division
(cleavage). After treatment at the hatched blastula stage,
embryo settlement on the bottom of the vessel together with
rapid spinning around the animal-vegetal axis suggest tub-
ulin-targeting microtubule destabilizing effect of a compound.
Compounds 6a, 6b, 7a, 7b, 15c, 16a, and 18a at a con-
centration of up to 4 μmol L–1 did not affect cell division
(Table 3). Nitro-substituted compound 17d caused cleav-
Acid 15 and 16 were decarboxylated by heating to
melting points (in the absence of solvent). Acid 15 was
completely decarboxylated for a shorter time (~30 s) than
acid 16 (~2 min).
Scheme 5

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Russ. Chem. Bull., Int. Ed., Vol. 67, No. 5, May, 2018
Samet et al.
7.09 (d, 2 Н, Ar, J = 8.9 Hz); 7.47 (d, 2 Н, Ar, J = 8.9 Hz); 7.96
(d, 2 Н, Ar, J = 8.9 Hz); 8.48 (s, 1 Н, HC). Found (%): С, 65.13;
Н, 5.09; N, 4.38. C17H15NO5. Calculated (%): С, 65.17; Н, 4.83;
N, 4.47.
3-(4-Chlorophenyl)-1-(4-methoxyphenyl)-2-nitroprop-2-en-
1-one (5b). The yield was 50%. M.p.. 117—118 °С (from ethanol).
1H NMR (DMSO-d6, 500 МHz), δ: 3.86 (s, 3 Н, OCH3); 7.09
(d, 2 Н, Ar, J = 8.9 Hz); 7.50 (m, 4 Н, Ar); 7.97 (d, 2 Н, Ar,
J = 8.9 Hz); 8.54 (s, 1 Н, HC). MS (EI, 70 eV), m/z (Irel (%)):
317 [M]+ (9), 166 (40), 135(41), 123 (100). Found (%): С, 60.16;
Н, 3.75; N, 4.29. C16H12ClNO4. Calculated (%): С, 60.48;
Н, 3.81; N, 4.41.
Synthesis of ethyl pyrrole-2-carboxylates 6a—d and 7a,b
(general procedure). The reagent DBU (0.75 mmol) was added
slowly to a solution of 1,2-diarylnitroethylene or 1,3-diaryl-2-
nitroprop-2-en-1-one (0.5 mmol) and ethyl isocyanoacetate
(85 mg, 0.75 mmol) in THF (2 mL). The mixture was stirred at
room temperature for 12 h, poured into water containing dilute
aqueous hydrochloric acid, and extracted with ethyl acetate. The
extract was washed with water and concentrated, the residue was
purified by flash-chromatography (ethyl acetate—heptane,
1 : 5).19
Ethyl 3,4-bis(4-methoxyphenyl)pyrrole-2-carboxylate (6a).
The yield was 39%. M.p. 133—135 °С (cf. Ref. 30: m.p. 136 °С).
1H NMR (DMSO-d6, 500 МHz), δ: 1.10 (t, 3 Н, CH3, J = 7.1 Hz);
3.68 (s, 3 Н, OCH3); 3.75 (s, 3 Н, OCH3); 4.07 (q, 2 Н, CH2,
J = 7.1 Hz); 6.75 (d, 2 Н, Ar, J = 8.7 Hz); 6.84 (d, 2 Н, Ar,
J = 8.6 Hz); 6.99 (d, 2 Н, Ar, J = 8.6 Hz); 7.07 (d, 2 Н, Ar,
J = 8.7 Hz); 7.15 (d, 1 Н, СHpyrr, J = 3.1 Hz); 11.87 (s, 1 Н, NH).
Ethyl 3-(4-chlorophenyl)-4-(4-methoxyphenyl)pyrrole-2-carb-
oxylate (6b). The yield was 43%. M.p.. 131—133 °С. 1H NMR
(DMSO-d6, 500 МHz), δ: 1.08 (t, 3 Н, CH3, J = 7.1 Hz); 3.69
(s, 3 Н, OCH3); 4.08 (q, 2 Н, CH2, J = 7.1 Hz); 6.77 (d, 2 Н,
Ar, J = 8.7 Hz); 6.97 (d, 2 Н, Ar, J = 8.6 Hz); 7.17 (d, 2 Н, Ar,
J = 8.6 Hz); 7.19 (d, 1 Н, СHpyrr, J = 3.1 Hz); 7.33 (d, 2 Н, Ar,
J = 8.7 Hz); 12.01 (s, 1 Н, NH). Found (%): С, 67.60; Н, 4.99;
N, 3.78. C20H18ClNO3. Calculated (%): C, 67.51; H, 5.10;
N, 3.94.
