Directed synthesis and immunoactive properties of (2-hydroxyethyl)ammonium salts of 1-R-indol-3-ylsulfanyl(sulfonyl)alkanecarboxylic acids

Article abstract of DOI:10.1007/s11172-010-0384-9

A general method for the synthesis of 1-alkyl(allyl)(benzyl)-substituted (indol-3-yl)-sulfanylalkanecarboxylic acids and hexane-1,6-diyl(1,4- phenylenemethylene)bisindol-3-ylsulfanylalkanecarboxylic acids from the corresponding N-substituted indoles and bisindoles, thiourea, iodine, and halogencarboxylic acids was developed. The oxidation of substituted (indol-3-yl)sulfanylalkanecarboxylic acids for the first time afforded their analogs containing the sulfonyl group. New (2-hydroxyethyl)ammonium salts of 1-R-indol-3-ylsulfanyl(sulfonyl)-alkanecarboxylic acids, which are structural analogs of highly active immunomodulators of indacetamin and VILIM, were synthesized. Among the studied (2-hydroxyethyl)ammonium salts of 1-R-indol-3-ylsulfanylacetic and -sulfonylalkanecarboxylic acids, the compounds exhibiting high dose-dependent antiproliferative activity by the ability to affect the spontaneous and mitogen-stimulated splenocyte proliferation of mice in vitro were found.

Full text of DOI:10.1007/s11172-010-0384-9

Russian Chemical Bulletin, International Edition, Vol. 59, No. 12, pp. 2236—2246, December, 2010
2236
Directed synthesis and immunoactive properties
of (2ꢀhydroxyethyl)ammonium salts of
1ꢀRꢀindolꢀ3ꢀylsulfanyl(sulfonyl)alkanecarboxylic acids
A. N. Mirskova,a G. G. Levkovskaya,a O. P. Kolesnikova,b O. M. Perminova,b E. V. Rudyakova,a and S. N. Adamovicha
aA. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences,
1 ul. Favorskogo, 664033 Irkutsk, Russian Federation.
Eꢀmail: mirskova@irioch.irk.ru
bResearch Institute of Clinical Immunology,
Siberian Branch of the Russian Academy of Medical Sciences,
14 ul. Yadrintsevskaya, 630099 Novosibirsk, Russian Federation
A general method for the synthesis of 1ꢀalkyl(allyl)(benzyl)ꢀsubstituted (indolꢀ3ꢀyl)ꢀ
sulfanylalkanecarboxylic acids and hexaneꢀ1,6ꢀdiyl(1,4ꢀphenylenemethylene)bisindolꢀ3ꢀylꢀ
sulfanylalkanecarboxylic acids from the corresponding Nꢀsubstituted indoles and bisindoles,
thiourea, iodine, and halogencarboxylic acids was developed. The oxidation of substituted
(indolꢀ3ꢀyl)sulfanylalkanecarboxylic acids for the first time afforded their analogs containing
the sulfonyl group. New (2ꢀhydroxyethyl)ammonium salts of 1ꢀRꢀindolꢀ3ꢀylsulfanyl(sulfonyl)ꢀ
alkanecarboxylic acids, which are structural analogs of highly active immunomodulators of
indacetamin and VILIM, were synthesized. Among the studied (2ꢀhydroxyethyl)ammonium
salts of 1ꢀRꢀindolꢀ3ꢀylsulfanylacetic and ꢀsulfonylalkanecarboxylic acids, the compounds exhiꢀ
biting high doseꢀdependent antiproliferative activity by the ability to affect the spontaneous and
mitogenꢀstimulated splenocyte proliferation of mice in vitro were found.
Key words: indole, indolylsulfanylalkanecarboxylic acids, indolylsulfonylalkanecarboxylic
acids, triethanolamine, dimethylethanolamine, methylethanolamine, immunomodulators, antiꢀ
proliferative activity.
Tris(2ꢀhydroxyethyl)ammonium salts of aroxyacetic
acids, whose cation has the compact tricyclic atrane
(2,8,9ꢀtrihydroprotatrane) structure favoring the penetraꢀ
tion of a substance through cell membranes, are a new
class of pharmacologically active substances.1 They posꢀ
sess2—12 antiꢀaggregation, membraneꢀstabilizing, antioxꢀ
idant, antisclerotic, antiphlogistic, cardiotropic, analgeꢀ
sic, hypocholesterolemic, immunomodulating, and antiꢀ
tumor activity considerably exceeding or different from
the effect of the initial biologically active acids and triethꢀ
anolamine.
ical processes.18,19 Biological activity of alkanolammonium
salts of sulfurꢀcontaining acids is not inferior and often
exceeds the activity of related alkanolammonium salts of
aroxyacetic acids. The activity is enhanced with an increase
in the oxidation state of the sulfur atom and depends on the
structure of the (2ꢀhydroxyethyl)ammonium fragment.14,15
Indole derivatives,20 in particular, (indolꢀ3ꢀyl)sulfanylꢀ
alkanecarboxylic acids and their salts, are worthy of speꢀ
cial attention as biologically active substances,21 intermeꢀ
diates for the synthesis of medical preparations22—24 and
technically valuable products.25
Earlier synthesized analogs of these compounds,
viz., alkanolammonium salts of (het)arylsulfanylꢀ
(sulfonyl)acetic acids (Het)ArS(SO2)CH2COO–•
•N+R1R2(CH2CH2OH)n (R1, R2 = H, Alk, CH2CH2OH;
n = 1—3),13—15 and their complexes with salts of
We have earlier found by screening efficient nonꢀtoxic
(LD50 = 1300—3000 mg kg–1) immunoactive compounds,
viz., tris(2ꢀhydroxyethyl)ammonium indolꢀ3ꢀylꢀ and
1ꢀbenzylindolꢀ3ꢀylsulfanyl acetates (indacetamin and
VILIM, respectively).
biomicroelements16,17 are lowly toxic (LD50
=
Indacetamin has a wide range of biological activity
and is an efficient antiꢀaggregant, stabilizer of cell memꢀ
branes of erythrocytes and thrombocytes, and protector
during ultrasonication and γꢀirradiation.26,27
= 1300—6000 mg kg–1), also exhibit high and diverse bioꢀ
logical activity, such as hemoꢀ and immunotropic, carꢀ
diotropic, antiphlogistic, antithrombotic, antioxidant,
adaptogenic, hypocholesterolemic, etc., and are highly efꢀ
ficient growthꢀstimulating preparations for biotechnologꢀ
A distinctive feature of indacetamin28,29 and VILIM30—32
is the pronounced antiproliferative activity in the culture
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2181—2190, December, 2010.
1066ꢀ5285/10/5912ꢀ2236 © 2010 Springer Science+Business Media, Inc.

Indolꢀ3ꢀylsulfonylalkanecarboxylic acids
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 12, December, 2010
2237
in vitro and immunosuppressive properties in vivo at relaꢀ
tively low toxicity.
Results and Discussion
We have previously33 developed the method for the
synthesis of indolꢀ3ꢀylsulfanylalkane carboxylic acids from
1Hꢀ, 1ꢀmethyl(benzyl)ꢀ, and 2ꢀmethylindole, thiourea,
iodine, and halogencarboxylic acids; their waterꢀsoluble
tris(2ꢀhydroxyethyl)ammonium salts were also synꢀ
thesized.
At the same time, the possibility of using this method
for the synthesis of 1ꢀarylꢀ, 1ꢀalkyl, and 1ꢀalkenylꢀsubstiꢀ
tuted indolylsulfanylalkanecarboxylic acids was not studied.
The corresponding oxidized derivatives, viz., indolꢀ3ꢀylꢀ
sulfonylalkanecarboxylic acids, and their alkanolammoꢀ
nium salts were unknown as well.
The starting substances for the synthesis of 1ꢀRꢀindolꢀ
3ꢀylsulfanylalkanecarboxylic acids were Nꢀsubstituted inꢀ
doles 1 and 2 prepared from indole and alkyl, nitrophenyl,
benzyl, or allyl halides using the known procedure,34 which
was developed for the synthesis of 1ꢀmethylindole and
improved by us.35 We succeeded to decrease the amounts
of the solvent (by 2—3 times) and alkali (KOH) (by
1.5 used) by using more available NaOH as a base, and the
yield of Nꢀsubstituted indoles was increased by 10—15%
(Scheme 1).
Indacetamin possesses pronounced erythroꢀ and imꢀ
munopoiesismodulating properties by the reduction of the
proliferativeꢀdifferentiating parameters of haemopoiesis
precursors of erythropoiesis (inhibits the production of
antiphlogistic cytokines ILꢀ1 β and FNOα, decreases the
number of early erythroid precursors, and stimulates the
number of precursors of the granuloidꢀmacrophagal seꢀ
ries) in mice with different clinical variants of immunoꢀ
pathology, such as immunodeficiency, anaemia, and imꢀ
munocomplex glomerulonephritis; eliminates anaemia;
and prevents leucocyte decreasing in blood. In the experiꢀ
mental model of the autoimmune disease (immunocomꢀ
plex glomerulonephritis), it exhibits a pronounced clinical
effect (eliminates anaemia, increases the weight of an anꢀ
imal body, and decreases erythrocyte sedimentation rate
(ESR) and proteinuria), which is due to the suppression of
antiphlogistic cytokine production and a decrease in the
erythropoietic hyperplasia from the early stages of erythꢀ
ron differentiation in sick mice. According to the data of
morphological studied, the compound retards the deꢀ
velopment of mesangial proliferative glomerulonephritis.
VILIM in the culture in vitro suppresses the mitogenꢀ
stimulated proliferation of spleen cells in mice and lymphoꢀ
cytes of human blood, as well as the testosteroneꢀstimuꢀ
lated proliferation of haematogenic stem cells in mice
marrow.32
Scheme 1
VILIM is an immunosuppressive drug with the antituꢀ
mor effect. It was demonstrated by comparing this comꢀ
pound with the known immunosuppressive agent cycloꢀ
phosphane that thymus atrophy observed in animals is not
related to apoptosis but to a decrease in the proliferative
activity of thymus cells ("arrest" in the phase G0 + G1).30
VILIM was shown to possess the properties of suppressing
the Тh2ꢀdependent activation of Bꢀcells (inhibition of anꢀ
tibody formation, production of IgE); i.e., it has antiꢀ
allergic properties.
The immunosuppressive agent VILIM is characterized
by a poor ability to cumulation, does not oppress haemoꢀ
poiesis, and exhibits no side nephroꢀ and hepatotoxic propꢀ
erties of the known immunosuppressive drugs cyclosporin
A and azathioprine.32
It should be mentioned that indacetamin28,29 and
VILIM30—32 can selectively affect the ratio of the function
of Tꢀ or Bꢀsystem of immunity inducing the deviation of
the immune response in certain (Th1 or Th2) required
direction.
In development of these studies with the purpose
of preparing new promising immunosuppressive agents,
analogs of indacetamin and VILIM, we synthesized
earlier unknown 1ꢀRꢀindolꢀ3ꢀylsulfanyl(sulfonyl)alkaneꢀ
carboxylic acids and their (2ꢀhydroxyethyl)ammonium
salts and estimated the immunomodulating activity of
the latter.
Hal is halogen
1
a
b
c
d
e
R1
H
H
H
H
H
R2
Me
Et
Bu
All
Bn
1
f
g
h
i
R1
H
Me
Me
Me
Me
R2
4ꢀNO2C6H4
Me
Et
All
Bn
j
2: R = CH2(CH2)4CH2 (a), 4ꢀCH2C6H4CH2 (b)

2238
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 12, December, 2010
Mirskova et al.
Scheme 3
The constants of obtained substituted indoles 1a—h
and 2а,b correspond to the literature data.35 The structure
of 1ꢀallylꢀ and 1ꢀbenzylꢀ2ꢀmethylindoles 1i,j was proved
by spectral methods and confirmed by elemental analyꢀ
sis data.
It was shown that the reactions of indoles 1a—j and
bisindoles 2а,b with thiourea and potassium triiodide in
the ratios 1 : 2 : 1 and 1 : 4 : 2, respectively, in an inert
medium afforded indolylisothiuronium iodide, whose subꢀ
sequent treatment (without their preliminary isolation)
with monohalogencarboxylic acids in the presence of a base
resulted in indolylsulfanylalkanecarboxylic acids 3а—q and
4a,b, respectively, in high and stable yields (except for
acids 3h,l) (Schemes 2 and 3).
Scheme 2
4: R = CH2(CH2)4CH2 (a), CH2C6H4CH2 (b)
process at the stage of interaction of isothiuronium salts
with halogencarboxylic acids made it possible to increase
the yield and purity of the final products, most likely, due
to the exclusion of side processes of oxidation of indoꢀ
lethiol and isothiuronium salts.
The reaction can be carried out in methanol, ethanol,
or propanꢀ2ꢀol. The purity of the acids that were obtained
by the developed method and were not subjected to addiꢀ
tional purification was determined by the potentiometric
titration of a methanol solution of the acid with a solution
of sodium methylate as 94—99%.
The yield of 1ꢀ(4ꢀnitrophenyl)indolꢀ3ꢀylsulfanylaceꢀ
tic acid (3h) prepared by this method did not exceed 8%
even after the temperature of the process was increased to
50—80 °С and the duration was elongated to 18 h at the
stage of isothiuronium salt formation. No formation of
byꢀproducts was observed, and only unreacted 1ꢀ(4ꢀnitroꢀ
phenyl)indole (1f) was quantitatively isolated from the
reaction mixture. Its low reactivity in this reaction can be
explained by the decreased nucleophilicity and also by the
poor solubility in alcohols even on heating and at large
dilution.
Nꢀ(4ꢀNitrophenyl)ꢀsubstituted acid 3h and 1ꢀ(4ꢀnitroꢀ
phenylindolꢀ3ꢀylꢀ1ꢀmethylacetic acid 3r were obtained in
a yield higher than 70% by the arylation of indoleꢀ3ꢀsulfaꢀ
nylalkanecarboxylic acids 3а,b with 4ꢀnitrofluorobenzene
(Scheme 4).
3
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
R1
H
H
Me
Et
Bu
All
Bn
R2
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
R3
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
R4
H
Me
H
H
H
H
H
H
H
Me
Et
Me
H
H
H
4ꢀNO2C6H4
Bn
Bn
Bn
Bn
Me
Et
All
All
Bn
Et
H
In spite of the possible occurrence of side processes of
esterification and decarboxylation of indolylsulfanylalkaneꢀ
carboxylic acids, the approach proposed for the synthesis
of acids 3h,r (see Scheme 4) is very promising for the
preparation of various 1ꢀsubstituted (indolꢀ3ꢀyl)sulfanylꢀ
alkanecarboxylic acids if the corresponding 1ꢀunsubstiꢀ
tuted indole derivatives are available.
Hal = Cl, Br; n = 1 (3a—h,j—q), 2 (3i)
An advantage of the proposed method for the synthesis
of Nꢀsubstituted (indolꢀ3ꢀyl)sulfanylalkanecarboxylic acꢀ
ids is that isothiuronium salts of indoles formed in situ
from available raw materials are used instead of unstable
or presently nonꢀobtained Nꢀsubstituted indolethiols.