age delay without visible alteration of early sea urchin
embryos morphology. Pyrrole 17b inhibited cleavage only
at the maximal tested concentration (4 μmol L–1). Pyrrole
17с unsubstituted at position 2 exhibited antimitotic effect
due to the microtubule destabilization. Its 2-carbethoxy-
substituted analog 6с showed markedly lower antitubulin
activity. Compound 6с did not cause embryo spinning,
however, the arrested eggs acquired a specific tuberculate
shape typical of antitubulin agents. Interestingly, hydro-
lysis of the ester group resulted in a complete loss of activ-
ity in 2-carboxy analog 15с. Analysis of the structure—
activity relationship for the tested pyrroles identified
3-(3,5-dimethoxyphenyl)-4-(4-methoxyphenyl)pyrrole
(17с) as the most potent antimitotic antitubulin molecule.
Experiment
NMR spectra were recorded on Bruker-DRX 500 (500.13 МHz
for 1H, 125.76 МHz for 13С) and Bruker-AM 300 (300.13 МHz
for 1H, 75.47 МHz for 13С) spectrometers. Mass spectra were
recorded on a Finningan MAT/INCOS50 spectrometer with
ionization energy of 70 eV. The eluent for TLC was a mixture of
ethyl acetate—heptane (1 : 5). The starting 4-methoxyphenyl
nitromethane and 1-(4-methoxyphenyl)-2-nitroethanone were
obtained according to the known procedures.24,25 THF was
purified by keeping over NaOH with subsequent distillation over
sodium metal under Ar atmosphere. Compounds 4c,d were ob-
tained according to the procedure described in the literature.26
Synthesis of 1,2-diarylnitroethylenes 4a,b (general procedure).
A mixture of aromatic aldehyde (2 mmol) and 4-methoxyphenyl-
nitromethane (334 mg, 2 mmol) was dissolved in methanol
(0.25 mL) and after addition of n-butylamine (1 drop) was allowed
to stand for several days. Once layers were formed, methanol
(0.25 mL) was added and a precipitate formed was collected by
filtration. Yellow crystals of 4a,b were obtained by recrystalliza-
tion from ethanol (7 mL).27
1,2-Bis(4-methoxyphenyl)-1-nitroethylene (4a). The yield was
44%. M.p. 137—138 °С (from ethanol); cf. Ref. 28: m.p. 142—144 °С.
1H NMR (CDCl3, 500 МHz), δ: 3.78 (s, 3 Н, OCH3); 3.88
(s, 3 Н, OCH3); 6.76 (d, 2 Н, Ar, J = 8.9 Hz); 7.01 (d, 2 Н, Ar,
J = 8.7 Hz); 7.08 (d, 2 Н, Ar, J = 8.9 Hz); 7.25 (d, 2 Н, Ar,
J = 8.7 Hz); 8.20 (s, 1 Н, HC).
2-(4-Chlorophenyl)-1-(4-methoxyphenyl)-1-nitroethylene (4b).
The yield was 49%. M.p.. 118—119 °С (from ethanol). 1H NMR
(CDCl3, 500 МHz), δ: 3.87 (s, 3 Н, OCH3); 7.00 (d, 2 Н, Ar,
J = 8.5 Hz); 7.06 (d, 2 Н, Ar, J = 8.4 Hz); 7.21—7.26 (m, 4 Н,
Ar); 8.12 (s, 1 Н, HC). Found (%): С, 62.28; Н, 4.22; N, 4.63.
C15H12ClNO3. Calculated (%): С, 62.19; Н, 4.17; N, 4.83.
Synthesis of 1,3-diaryl-2-nitroprop-2-en-1-ones 5a,b (gen-
eral procedure). A mixture of 1-(4-methoxyphenyl)-2-nitro-
ethanone (780 mg, 4 mmol), arylaldehyde (4.2 mmol), β-alanine
(30 mg, 0.33 mmol), and acetic acid (0.64 mL) in benzene
(6.4 mL) was refluxed in a flask equipped with a Dean—Stark
trap for 4 h. Then, the reaction mixture was washed with water
(3×6 mL), benzene was removed in vacuo of a water-jet pump.
The residue was recrystallized from ethanol (14 mL).29
Ethyl 3-(3,5-dimethoxyphenyl)-4-(4-methoxyphenyl)pyrrole-
2-carboxylate (6c). The yield was 37%. M.p.. 168—169 °С.