We found that the introduction of hydrazine hydrate in
an amount equimolar to that of indole into the reaction
The structures of earlier undescribed compounds
3с—f,h—r and 4a,b were determined by IR spectroscopy,

Indolꢀ3ꢀylsulfonylalkanecarboxylic acids
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 12, December, 2010
2239
Scheme 4
Table 1. Yields, physicochemical characteristics, and elemental
analysis data for compounds 3c—f,h—r and 4a,b
Comꢀ Yield M.p.
pound (%) /°C
Found
Calculated
Empirical
formula
(%)
C
H
N
S
3c
3d
3e
3f
89 98—100 59.78 4.99 6.37 14.36 C11H11NO2S
59.71 5.01 6.33 14.49
85 102—105 61.30 5.52 5.99 13.66 C12H13NO2S
61.25 5.57 5.95 13.63
87 59—62
63.81 6.55 5.28 12.20 C14H17NO2S
63.85 6.51 5.32 12.15
3: R = H (h), Me (r)
83 Oil
63.20 5.31 5.69 12.94 C13H13NO2S
63.13 5.30 5.66 12.97
8a 128—131 58.62 3.70 8.57 9.70 C16H12N2O4S
(74b)
1H NMR spectroscopy, and potentiometric titration, and
the compositions were confirmed by elemental analysis
data (Tables 1 and 2). The IR spectra of the synthesized
acids contain absorption spectra of the heterocycle and
intense absorption bands of the carboxyl groups (see Table 2).
3h
3i
58.53 3.68 8.53 9.77
53 84—86
86 95—97
69.49 5.54 4.44 10.08 C18H17NO2S
69.43 5.50 4.50 10.30
69.45 5.53 4.52 10.34 C18H17NO2S
69.43 5.50 4.50 10.30
3j
1
The H NMR spectra of acids 3 and 4 contain signals
3k
3l
85 119—121 70.11 5.85 4.28 9.83 C19H19NO2S
70.12 5.88 4.30 9.85
46 100—105 70.15 5.91 4.29 9.87 C19H19NO2S
70.12 5.88 4.30 9.85
of protons of the indole fragment and substituents in posiꢀ
tions 1—3 of indole with the characteristic multiplicity
(see Table 2). It should be mentioned that the H NMR
1
3m
3n
3o
3p
3q
3r
4a
4b
90 109—112 61.27 5.60 5.61 13.65 C12H13NO2S
61.25 5.57 5.95 13.63
88 98—101 62.60 6.04 5.56 12.73 C13H15NO2S
62.62 6.06 5.62 12.86
70 Масло 64.30 5.82 5.39 12.30 C14H15NO2S
64.34 5.79 5.36 12.27
68 Масло 66.34 6.66 4.88 11.16 C16H19NO2S
66.41 6.62 4.84 11.08
90 105—108 69.55 5.54 4.55 10.32 C18H17NO2S
69.43 5.50 4.50 10.30
70c 109—111 59.50 4.11 8.21 9.30 C17H14N2O4S
59.64 4.12 8.18 9.37
89 171—174 62.73 5.65 5.69 12.77 C26H28N2O4S2
62.88 5.68 5.64 12.91
91 120—123 65.16 4.70 5.48 12.36 C28H24N2O4S2
65.09 4.68 5.42 12.41
spectra of compounds 3а—l,r and 4a,b exhibit the singlet
signal of the proton in position 2 of the indole cycle, which
is not observed in the spectra of acids 3m—q.
The oxidation of Nꢀsubstituted indolylsulfanylalkaneꢀ
carboxylic acids 3g,h,j—l,r gave earlier unknown indolylꢀ
sulfonylalkanecarboxylic acids 5a—f in 88—92% yields
(Scheme 5). The reactions were carried out by the treatꢀ
ment with 50% hydrogen peroxide in acetic anhydride.
The oxidation with commercial 30% H2O2 in acetic acid
at 20 °С also affords indolylsulfonylalkanecarboxylic acids
but with a lower yield (70%).
Scheme 5
a From 1ꢀ(4ꢀnitrophenyl)indole.
b Synthesis by the Nꢀarylation of indolꢀ3ꢀylsulfanylacetic acid.
c Synthesis by the Nꢀarylation of indolꢀ3ꢀylsulfanylmethylacetic acid.
Alkanolammonium salts of indolylsulfanyl(sulfonyl)ꢀ
alkanecarboxylic acids 6a—h were obtained in yields higher
than 80% on heating for 5—15 min of equimolar amounts
of acids 3a,g and 5a,b with N,Nꢀdimethylethanolamine,
Nꢀmethyldiethanolamine, and triethanolamine in alcohol
media (Scheme 6).
5
a
b
c
R1
Bn
Bn
Bn
R2
H
H
R3
H
Me
Et
5
d
e
f
R1
Bn
R2
Me
H
R3
Me
H
4ꢀNO2C6H4
4ꢀNO2C6H4
H
H
Me
Synthesized compounds 6a—h are hygroscopic solid or
viscous odorless substances, whose color ranges from white to
pink; they are highly soluble in water, alcohol, and DMSO,
restrictedly soluble in acetone, and insoluble in diethyl ether.
The structures of the synthesized compounds were
The yields, physicochemical and spectral characterisꢀ
tics, and elemental analysis data for compounds 5a—f are
presented in Tables 3 and 4.
An attempt to perform the chemiselective oxidation of
NНꢀ and Nꢀalkylindolylsulfanylalkanecarboxylic acids
under the studied conditions was unsuccessful.
1
proved by IR spectroscopy and H NMR spectroscopy,
and the compositions were confirmed by the elemental

2240
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 12, December, 2010
Mirskova et al.
Table 2. 1H NMR and IR spectra of compounds 3c—f,h—r and 4a,b
Comꢀ
pound
Solvent
1H NMR, δ (J/Hz)
IR,
ν/cm–1
3c
3d
(CD3)2CO
CDCl3
3.39 (s, 2 H, CH2S); 3.72 (s, 3 H, NMe); 7.15—7.27 (m, 2 H, H(5), H(6)); 7.42—7.44
(m, 1 H, H(7)); 7.45 (s, 1 H, H(2)); 7.75 (m, 1 H, H(4))
1.41 (t, 3 H, Me, J = 7.2); 3.39 (s, 2 H, CH2S); 4.10 (q, 2 H, NCH2Me, J = 7.2);
7.17—7.23 (m, 2 H, H(5), H(6)); 7.30 (s, 1 H, H(2)); 7.32 (m, 1 H, H(7));
7.74 (m, 1 H, H(4))
1700, 1510,
1460, 1420
1690, 1500,
1460
3e
3f
(CD3)2CO
CDCl3
0.87 (t, 3 H, Me, J = 7.4); 1.28 (d, 2 H, CH2, J = 7.4); 1.75 (dd, 2 H, CH2, J = 7.4,
J = 7.1); 3.39 (s, 2 H, CH2S); 4.15 (t, 2 H, CH2N, J = 7.1); 7.10—7.43 (m, 3 H,
H(5), H(6), H(7)); 7.44 (s, 1 H, H(2)); 7.70 (m, 1 H, H(4))
3.31 (s, 2 H, CH2S); 4.48 (d, 2 H, CH2N, J = 9.2); 4.93 (d, 1 H, =CH2, J = 17.2);