1H NMR (DMSO-d6, 500 МHz), δ: 1.08 (t, 3 Н, CH3, J = 7.1 Hz);
3.65 (s, 6 Н, OCH3); 3.69 (s, 3 Н, OCH3); 4.08 (q, 2 Н, CH2,
J = 7.1 Hz); 6.31 (d, 2 Н, Ar, J = 2.1 Hz); 6.40 (s, 1 Н, Ar); 6.76
(d, 2 Н, Ar, J = 8.5 Hz); 7.03 (d, 2 Н, Ar, J = 8.6 Hz); 7.17 (d,
1 Н, СHpyrr, J = 3.1 Hz); 11.94 (s, 1 Н, NH). 13C NMR
(DMSO-d6, 125.76 МHz), δ: 14.1 (CH3), 54.9 (OCH3), 55.0
(2 С, OCH3), 59.3 (CH2), 98.5 (CHarom), 108.9 (2 C, CHarom),
113.6 (2 C, CHarom), 119.3 (Carom), 121.0 (CHpyrr), 124.6 (Carom),
127.1 (Carom), 128.0 (Carom), 128.8 (2 C, CHarom), 137.1 (Carom),
157.5 (Carom), 159.6 (2 С, Carom), 160.4 (COOH). MS (EI, 70 eV),
m/z (Irel (%)): 381 [M]+ (85), 366 (36), 335 (100), 320 (48).
Found (%): С, 69.07; Н, 6.15; N, 3.72. C22H23NO5. Calculat-
ed (%): C, 69.28; H, 6.08; N, 3.67.
Ethyl 4-(4-methoxyphenyl)-3-(4-nitrophenyl)pyrrole-2-carb-
oxylate (6d). The yield was 34%. M.p.. 158—161 °С. 1H NMR
(DMSO-d6, 500 МHz), δ: 1.08 (t, 3 Н, CH3, J = 7.1 Hz); 3.69
(s, 3 Н, OCH3); 4.10 (q, 2 Н, CH2, J = 7.1 Hz); 6.78 (d, 2 Н,
Ar, J = 8.8 Hz); 6.96 (d, 2 Н, Ar, J = 8.7 Hz); 7.25 (d, 1 Н,
СHpyrr, J = 3.2 Hz); 7.45 (d, 2 Н, Ar, J = 8.8 Hz); 8.15 (d, 2 Н,
Ar, J = 8.8 Hz); 12.21 (s, 1 Н, NH). MS (EI, 70 eV), m/z (Irel (%)):
366 [M] + (85), 320 (100), 203 (18), 135 (15), 29 (27). Found (%):
1,3-Bis(4-methoxyphenyl)-2-nitroprop-2-en-1-one (5a). The
yield was 40%. An oil. 1H NMR (DMSO-d6, 500 МHz), δ: 3.77
(s, 3 Н, OCH3); 3.86 (s, 3 Н, OCH3); 6.99 (d, 2 Н, Ar, J = 8.9 Hz);

Synthesis of 3,4-diaryl- and 4-acyl-3-arylpyrroles
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 5, May, 2018
863
С, 65.73; Н, 4.84; N, 7.59. C20H18N2O5. Calculated (%):
С, 65.57; Н, 4.95; N, 7.65.
(OCH3), 55.9 (OCH3), 82.5 (СHizox), 114.1 (2 С, CHarom), 114.2
(2 C, CHarom), 116.0 (Carom), 118.0 (Carom), 127.5 (2 С, CHarom),
128.2 (2 С, CHarom), 129.0 (2 С, CHarom), 129.4 (2 С, CHarom),
130.0 (Carom), 132.5 (Carom), 138.2 (Carom), 159.6 (Carom), 159.7
(Carom). Found (%): С, 67.44; Н, 4.78; N, 3.65. C23H20ClNO4.
Calculated (%): С, 67.40; Н, 4.92; N, 3.42.
Synthesis of pyrrole-2-carboxylic acids 15a—d and 16a,b
(general procedure). A solution of ethyl ester 6 or 7 (0.15 mmol)
and sodium hydroxide (12 mg, 0.3 mmol) in a mixture of ethanol
(3 mL) with water (0.3 mL) was refluxed until disappearance of
the starting compound, monitoring by TLC (ethyl acetate—hept-
ane, 1 : 2). Once the reaction reached completion, a solution of
aqueous alkali (1 М, 9 mL) was added and the reaction mixture
was heated to boiling. The hot suspension was filtered. The filtrate
was acidified (pH 1—2), a precipitate formed was collected by
filtration.
3,4-Bis(4-methoxyphenyl)pyrrole-2-carboxylic acid (15a).
The yield was 80%. M.p. 192—193 °С (cf. Ref. 30: m.p. 184 °С).
1H NMR (DMSO-d6, 500 МHz), δ: 3.68 (s, 3 H, OCH3); 3.75
(s, 3 H, OCH3); 6.73 (d, 2 Н, Ar, J = 8.8 Hz); 6.82 (d, 2 Н, Ar,
J = 8.7 Hz); 6.96 (d, 2 Н, Ar, J = 8.7 Hz); 7.07 (d, 2 Н, Ar,
J = 8.8 Hz); 7.09 (s, 1 Н, CHpyrr); 11.70 (s, 1 Н, NH); 11.97 (br.s,
1 H, COOH). MS (EI, 70 eV), m/z (Irel (%)): 323 [M]+ (93), 305
(100), 279 (55), 191 (23).
3-(4-Chlorophenyl)-4-(4-methoxyphenyl)pyrrole-2-carboxylic
acid (15b). The yield was 57%. M.p. 222—224 °С. 1H NMR
(DMSO-d6, 500 МHz), δ: 3.69 (s, 3 H, OCH3); 6.76 (d, 2 Н,
Ar, J = 8.6 Hz); 6.95 (d, 2 Н, Ar, J = 8.6 Hz); 7.13 (d, 1 Н,
CHpyrr, J = 3.1 Hz); 7.17 (d, 2 Н, Ar, J = 8.3 Hz); 7.32 (d, 2 Н,
Ar, J = 8.3 Hz); 11.89 (s, 1 Н, NH); 12.19 (br.s, 1 H, COOH).
13C NMR (DMSO-d6, 125.76 МHz), δ: 55.0 (OCH3), 113.7
(2 С, CHarom), 119.9 (Carom), 120.8 (CHpyrr), 124.7 (Carom),
126.4 (Carom), 127.0 (Carom), 127.5 (2 С, CHarom), 129.0 (2 С,
CHarom), 131.1 (Carom), 132.5 (2 С, CHarom), 134.3 (Carom), 157.5
(COOH), 161.8 (Carom). MS (EI, 70 eV), m/z (Irel (%)): 327 [M]+
(96), 309 (100), 294 (18), 45 (19), 28 (27). Found (%): С, 65.78;
Н, 4.34; N, 4.39. C18H14ClNO3. Calculated (%): С, 65.96;
Н, 4.31; N, 4.27.
Ethyl 4-(4-methoxybenzoyl)-3-(4-methoxyphenyl)pyrrole-2-
carboxylate (7а). The yield was 37%. M.p.. 10 9—111 °С. 1H NMR
(DMSO-d6, 500 МHz), δ: 1.12 (t, 3 Н, CH3, J = 7.1 Hz); 3.73
(s, 3 Н, OCH3); 3.81 (s, 3 Н, OCH3); 4.12 (q, 2 Н, CH2, J = 7.1 Hz);
6.79 (d, 2 Н, Ar, J = 8.7 Hz); 6.95 (d, 2 Н, Ar, J = 8.7 Hz); 7.14
(d, 2 Н, Ar, J = 8.7 Hz); 7.31 (d, 1 Н, CHpyrr, J =3.5 Hz); 7.67
(d, 2 Н, Ar, J = 8.7 Hz); 12.33 (s, 1 Н, NH). 13C NMR
(DMSO-d6, 125.76 МHz), δ: 13.9 (CH3), 54.9 (OCH3), 55.3
(OCH3), 59.6 (CH2), 112.3 (2 C, CHarom), 113.4 (2 C, CHarom),
119.8 (Carom), 123.8 (Carom), 125.9 (Carom), 127.5 (CHpyrr), 131.1
(Carom), 131.3 (2 C, CHarom), 131.5 (2 C, CHarom), 158.0 (Carom),
160.2 (COOH), 162.3 (Carom), 188.9 (CO). MS (EI, 70 eV), m/z
(Irel (%)): 379 [M]+ (100), 333 (20), 226 (8), 135 (12). Found (%):
С, 69.81; Н, 5.63; N, 3.34. C22H21NO5. Calculated (%): С, 69.64;
Н, 5.58; N, 3.69.