5.05 (d, 1 H, =CH2, J = 9.9); 5.79 (ddd, 1 H, =CH, J = 9.2, J = 9.9, J = 17.2);
7.09—7.21 (m, 4 H, H(6), H(5), H(7), H(2)); 7.68 (m, 1 H, H(4))
1700, 1500,
1460
1700, 1500,
1440
3h
3i
(CD3)2SO
CDCl3
3.59 (s, 2 H, CH2S); 7.24—7.32 (m, 2 H, H(6), H(5)); 7.69—7.72 (m, 2 H, H(7), H(4)); 1725, 1591,
7.87 (m, 2 H, H(2)Ar, H(6)Ar); 7.96 (s, 1 H, H(2)); 8.36 (m, 2 H, H(3)Ar, H(5)Ar
2.55 (t, 2 H, CH2, J = 7.0); 2.89 (t, 2 H, CH2S, J = 7.0); 5.26 (s, 2 H, CH2Ar);
)
1522, 1345, 1331
1697, 1510,
1453
7.08—7.34 (m, 8 H, HAr, HHet); 7.27 (s, 1 H, H(2)Het); 7.75 (m, 1 H, H(4)Het
1.36 (d, 3 H, Me, J = 7.2); 3.50 (q, 1 H, CHS, J = 7.2); 5.19 (s, 2 H, CH2Ar);
7.01—7.33 (m, 8 H, HAr, HHet); 7.24 (s, 1 H, H(2)Het); 7.75 (m, 1 H, H(4)Het
)
3j
CDCl3
1704, 1517,
1454
)
3k
CDCl3
1.02 (t, 3 H, Me, J = 7.2); 1.78 (dd, 2 H, CH2, J = 7.2, J = 8.8); 3.28 (t, 1 H, CH,
J = 7.8); 5.22 (s, 2 H, CH2Ar); 7.03—7.34 (m, 8 H, HAr, HHet); 7.25 (s, 1 H, H(2)Het);
1706, 1700,
1504, 1459
7.76 (m, 1 H, H(4)Het
)
3l
CDCl3
CDCl3
CDCl3
CDCl3
1.44 (s, 6 H, 2 Me); 5.21 (s, 2 H, CH2Ar); 7.01—7.39 (m, 8 H, HAr, HHet); 7.24 (s, 1 H, 1690, 1685,
H(2)Het); 7.74 (m, 1 H, H(4)Het
2.51 (s, 3 H, Me); 3.30 (s, 2 H, CH2S); 3.67 (s, 3 H, NMe); 7.12—7.27 (m, 3 H, H(5),
H(6), H(7)); 7.67 (m, 1 H, H(4))
)
1510, 1460
1700, 1500,
1440
3m
3n
3o
1.30 (t, 3 H, Me, J = 7.2); 2.49 (s, 3 H, Me); 3.29 (s, 2 H, CH2S); 4.10 (q, 2 H,
CH2N, J = 7.2); 7.11—7.28 (m, 3 H, H(5), H(6), H(7)); 7.67 (m, 1 H, H(4))
2.46 (s, 3 H, Me); 3.30 (s, 2 H, CH2S); 4.67 (d, 2 H, CH2N, J = 2.4); 4.74 (d, 1 H,
=CH2, J = 17.1); 5.08 (d, 1 H, =CH2, J = 10.4); 5.87 (ddd, 1 H, =CH, J = 2.4,
J = 10.4, J = 17.1); 7.13—7.22 (m, 3 H, H(6), H(5), H(7)); 7.68 (m, 1 H, H(4))
1.03 (t, 3 H, Me, J = 7.2); 1.78 (dd, 2 H, CH2, J = 7.2, J = 8.8); 2.45 (s, 3 H, Me);
3.22 (d, 1 H, CHS, J = 7.1); 4.66 (d, 2 H, CH2N, J = 2.2); 4.72 (d, 1 H, =CH2,
J = 13.2); 5.07 (d, 1 H, =CH2, J = 10.4); 5.88 (ddd, 1 H, =CH, J = 2.2, J = 10.4,
J = 13.2); 7.12—7.22 (m, 3 H, H(6), H(5), H(7)); 7.68 (m, 1 H, H(4))
2.46 (s, 3 H, Me); 3.33 (s, 2 H, CH2S); 5.30 (s, 2 H, CH2N); 6.93—7.24 (m, 8 H,
1700, 1680,
1510, 1450
1700, 1680,
1510, 1450
3p
CDCl3
1700, 1680,
1510, 1450
3q
3r
CDCl3
1690, 1520,
1450
H
Ar, HHet); 7.74 (m, 1 H, H(4)Het)
(CD3)2SO
1.34 (d, 3 H, Me, J = 7.2); 3.64 (q, 1 H, CHS, J = 7.2); 7.27—7.35 (m, 2 H, H(5),
H(6)); 7.74 (m, 2 H, H(4), H(7)); 7.95 (m, 2 H, H(2)Ar, H(6)Ar); 8.01 (s, 1 H, H(2));
1696, 1594,
1518, 1348,
1333
8.42 (m, 2 H, H(3)Ar, H(5)Ar
)
4a
4b
(CD3)2SO
(CD3)2SO
1.29 (br.s, 4 H, 2 CH2); 1.76 (br.m, 4 H, 2 CH2); 3.36 (s, 4 H, 2 CH2S); 4.14
(t, 4 H, 2 CH2N, J = 6.8); 7.10—7.18, 7.45—7.47 (both m, 3 H each, 2 H(6), 2 H(5),
2 H(7)); 7.49 (s, 2 H, 2 H(2)); 7.68 (m, 2 H, 2 H(4))
3.38 (s, 4 H, 2 CH2S); 5.36 (s, 4 H, 2 CH2N); 7.11—7.13 (m, 8 H, 4 HAr, 2 H(6),
2 H(7)); 7.41 (m, 2 H, 2 H(5)); 7.62 (m, 2 H, 2 H(4)); 7.69 (s, 2 H, 2 H(2))
1700, 1500
1695, 1530,
1450
Scheme 6
6
a
b
c
d
R1
H
H
R2
Me
Me
R3
Me
CH2CH2OH
CH2CH2OH
CH2CH2OH
X
n
0
0
0
0
6
e
f
g
h
R1
Bn
Bn
R2
Me
Me
R3
X
n
2
2
2
2
CH2
CH2
CH2
CH2
CH2CH2OH
Me
CH2CH2OH
CH2
CH2
CH2
Bn CH2CH2OH
Bn Me
Bn CH2CH2OH
Bn CH2CH2OH
CH2CH2OH CHMe

Indolꢀ3ꢀylsulfonylalkanecarboxylic acids
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 12, December, 2010
2241
Table 3. Yields, physicochemical characteristics, and elemental
analysis data for compounds 5a—f
ance of the corresponding cytokines dictates the necessity
to develop new immunoactive drugs for the treatment of
autoimmune, immunodeficiency, lymphoproliferative,
oncologic, and allergic diseases, as well as complicated
diseases after transplantations of organs, marrow, etc.,
which are related to the activation of the immunity
Bꢀsystem and production of various antibodies.
At present there are no drugs that are allowed for medꢀ
ical application and capable of selective changing the
Th1/Th2 balance in a required direction.36
We performed screening of the immunoactive properꢀ
ties of (2ꢀhydroxyethyl)ammonium salts 6a—h, which are
structural analogs of indacetamin and VILIM, but differ
from them by the structure of the alkanolammonium fragꢀ
ment (6c,g,h are the triethanolamine derivatives, 6a,f are
the dimethylethanolamine derivatives, and 6b,d,e are the
methyldiethanolamine derivatives), which contain the sulfur
atom in the diꢀ (6a—d) or hexavalent (6e—h) states. The
ability of these compounds to affect both spontaneous and
mitogenꢀstimulated by concanavalin (Con A) in a concentraꢀ
tion of 2 μg mL–1 splenocyte proliferation in mice in vitro
(antiproliferative properties) was estimated (Table 6).
As follows from the data presented (see Table 6), the
compounds manifesting the high doseꢀdependent activity
to the spontaneous and stimulated proliferation of splenoꢀ
cytes were found in the series of studied (2ꢀhydroxyꢀ
ethyl)ammonium salts of both 1ꢀRꢀindolꢀ3ꢀylsulfanylaceꢀ
tic and ꢀsulfonylalkanecarboxylic acids. Compounds
6c,d,f,g are most efficient (see Table 6).