Ethyl 3-(4-chlorophenyl)-4-(4-methoxybenzoyl)pyrrole-2-
carboxylate (7b). The yield was 41%. M.p. 136—137 °С. 1H NMR
(DMSO-d6, 500 МHz), δ: 1.10 (t, 3 Н, CH3, J = 7.1 Hz); 3.81
(s, 3 Н, OCH3); 4.12 (q, 2 Н, CH2, J = 7.1 Hz); 6.98 (d, 2 Н,
Ar, J = 8.8 Hz); 7.24 (d, 2 Н, Ar, J = 8.5 Hz); 7.29 (d, 2 Н, Ar,
J = 8.5 Hz); 7.37 (s, 1 Н, CHpyrr); 7.69 (d, 2 Н, Ar, J = 8.8 Hz);
12.50 (s, 1 Н, NH). 13C NMR (DMSO-d6, 125.76 МHz), δ: 13.9
(CH3), 55.5 (OCH3), 60.0 (CH2), 113.6 (2 C, CHarom), 120.4
(Carom), 123.8 (Carom), 126.9 (2 C, CHarom), 128.1 (CHpyrr), 130.1
(Carom), 131.3 (Carom), 131.4 (2 C, CHarom), 131.5 (Carom), 132.2
(2 C, CHarom), 133.1 (Carom), 160.1 (COOH), 162.5 (Carom),
188.6 (CO). MS (EI, 70 eV), m/z (Irel (%)): 383 [M]+ (100), 336
(35), 310 (18), 230 (23), 135 (15). Found (%): С, 66.01; Н, 4.57;
N, 3.38. C21H18ClNO4. Calculated (%): С, 65.71; Н, 4.73; N, 3.65.
Diethyl 3-(4-chlorophenyl)pyrrole-2,4-dicarboxylate (10b).
The yield was 5%. M.p. 116—118 оС (cf. Ref. 31: m.p. 117—120 °С).
1H NMR (DMSO-d6, 500 МHz), δ: 1.05 (t, 3 Н, CH3,
J = 7.1 Hz); 1.07 (t, 3 Н, CH3, J = 7.1 Hz); 4.02 (q, 2 Н, CH2,
J = 7.1 Hz); 4.06 (q, 2 Н, CH2, J = 7.1 Hz); 7.25 (d, 2 Н, Ar,
J = 8.7 Hz); 7.35 (d, 2 Н, Ar, J = 8.7 Hz); 7.58 (d, 1 Н, CHpyrr
,
J =3.5 Hz); 12.49 (s, 1 Н, NH). Found (%): С, 59.99; Н, 5.10;
N, 4.07. C16H16ClNO4. Calculated (%): С, 59.73; Н, 5.01; N, 4.35.
Diethyl 3-(3,5-dimethoxyphenyl)pyrrole-2,4-dicarboxylate (10c).
3-(3,5-Dimethoxyphenyl)-4-(4-methoxyphenyl)pyrrole-2-
carboxylic acid (15c). The yield was 80%. M.p. 205‒208 °С.
1H NMR (DMSO-d6, 500 МHz), δ: 3.64 (s, 6 H, OCH3); 3.69
(s, 3 H, OCH3); 6.31 (d, 2 Н, Ar, J = 2.1 Hz); 6.38 (s, 1 Н, Ar);
6.75 (d, 2 Н, Ar, J = 8.6 Hz); 7.01 (d, 2 Н, Ar, J = 8.6 Hz); 7.11
(d, 1 Н, CHpyrr, J = 3.1 Hz); 11.80 (s, 1 Н, NH); 12.09 (br.s,
1 H, COOH). MS (EI, 70 eV), m/z (Irel (%)): 353 [M]+ (84), 335
(100), 309 (21). Found (%): С, 67.82; Н, 5.34; N, 4.20.
1
The yield was 7%. An oil. H NMR (DMSO-d6, 500 МHz), δ:
1.05 (t, 3 Н, CH3, J = 7.1 Hz); 1.07 (t, 3 Н, CH3, J = 7.1 Hz);
3.72 (s, 6 Н, OCH3); 4.02 (q, 2 Н, CH2, J = 7.1 Hz); 4.06 (q, 2 Н,
CH2, J = 7.1 Hz); 6.37 (d, 2 Н, Ar, J = 2.3 Hz); 6.43 (t, 1 Н, Ar,
J = 2.3 Hz); 7.54 (d, 1 Н, CHpyrr, J = 3.5 Hz); 12.41 (s, 1 Н,
NH). Found (%): С, 61.98; Н, 6.13; N, 4.25. C18H21NO6.
Calculated (%): С, 62.24; Н, 6.09; N, 4.03.
C
20H19NO5. Calculated (%): С, 67.98; Н, 5.42; N, 3.96.