Comꢀ Yield M.p.
pound (%) /°C
Found
Calculated
Empirical
formula
(%)
C
H
N
S
5a
5b
5c
5d
5e
5f
92 165—168 61.94 4.57 4.23 9.79 C17H15NO4S
61.99 4.59 4.25 9.74
90 184—186 62.99 4.98 4.11 9.37 C18H17NO4S
62.96 4.99 4.08 9.34
88 190—192 63.77 5.37 3.90 9.01 C19H19NO4S
63.85 5.36 3.92 8.97
88 161—163 63.81 5.37 3.95 8.95 C19H19NO4S
63.85 5.36 3.92 8.97
92 166—168 53.38 3.38 7.74 8.93 C16H12N2O6S
53.33 3.36 7.77 8.90
91
80*
54.59 3.76 7.48 8.58 C17H14N2O6S
54.54 3.77 7.48 8.57
* Becomes diffuse.
analysis data (Table 5). The IR spectra of salts 6a—h exꢀ
hibits the COO– group at 1600—1590 cm–1 and signals of
the alkanolammonium fragments (see Table 5). In the
1H NMR spectra of compounds 6a—h, the signals of the
indole cycles correspond to those for the initial acids.
Biological assays. Selective immunomodulators repreꢀ
sent a new and urgent section of immunopharmacology.
The effect of the existing drugs (both immunostimulators
and immunosuppressive agents) is nonꢀspecific, and imꢀ
munosuppressive drugs are characterized by pronounced
toxicity, high risk of development side reactions, and a
series of contraꢀindications.
Such established immunopharmacologic properties of
the biologically active compounds of the new type, viz.,
(2ꢀhydroxyethyl)ammonium salts of indolꢀ3ꢀylsulfanylꢀ
(sulfonyl)alkanecarboxylic acids, as relative low toxicity,
pronounced antiproliferative properties due to cell "arrest"
in the phase of the cycle G0 + G1, the presence of the
Modern knowledge on pathogenesis of diseases associꢀ
ated with the distortion of immune processes during misꢀ
matching of the Th1/Th2 regulatory effects and the balꢀ
Table 4. 1H NMR and IR spectra of compounds 5a—f
Comꢀ
pound
Solvent
1H NMR, δ (J/Hz)
IR, ν/cm–1
5a
5b
(CD3)2SO
(CD3)2SO
4.27 (s, 2 H, CH2SO2); 5.50 (s, 2 H, CH2N); 7.19—7.28, 7.50—7.52, 7.74—7.76
(all m, 9 H, 5 HAr, H(4), H(5), H(6), H(7)); 8.27 (s, 1 H, H(2))
1.42 (d, 3 H, Me, J = 6.8); 4.17 (q, 1 H, CHSO2, J = 6.8); 5.57 (s, 2 H, CH2N);
7.25—7.35 (m, 7 H, 5 HAr, H(5), H(6)); 7.56 (m, 1 H, H(4)); 7.79 (m, 1 H, H(7));
8.31 (s, 1 H, H(2))
1705, 1510,
1460
1704, 1517,
1454, 1310,
1136
5c
(CD3)2SO
0.89 (t, 3 H, Me, J = 7.2); 1.82—1.98 (dd, 2 H, CH2, J = 7.4, J = 10.8); 3.98
1707, 1516,
1454, 1310,
1136
(q, 1 H, CHSO2, J = 10.8); 5.57 (s, 2 H, CH2N); 7.26—7.57 (m, 7 H, 5 HAr
,
H(5), H(6)); 7.56 (m, 1 H, H(4)); 7.78 (m, 1 H, H(7)); 8.31 (s, 1 H, H(2))
5d
5e
5f
CDCl3
1.65 (s, 6 H, 2 Me); 5.37 (s, 2 H, CH2N); 7.15—7.31 (m, 8 H, 5 HAr, H(6), H(5),
H(7)); 7.74 (br.s, 1 H, H(4)); 8.01 (br.s, 1 H, H(2))
4.45 (s, 2 H, CH2SO2); 7.42 (br.s, 2 H, H(5), H(6)); 7.73 (br.s, 1 H, H(4)); 7.99
(m, 3 H, H(2)Ar, H(6)Ar, H(7)); 8.45 (m, 2 H, H(3)Ar, H(5)Ar); 8.49 (s, 1 H, H(2))
1.63 (d, 3 H, Me, J = 7.0); 4.19 (q, 1 H, CHSO2, J = 7.0); 7.36—7.48 (m, 2 H, H(6),
H(5)); 7.72 (m, 2 H, H(2)Ar, H(6)Ar); 7.98—8.02 (m, 2 H, H(7), H(4)); 8.39 (s, 1 H,
1714, 1514, 1461,
1307, 1154
1767, 1596, 1522,
1353, 1147
1741, 1595, 1520,
1350, 1315, 1135
(CD3)2SO
CDCl3
H(2)); 8.41 (m, 2 H, H(3)Ar, H(5)Ar
)

2242
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 12, December, 2010
Mirskova et al.
Table 5. Yields, physicochemical characteristics, and elemental analysis data for compounds 6a—h
Comꢀ Yield
pound (%)
M.p.
/°C
Found
Calculated
Empirical
formula
1H NMR ((CD3)2SO)*,
IR,
ν/cm–1
(%)
δ (J/Hz)
C
H
N
S
6a
6b
6c
6d
6e
6f
99
92
97
72
89
86
96
88
Oil
Oil
57.95 6.88 9.40 10.86 C14H20N2O3S 2.60 (s, 6 H, 2 Me); 3.03 (t, 2 H, CH2N,
1560, 1610
1560, 1620
56.73 6.80 9.45 10.82
J = 5.1); 3.70 (t, 2 H, CH2OH, J = 5.1)
55.39 6.72 8.55 9.87
55.19 6.79 8.58 9.82
C15H22N2O4S 2.63 (s, 3 H, Me); 3.02 (t, 4 H, 2 CH2N,
J = 5.3); 3.72 (t, 4 H, 2 CH2OH, J = 5.3)
92—93 61.01 6.72 6.25 7.20
61.86 6.77 6.27 7.18
C23H30N2O5S 2.99 (t, 6 H, 3 CH2N, J = 5.3); 3.61 (t,
6 H, 3 CH2OH, J = 5.3)
1560, 1600,
3280
Oil
138
Oil
63.30 6.72 6.59 7.76
63.44 6.78 6.73 7.70
C22H28N2O4S 2.64 (s, 3 H, Me); 3.03 (t, 4 H, 2 CH2N,
1560, 1620
1560, 1620
1560, 1610
J = 5.1); 3.73 (t, 4 H, 2 CH2OH, J = 5.1)
58.35 6.22 6.20 7.10
58.91 6.29 6.25 7.15
C22H28N2O6S 2.65 (s, 3 H, Me); 3.05 (t, 4 H, 2 CH2N,
J = 5.2); 3.74 (t, 4 H, 2 CH2OH, J = 5.2)
60.20 6.27 6.65 7.63
60.27 6.26 6.69 7.66
C21H26N2O5S 2.62 (s, 6 H, 2 Me); 3.05 (t, 2 H, CH2N,
J = 5.1); 3.72 (t, 2 H, CH2OH, J = 5.1)
6g
6h
108—110 57.79 6.34 5.95 6.77
57.72 6.32 5.85 6.70
C23H30N2O7S 3.05 (t, 6 H, 3 CH2N, J = 5.3); 3.63 (t,
6 H, 3 CH2OH, J = 5.3)
1560, 1600,
3290
126—128 58.59 6.57 5.63 6.58
58.52 6.55 5.69 6.51
C24H32N2O7S 3.04 (t, 6 H, 3 CH2N, J = 5.3); 3.62 (t,
6 H, 3 CH2OH, J = 5.3)
1560, 1600,
3285
* Only the signals of the alkanolammonium fragments are presented.
indole fragment in the structure of these compounds, and
inducible activity toward a gen of cytochrome P4501А1
suggest that the immunoactive action of these compounds
at the cell level follows an original mechanism involving
a new molecular target: arylhydrocarboxylic receptor
(AhR) for which they act as promising AhR ligands selecꢀ
tively modulating the immune functions.
containing 1ꢀRꢀindolylalkanecarboxylic acids for selecꢀ
tive immunomodulators for the development of modern
medical preparations is promising.
Experimental
1
Н NMR spectra were recorded on a Bruker DPXꢀ400 inꢀ
Thus, the tests of antiproliferative activity of the new
compounds indicate that the search in the series of sulfurꢀ
strument (400.6 MHz). IR spectra were obtained on a Bruker
IFSꢀ25 spectrometer in KBr pellets and in microlayer. Potentioꢀ
Table 6. Influence of compounds 6a—h on the spontaneous and mitogenꢀstimulated proliferation of spleen cells of intact mice in vitro
Comꢀ
pound
Dose
/μg mL–1
Proliferation/pulse min–1
Comꢀ
pound
Dose
/μg mL–1
Proliferation/pulse min–1
spontaneous
Con A
spontaneous
Con A
Reference
6a
—
3
30
300
—
2906
44304
51247 (+15.7%)
38067 (–26%)
27633 (–46%)
44304
Reference
6e
—
3
30
300
—
6992
7431 (+6.3%)
6141 (–12.2%)
732 (–89.5%)
1015
47972
3156 (+8.6%)
2063 (–29%)
478 (–83%)
2906
57307 (+19.5%)
56914 (+18.6%)
38024 (–20.7%)
20313
Reference
Reference
6b
3
5033 (+73%)
3656 (+26%)
1512 (–48%)
179
42915 (–3%)
46562 (+5%)
33936 (–23.4%)
4150
6f
3
472 (–53%)
349 (–66%)
625 (–38%)
122
19384 (–5%)
13240 (–34.8%)
5280 (–74%)
1652
30
300
—
30
300
—
Reference
Reference
6c
3
115 (–35%)
48 (–73.2%)
19 (–89.4%)
6992
3399 (–18.1%)
2954 (–28.8%)
30 (–99.3%)
47972
6g
3
123
1378 (–16.6%)
1160 (–29.8%)
161 (–90.2%)
20313
30
300
—
30
300
—
50 (–59%)
31 (–74.6%)
1015
Reference
Reference
6d
3
30
300
6183 (–11.6%)
2671 (–61.8%)
320 (–95.4%)
48330
66644 (+38.9%)
306 (–99.4%)
6h
3
30
300
475 (–53.2%)
368 (–63.7%)
69 (–93.2%)
21142 (+4%)
20782 (+2%)
10311 (–49.2%)

Indolꢀ3ꢀylsulfonylalkanecarboxylic acids
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 12, December, 2010
2243
metric titration was carried out on an EAꢀ74 ionometer. Meltꢀ
ing points were determined on a Boetius heating stage (Gerꢀ
many). Purity of substances was monitored on a Khrom 5
chromatograph, column 2 m, CromatonꢀNꢀAWꢀDMCS,
0.200—0.250 mm, impregnated with 5% Silicone, helium as carꢀ
and monochloroacetic acid (11.40 g, 0.12 mol). The product was
isolated in a yield of 19.97 g.
[(1ꢀButylindolꢀ3ꢀyl)sulfanyl]acetic acid (3e) was synthesized
from 1ꢀbutylindole (17.32 g, 0.1 mol), thiourea (15.22 g, 0.2 mol),
iodine (25.38 g, 0.1 mol), potassium iodide (16.60 g, 0.1 mol),
hydrazine hydrate (5.00 g, 0.1 mol), NaOH (20.00 g, 0.5 mol),
and monochloroacetic acid (11.40 g, 0.12 mol). The product was
isolated in a yield of 22.87 g.
{[1ꢀ(Propꢀ2ꢀenꢀ1ꢀyl)indolꢀ3ꢀyl]sulfanyl}acetic acid (3f) was
synthesized from 1ꢀallylindole (15.72 g, 0.1 mol), thiourea (15.22 g,
0.2 mol), iodine (25.38 g, 0.1 mol), potassium iodide (16.60 g,
0.1 mol), hydrazine hydrate (5.00 g, 0.1 mol), NaOH (20.00 g,
0.5 mol), and monochloroacetic acid (11.40 g, 0.12 mol). The
product was isolated in a yield of 20.50 g.
{[1ꢀ(4ꢀNitrophenyl)indolꢀ3ꢀyl]sulfanyl}acetic acid (3h). A.
Acid 3h was synthesized from 1ꢀ(4ꢀnitrophenyl)indole (23.82 g,
0.1 mol), thiourea (15.22 g, 0.2 mol), iodine (25.38 g, 0.1 mol),
potassium iodide (16.60 g, 0.1 mol), hydrazine hydrate (5.00 g,
0.1 mol), NaOH (20.00 g, 0.5 mol), and monochloroacetic acid
(11.40 g, 0.12 mol). The reaction was carried out in ethanol.
A solution of KI3 was added dropwise and the stage of isothiuroꢀ
nium salt formation was performed on solvent boiling. The
product was isolated in a yield of 2.60 g.
B. (Indolꢀ3ꢀyl)sulfanylacetic acid (3а) (10.36 g, 0.05 mol)
was added to a solution of NaOH (12 g, 0.15 mol) in DMSO
(50 mL). The mixture was stirred for 15—20 min. Then 4ꢀfluoroꢀ
nitrobenzene (7.06 g, 0.05 mol) was slowing added dropwise on
cooling to 10—15 °С. The reaction mixture was stirred for 3 h at
room temperature and then poured into iceꢀcold water (200 mL).
The precipitate formed was filtered off, washed with water, and
dried. The product was isolated in a yield of 12.15 g.
rier gas, 30 mL min–1
.
1ꢀBenzylꢀ2ꢀmethylindole (1j). 2ꢀMethylindole (13.18 g,
0.1 mol) was added to a solution of NaOH (12 g, 0.3 mol) in
DMSO (50 mL). The mixture was stirred for 15—20 min. Then
benzyl chloride (12.66 g, 0.1 mol) was slowly added dropwise on
cooling to 10—15 °С. The mixture was stirred for 3 h without
heating and then poured into iceꢀcold water (200 mL). The
precipitate formed was washed with water, dried, and disꢀ
tilled under reduced pressure. The yield was 16.83 g (76%), b.p.
200—204 °C (15 Torr). 1H NMR (CDCl3), δ: 2.28 (s, 3 H, Me);
5.18 (s, 2 H, CH2N); 6.28 (s, 1 H, H(3)); 6.86—7.18 (m, 8 H,
5 HAr, H(5), H(6), H(7)); 7.52 (m, 1 H, H(4)). Found (%):
С, 86.90; H, 6.81; N, 6.35. C16H15N. Calculated (%): С, 86.84;
H, 6.83; N, 6.33.
1ꢀAllylꢀ2ꢀmethylindole (1i) was synthesized similarly from
2ꢀmethylindole (13.18 g, 0.1 mol) and allyl bromide (11.10 g,
0.1 mol). The yield was 12.27 g (71%), b.p. 132—135 °C (15 Torr).
1H NMR (CDCl3), δ: 2.31 (s, 3 H, Me); 4.56 (m, 2 H, CH2N);
4.72—5.04 (m, 3 H, СH=СH2); 6.25 (s, 1 H, H(3)); 7.00—7.27
(m, 8 H, 5 HAr, H(5), H(6), H(7)); 7.48 (m, 1 H, H(4)).
Found (%): С, 84.23; H, 7.66; N, 8.21. C12H13N. Calculatꢀ
ed (%): С, 84.17; H, 7.65; N, 8.18.