4-(4-Methoxyphenyl)-3-(4-nitrophenyl)pyrrole-2-carboxylic
Diethyl 3-(4-nitrophenyl)pyrrole-2,4-dicarboxylate (10d). The
1
yield was 5%. An oil. H NMR (DMSO-d6, 500 МHz), δ: 1.03
acid (15d). The yield was 85%. M.p. 236‒237 °С. 1H NMR
(DMSO-d6, 500 МHz), δ: 3.68 (s, 3 H, OCH3); 6.77 (d, 2 Н,
Ar, J = 8.7 Hz); 6.94 (d, 2 Н, Ar, J = 8.6 Hz); 7.18 (d, 1 Н,
CHpyrr, J = 3.1 Hz); 7.44 (d, 2 Н, Ar, J = 8.6 Hz); 8.14 (d, 2 Н,
Ar, J = 8.6 Hz); 12.09 (s, 1 Н, NH); 12.39 (br.s, 1 H, COOH).
MS (EI, 70 eV), m/z (Irel (%)): 338 [M] + (87), 320 (100), 305 (15),
294 (9). Found (%): С, 63.98; Н, 4.28; N, 8.15. C18H14N2O5.
Calculated (%): С, 63.90; Н, 4.17; N, 8.28.
(t, 3 Н, CH3, J = 7.1 Hz); 1.06 (t, 3 Н, CH3, J = 7.1 Hz); 4.02
(q, 2 Н, CH2, J = 7.1 Hz); 4.06 (q, 2 Н, CH2, J = 7.1 Hz); 7.54
(d, 2 Н, Ar, J = 8.8 Hz); 7.65 (d, 1 Н, CHpyrr, J = 3.5 Hz); 8.18
(d, 2 Н, Ar, J = 8.8 Hz); 12.49 (s, 1 Н, NH). Found (%): С, 57.74;
Н, 4.71; N, 8.69. C16H16N2O6. Calculated (%): С, 57.83; Н, 4.85;
N, 8.43.
4-(4-Chlorophenyl)-3,5-bis(4-methoxyphenyl)isoxazoline
1
N-oxide (13b). The yield was 11%. M.p. 149—151 °С. H NMR
4-(4-Methoxybenzoyl)-3-(4-methoxyphenyl)pyrrole-2-carb-
oxylic acid (16а). The yield was 83%. M.p. 210—211 °С. 1H NMR
(DMSO-d6, 500 МHz), δ: 3.73 (s, 3 H, OCH3); 3.81 (s, 3 H,
OCH3); 6.77 (d, 2 Н, Ar, J = 8.7 Hz); 6.95 (d, 2 Н, Ar,
J = 8.8 Hz); 7.14 (d, 2 Н, Ar, J = 8.7 Hz); 7.23 (s, 1 Н, CHpyrr);
7.66 (d, 2 Н, Ar, J = 8.8 Hz); 12.20 (s, 1 Н, NH); 12.60 (br.s,
(DMSO-d6, 500 МHz), δ: 3.74 (s, 3 Н, ОCH3); 3.76 (s, 3 Н,
ОCH3); 5.30 (d, 1 Н, CHizox, J = 4.5 Hz); 5.47 (d, 1 Н, CHizox
,
J = 4.5 Hz); 6.96 (d, 2 Н, Ar, J = 8.9 Hz); 7.01 (d, 2 Н, Ar,
J = 8.6 Hz); 7.39—7.46 (m, 6 Н, Ar); 7.82 (d, 2 Н, Ar, J = 8.8 Hz).
13C NMR (DMSO-d6, 125.76 МHz), δ: 55.1 (CHizox), 55.2

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Samet et al.
1 H, COOH). MS (EI, 70 eV), m/z (Irel (%)): 351 [M]+ (100),
307 (20), 226 (13), 135 (31). Found (%): С, 68.40; Н, 4.74;
N, 4.19. C20H17NO5. Calculated (%): С, 68.37; Н, 4.88; N, 3.99.
3-(4-Chlorophenyl)-4-(4-methoxybenzoyl)pyrrole-2-carb-
oxylic acid (16b). The yield was 83%. M.p. 212—213 °С. 1H NMR
(DMSO-d6, 500 МHz), δ: 3.82 (s, 3 H, OCH3); 6.97 (d, 2 Н,
Ar, J = 8.8 Hz); 7.24 (d, 2 Н, Ar, J = 8.5 Hz); 7.28 (d, 2 Н, Ar,
J = 8.5 Hz); 7.31 (d, 1 Н, CHpyrr, J = 3.4 Hz); 7.68 (d, 2 Н, Ar,
J = 8.7 Hz); 12.39 (s, 1 Н, NH); 12.62 (br.s, 1 H, COOH).