1ꢀSubstituted indoles 1a—h and 2a,b were synthesized acꢀ
cording to the described procedure, and their constants correꢀ
sponded to the literature data.35
Synthesis of (indolꢀ3ꢀyl)sulfanylalkanecarboxylic acids 3a—q
and 4a,b (general procedure). A solution of iodine (25.38 g,
0.1 mol) and potassium iodide (16.60 g, 0.1 mol) in 50% ethanol
(50 mL) was added to a solution of indole (0.1 mol) and thiourea
(15.20 g, 0.2 mol) in ethanol (50 mL) by portions in an argon
flow preventing an increase in the temperature of the reaction
mixture higher than 40 °С. The reaction mixture was stored for
3 h at 30—40 °С, then hydrazine hydrate (5.00 g, 0.1 mol) was
added dropwise, and a solution of NaOH (20.00 g, 0.5 mol) in
water (30 mL) and monochloro(bromo)alkanecarboxylic acid
(0.12 mol) in water (5 mL) were slowly added. The mixture was
stored for 2 h in a boiling water bath. After the end of the reacꢀ
tion, the alcohol was evaporated, and the precipitate formed was
dissolved on heating in water with the addition of active carbon,
stored for 0.5—1 h, filtered, acidified with 10% HCl until the
precipitate stopped to form (pH 1), and stored for at least 12 h at
5 °С to the complete precipitation and crystallization of the
product. The precipitated acid was filtered off and dried in air.
Acids 3а,b,g were synthesized according to the described
procedure, and their constants corresponded to the literature
data.33
[(1ꢀMethylindolꢀ3ꢀyl)sulfanyl]acetic acid (3c) was syntheꢀ
sized from 1ꢀmethylindole (13.11 g, 0.1 mol), thiourea (15.22 g,
0.2 mol), iodine (25.38 g, 0.1 mol), potassium iodide (16.60 g,
0.1 mol), hydrazine hydrate (5.00 g, 0.1 mol), NaOH (20.00 g,
0.5 mol), and monochloroacetic acid (11.40 g, 0.12 mol). The
product was isolated in a yield of 19.69 g.
[(1ꢀEthylindolꢀ3ꢀyl)sulfanyl]acetic acid (3d) was synthesized
from 1ꢀethylindole (14.52 g, 0.1 mol), thiourea (15.22 g, 0.2 mol),
iodine (25.38 g, 0.1 mol), potassium iodide (16.60 g, 0.1 mol),
hydrazine hydrate (5.00 g, 0.1 mol), NaOH (20.00 g, 0.5 mol),
[(1ꢀBenzylindolꢀ3ꢀyl)sulfanyl]propionic acid (3i) was syntheꢀ
sized from 1ꢀbenzylindole (20.72 g, 0.1 mol), thiourea (15.22 g,
0.2 mol), iodine (25.38 g, 0.1 mol), potassium iodide (16.60 g,
0.1 mol), hydrazine hydrate (5.00 g, 0.1 mol), NaOH (20.00 g,
0.5 mol), and 3ꢀbromopropionic acid (18.36 g, 0.12 mol). The
product was isolated in a yield of 16.51 g.
2ꢀ[(1ꢀBenzylindolꢀ3ꢀyl)sulfanyl]propionic acid (3j) was synꢀ
thesized from 1ꢀbenzylindole (20.72 g, 0.1 mol), thiourea (15.22 g,
0.2 mol), iodine (25.38 g, 0.1 mol), potassium iodide (16.60 g,
0.1 mol), hydrazine hydrate (5.00 g, 0.1 mol), NaOH (20.00 g,
0.5 mol), and 2ꢀchloropropionic acid (13.02 g, 0.12 mol). The
product was isolated in a yield of 26.80 g.
2ꢀ[(1ꢀBenzylindolꢀ3ꢀyl)sulfanyl]butanoic acid (3k) was synꢀ
thesized from 1ꢀbenzylindole (20.72 g, 0.1 mol), thiourea (15.22 g,
0.2 mol), iodine (25.38 g, 0.1 mol), potassium iodide (16.60 g,
0.1 mol), hydrazine hydrate (5.00 g, 0.1 mol), NaOH (20.00 g,
0.5 mol), and 2ꢀbromobutanoic acid (20.04 g, 0.12 mol). The
product was isolated in a yield of 27.66 g.
2ꢀ[(Benzylindolꢀ3ꢀyl)sulfanyl]ꢀ2ꢀmethylpropionic acid (3l)
was synthesized from 1ꢀbenzylindole (20.72 g, 0.1 mol), thioꢀ
urea (15.22 g, 0.2 mol), iodine (25.38 g, 0.1 mol), potassium
iodide (16.60 g, 0.1 mol), hydrazine hydrate (5.00 g, 0.1 mol),
NaOH (20.00 g, 0.5 mol), and 2ꢀbromoꢀ2ꢀmethylpropionic acid
(20.04 g, 0.12 mol). The product was isolated in a yield of 14.95 g.
[(1,2ꢀDimethylindolꢀ3ꢀyl)sulfanyl]acetic acid (3m) was synꢀ
thesized from 1,2ꢀdimethylindole (14.52 g, 0.1 mol), thioꢀ
urea (15.22 g, 0.2 mol), iodine (25.38 g, 0.1 mol), potassium
iodide (16.60 g, 0.1 mol), hydrazine hydrate (5.00 g, 0.1 mol),
NaOH (20.00 g, 0.5 mol), and monochloroacetic acid (11.40 g,
0.12 mol). The product was isolated in a yield of 21.16 g.

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Russ.Chem.Bull., Int.Ed., Vol. 59, No. 12, December, 2010
Mirskova et al.
[(2ꢀMethylꢀ1ꢀethylindolꢀ3ꢀyl)sulfanyl]acetic acid (3n) was
synthesized from 1ꢀethylꢀ2ꢀmethylindole (15.92 g, 0.1 mol), thioꢀ
urea (15.22 g, 0.2 mol), iodine (25.38 g, 0.1 mol), potassium
iodide (16.60 g, 0.1 mol), hydrazine hydrate (5.00 g, 0.1 mol),
NaOH (20.00 g, 0.5 mol), and monochloroacetic acid (11.40 g,
0.12 mol). The product was isolated in a yield of 21.88 g.
{[2ꢀMethylꢀ1ꢀ(propꢀ2ꢀenꢀ1ꢀyl]indolꢀ3ꢀyl)sulfanyl}acetic acid
(3o) was synthesized from 1ꢀallylꢀ2ꢀmethylindole (17.12 g, 0.1 mol),
thiourea (15.22 g, 0.2 mol), iodine (25.38 g, 0.1 mol), potassium
iodide (1.60 g, 0.1 mol), hydrazine hydrate (5.00 g, 0.1 mol),
NaOH (20.00 g, 0.5 mol), and monochloroacetic acid (11.40 g,
0.12 mol). The product was isolated in a yield of 18.21 g.
2ꢀ{[2ꢀMethylꢀ1ꢀ(propꢀ2ꢀenꢀ1ꢀyl)indolꢀ3ꢀyl]sulfanyl}butanoic
acid (3p) was synthesized from 1ꢀallylꢀ2ꢀmethylindole (17.12 g,
0.1 mol), thiourea (15.22 g, 0.2 mol), iodine (25.38 g, 0.1 mol),
potassium iodide (1.60 g, 0.1 mol), hydrazine hydrate (5.00 g,
0.1 mol), NaOH (20.00 g, 0.5 mol), and 2ꢀbromobutanoic
acid (20.04 g, 0.12 mol). The product was isolated in a yield
of 19.73 g.
[(1ꢀBenzylꢀ2ꢀmethylindolꢀ3ꢀyl)sulfanyl]acetic acid (3q) was
synthesized from 1ꢀbenzylꢀ2ꢀmethylindole (22.13 g, 0.1 mol).
thiourea (15.22 g, 0.2 mol), iodine (25.38 g, 0.1 mol), potassium
iodide (1.60 g, 0.1 mol), hydrazine hydrate (5.00 g, 0.1 mol),
NaOH (20.00 g, 0.5 mol), and monochloroacetic acid (11.40 g,
0.12 mol). The product was isolated in a yield of 28.06 g.