13C NMR (DMSO-d6, 125.76 МHz), δ: 55.5 (OCH3), 113.6
(2 С, CHarom), 121.1 (Carom), 123.8 (Carom), 127.0 (2 С, CHarom),
127.7 (CHpyrr), 129.7 (Carom), 131.2 (Carom), 131.4 (2 С, CHarom),
131.6 (Carom), 132.3 (2 С, CHarom), 133.3 (Carom), 161.6 (COOH),
162.4 (Carom), 188.7 (CO). MS (EI, 70 eV), m/z (Irel (%)): 355
[M]+ (100), 230 (89), 135 (81), 92 (91), 77 (73), 64 (46).
Found (%): С, 64.25; Н, 3.82; N, 3.85. C19H14ClNO4. Calculat-
ed (%): С, 64.14; Н, 3.97; N, 3.94.
(d, 2 Н, Ar, J = 8.6 Hz); 7.12 (s, 1 Н, CHpyrr); 7.22 (s, 1 Н,
CHpyrr); 7.30 (d, 2 Н, Ar, J = 8.4 Hz); 7.36 (d, 2 Н, Ar, J = 8.4 Hz);
7.76 (d, 2 Н, Ar, J = 8.6 Hz); 11.61 (s, 1 Н, NH). 13C NMR
(DMSO-d6, 125.76 МHz), δ: 55.3 (OCH3), 113.4 (2 С, CHarom),
119.5 (Cpyrr), 120.5 (Carom), 123.9 (CHarom.), 127.2 (Cpyrr), 127.6
(2 С, CHarom), 129.7 (2 С, CHarom), 131.2 (2 С, CHarom), 132.1
(Carom), 134.2 (Carom), 162.1 (1 С, Carom), 189.1 (CO). MS (EI,
70 eV), m/z (Irel (%)): 311 [M]+ (100), 294 (19), 280 (28),
204 (49), 141 (15), 135 (17).
Biological tests (general procedure). Study of the antiproli-
ferative activity of compounds on a model of sea urchin embryos.23
Experiments were carried out at the biological laboratory of the
N. K. Kol´tsov Institute of Developmental Biology of RAS in
Cyprus. Adult sea urchins, Paracentrotus lividus L. (Echinidae)
were collected in the coastal area and kept in an aerated seawater
tank. Spawning was triggered by intracoelomic injection of
0.5 М KCl (1—2 mL) into the body cavity of animals. The result-
ing eggs were washed with sea water, filtered through a nylon
filter, and then fertilized by adding drops of diluted sperm. The
embryos (600—2000 mL–1) were incubated in filtered seawater
at room temperature (18—23 °С) in six-well culture plates.
The stock solutions of chemical compounds were prepared
in DMSO, followed by a 10-fold dilution with 96% ethanol.
This procedure increases the solubility of compounds in the
salt-containing media (sea water). The solubility of the test com-
pounds was monitored using an MBS-10 stereomicroscope.
Combretastatin A-4 (CA4), synthesized according to the de-
scribed procedure,34 was used as a positive control.
The treatment with compounds was carried out in six-well
culture plates. 5 mL of a suspension of fertilized eggs or em-
bryos was placed to each well, and a corresponding volume of
the test compound solution was added to achieve the desired
final concentration. The maximum concentration of the solvent
did not exceed the maximum tolerated one (1% for ethanol and
0.05% for DMSO). To evaluate the antimitotic activity, the eggs
were treated with test compounds at 8—15 min post fertilization,
and cleavage alteration and/or cleavage arrest was detected after
2.5—6 h. The ability of test compounds to affect tubulin and
destabilize microtubules was established by the characteristic
change in the swimming behavior of embryos exposed to the
compounds immediately after hatching of blastulae at 8.5—10 h
post fertilization. The lack of forward swimming of the embryos
at the surface of the seawater, settling to the bottom of the vessel,
and rapid spinning around the animal-vegetal axis suggest the
antitubulin mode of action of the test chemical compounds. In
the tests 2-fold decreasing concentrations of compounds were
used until the effect disappeared. The activity was assessed by
the lowest (threshold) concentration EC causing cleavage alter-
ation, cleavage arrest, or embryo spinning. Monitoring of em-
bryonic development was carried out until the beginning of active
feeding (mid-pluteus 2) using a Biolam LOMO optical micro-
scope (St. Petersburg, Russia).
3,4,5-Tris(4-methoxyphenyl)isoxazole (19a). The yield was
11%. M.p. 148—149 °С (cf. Ref. 27: m.p. 146—147 °С). 1H NMR
(DMSO-d6, 300 МHz), δ: 3.79 (m, 9 H, OCH3); 6.90—7.07 (m,
6 Н, Ar); 7.21 (d, 2 Н, Ar, J = 8.7 Hz); 7.33 (d, 2 Н, Ar,
J = 8.7 Hz); 7.45 (d, 2 Н, Ar, J = 8.7 Hz).
Synthesis of pyrroles 17a—d and 18a,b (general procedure).
A corresponding pyrrole-2-carboxylic acid (0.08 mmol) was
heated to melting point, the heating was continued until evolution
of gas ceased (30 s and 2 min for 17a—d and 18a,b, respectively),
and the heating was removed. A dilute aqueous alkali (3 mL) was
added, heated to boiling, cooled, and filtered.
3,4-Bis(4-methoxyphenyl)pyrrole (17a). The yield was 68%.
1
M.p. 117—118 оС (cf. Ref. 19: m.p. 116 °С). H NMR (CDCl3,
500 МHz), δ: 3.79 (s, 6 H, OCH3); 6.81 (d, 4 Н, Ar, J = 8.5 Hz);
6.84 (s, 2 Н, CHpyrr); 7.19 (d, 4 Н, Ar, J = 8.5 Hz); 8.21 (s, 1 Н, NH).
3-(4-Chlorophenyl)-4-(4-methoxyphenyl)pyrrole (17b). The
yield was 46%. An oil. 1H NMR (DMSO-d6, 500 МHz), δ: 3.73
(s, 3 H, OCH3); 6.84 (d, 2 Н, Ar, J = 8.7 Hz); 6.87 (t, 1 Н,
CHpyrr, J = 2.4 Hz); 6.98 (t, 1 Н, CHpyrr, J = 2.4 Hz); 7.08
(d, 2 Н, Ar, J = 8.7 Hz); 7.18 (d, 2 Н, Ar, J = 8.5 Hz); 7.28 (d, 2 Н,
Ar, J = 8.5 Hz); 11.09 (s, 1 Н, NH). Found (%): С, 71.77; Н, 4.83;
N, 5.01. C17H14ClNO. Calculated (%): С, 71.96; Н, 4.97; N, 4.94.
3-(3,5-Dimethoxyphenyl)-4-(4-methoxyphenyl)pyrrole (17с).
The yield was 46%. M.p. 127—128 °С. 1H NMR (DMSO-d6,
500 МHz), δ: 3.61 (s, 6 H, OCH3); 3.73 (s, 3 H, OCH3); 6.26
(s, 1 Н, Ar); 6.33 (d, 2 Н, Ar, J = 2.2 Hz); 6.84 (m, 3 Н,
CHpyrr,Ar); 6.98 (s, 1 Н, CHpyrr); 7.12 (d, 2 Н, Ar, J = 8.6 Hz);
11.09 (s, 1 Н, NH). Found (%): С, 73.92; Н, 6.07; N, 4.76.
C19H19NO3. Calculated (%): С, 73.77; Н, 6.19; N, 4.53.
4-(4-Methoxyphenyl)-3-(4-nitrophenyl)pyrrole (17d). The
yield was 67%. M.p. 189—190 °С. 1H NMR (DMSO-d6, 500 МHz),
δ: 3.75 (s, 3 Н, OCH3); 6.88 (d, 2 Н, Ar, J = 8.6 Hz); 6.92 (s, 1 Н,
CHpyrr); 7.12 (d, 2 Н, Ar, J = 8.6 Hz); 7.23 (s, 1 Н, CHpyrr); 7.43
(d, 2 Н, Ar, J = 8.7 Hz); 8.09 (d, 2 Н, Ar, J = 8.8 Hz); 11.39
(s, 1 Н, NH). Found (%): С, 69.47; Н, 4.97; N, 9.25. C17H14N2O3.
Calculated (%): С, 69.38; Н, 4.79; N, 9.52.
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 16-03-00648).
4-(4-Methoxybenzoyl)-3-(4-methoxyphenyl)pyrrole (18a).
The yield was 66%. M.p. 207—208 °С (cf. Ref. 32: m.p. 203—205 °С).
1H NMR (DMSO-d6, 500 МHz), δ: 3.72 (s, 3 Н, OCH3); 3.82
(s, 3 Н, OCH3); 6.82 (d, 2 Н, Ar, J = 8.3 Hz); 6.99 (m, 3 Н,
CHpyrr,Ar); 7.18 (s, 1 Н, CHpyrr); 7.27 (d, 2 Н, Ar, J = 8.3 Hz);
7.74 (d, 2 Н, Ar, J = 8.4 Hz); 11.49 (s, 1 Н, NH).
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1H NMR (DMSO-d6, 500 МHz), δ: 3.81 (s, 3 Н, OCH3); 7.00
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Received June 2, 2016;
in revised form October 11, 2016;
accepted December 27, 2017