2ꢀ{[1ꢀ(4ꢀNitrophenyl)indolꢀ3ꢀyl]sulfanyl}propionic acid (3r)
was synthesized similarly to 3h (method B) from NaOH (12 g,
0.15 mol), 2ꢀ(indolꢀ3ꢀyl)sulfanylpropionic acid (11.07 g, 0.05 mol),
and 4ꢀfluoronitrobenzene (7.06 g, 0.05 mol). The product was
isolated in a yield of 12.01 g.
Hexaneꢀ1,6ꢀdiylbis(3ꢀcarboxymethylsulfanylindole) (4а) was
synthesized from 1,1´ꢀhexaneꢀ1,6ꢀdiylbisindole (15.82 g, 0.05 mol),
thiourea (15.22 g, 0.2 mol), iodine (25.38 g, 0.1 mol), potassium
iodide (16.60 g, 0.1 mol), hydrazine hydrate (5.00 g, 0.1 mol),
NaOH (20.00 g, 0.5 mol), and monochloroacetic acid (11.40 g,
0.12 mol). The product was isolated in a yield of 22.14 g.
1,4ꢀPhenylenemethylenebis(3ꢀcarboxymethylsulfanylindole)
(4b) was synthesized from 1,1´ꢀ(benzeneꢀ1,4ꢀdiyldimethaneꢀ
diyl)bisindole (16.82 g, 0.05 mol), thiourea (15.22 g, 0.2 mol),
iodine (25.38 g, 0.1 mol), potassium iodide (16.60 g, 0.1 mol),
hydrazine hydrate (5.00 g, 0.1 mol), NaOH (20.00 g, 0.5 mol),
and monochloroacetic acid (11.40 g, 0.12 mol). The product was
isolated in a yield of 23.48 g.
Synthesis of 1ꢀRꢀ(indolꢀ3ꢀyl)sulfonylalkanecarboxylic acids
5a—f (general procedure). 1ꢀRꢀ(Indolꢀ3ꢀyl)sulfanylalkanecarbꢀ
oxylic acid (0.01 mol) was dissolved in acetic anhydride (5 mL).
The reaction mixture was cooled to 0 °С, and a 50% solution of
hydrogen peroxide (0.05 mol) was added dropwise. The temperꢀ
ature of the reaction mixture was slowly increased to 20 °С, and
the mixture was stirred for 24 h. Then cold water (100 mL) was
added to the solution. The precipitated target product was filꢀ
tered off, washed with water, and dried in air.
2ꢀ[(1ꢀBenzylindolꢀ3ꢀyl)sulfonyl]ꢀ2ꢀmethylpropionic acid (5d)
was synthesized from acid 3l (3.25 g, 0.01 mol). The product was
isolated in a yield of 4.05 g.
{[1ꢀ(4ꢀNitrophenyl)indolꢀ3ꢀyl]sulfonyl}acetic acid (5e) was
synthesized from acid 3h (3.28 g, 0.01 mol). The product was
isolated in a yield of 3.30 g.
2ꢀ{[1ꢀ(4ꢀNitrophenyl)indolꢀ3ꢀyl]sulfonyl}propionic acid (5f)
was synthesized from acid 3r (3.42 g, 0.01 mol). The product was
isolated in a yield of 3.42 g.
Synthesis of alkanolammonium salts of Nꢀsubstituted indolylꢀ
sulfanyl(sulfonyl)alkanecarboxylic acids 6a—h (general proceꢀ
dure). A solution of alkanolamine (0.01 mol) in ethanol (10 mL)
was poured to a solution of (indolꢀ3ꢀyl)sulfanyl(sulfonyl)ꢀ
alkanecarboxylic acid (0.01 mol) in ethanol (10 mL). The reacꢀ
tion mixture was heated for 10—15 min to 45—50 °С and then
stored for 30 min at 20—22 °С. At the end of the reaction, ethaꢀ
nol was partially evaporated in air, then diethyl ether was added
with vigorous stirring to the reaction mixture until the undisapꢀ
peared precipitate was formed, and the mixture was stored for
24 h at 5—10 °С. The precipitate formed was filtered off, washed
with diethyl ether, and dried in vacuo over P2O5.
2ꢀHydroxyꢀN,Nꢀdimethylethaneammonium(indolꢀ3ꢀylsulꢀ
fanyl)acetate (6a) was synthesized from acid 3a (2.07 g, 0.01 mol)
and N,Nꢀdimethylethanolamine (0.89 g, 0.01 mol). The product
was isolated in a yield of 2.95 g.
2ꢀHydroxyꢀNꢀ(2ꢀhydroxyethyl)ꢀNꢀmethylethaneammoniumꢀ
(indolꢀ3ꢀylsulfanyl)acetate (6b) was synthesized from acid 3a
(2.07 g, 0.01 mol) and Nꢀmethylbis(2ꢀhydroxyethyl)amine (1.19 g,
0.01 mol). The product was isolated in a yield of 3.0 g.
2ꢀHydroxyꢀN,Nꢀbis(2ꢀhydroxyethyl)ethaneammonium[(1ꢀ
benzylindolꢀ3ꢀyl)sulfanyl]acetate (6с) was synthesized from acid
3g (2.97 g, 0.01 mol) and triethanolamine (1.49 g, 0.01 mol).
The product was isolated in a yield of 4.32 g. The physicochemꢀ
ical properties of alkanolammonium salt 6с correspond to the
literature data.30—32
2ꢀHydroxyꢀNꢀ(2ꢀhydroxyethyl)ꢀNꢀmethylethaneammoniumꢀ
[(1ꢀbenzylindolꢀ3ꢀyl)sulfanyl]acetate (6d) was synthesized from
acid 3g (2.97 g, 0.01 mol) and Nꢀmethylbis(2ꢀhydroxyethyl)ꢀ
amine (1.19 g, 0.01 mol). The product was isolated in a yield
of 3.01 g.
2ꢀHydroxyꢀNꢀ(2ꢀhydroxyethyl)ꢀNꢀmethylethaneammoniumꢀ
[(1ꢀbenzylindolꢀ3ꢀyl)sulfonyl]acetate (6e) was synthesized from
acid 5a (3.29 g, 0.01 mol) and Nꢀmethylbis(2ꢀhydroxyethyl)ꢀ
amine (1.19 g, 0.01 mol). The product was isolated in a yield
of 3.98 g.
2ꢀHydroxyꢀN,Nꢀdimethylethaneammonium[(1ꢀbenzylindolꢀ
3ꢀyl)sulfonyl]acetate (6f) was synthesized from acid 5a (3.29 g,
0.01 mol) and N,Nꢀdimethylethanolamine (0.89 g, 0.01 mol).
The product was isolated in a yield of 3.70 g.
2ꢀHydroxyꢀN,Nꢀbis(2ꢀhydroxyethyl)ethaneammonium[(1ꢀ
benzylindolꢀ3ꢀyl)sulfonyl]acetate (6g) was synthesized from acid
5a (3.29 g, 0.01 mol) and triethanolamine (1.49 g, 0.01 mol).
The product was isolated in a yield of 4.59 g.
2ꢀHydroxyꢀN,Nꢀbis(2ꢀhydroxyethyl)ethaneammoniumꢀ2ꢀ
[(1ꢀbenzylindolꢀ3ꢀyl)sulfonyl]propanoate (6h) was synthesized
from acid 5b (3.43 g, 0.01 mol) and triethanolamine (1.49 g,
0.01 mol). The product was isolated in a yield of 4.34 g.
Biological assays. Screening of the immunoactive properties
of compounds 6a—h was carried out in the culture in vitro. The
ability of these compounds to affect the spontaneous and mitoꢀ
genꢀstimulated proliferation of splenocytes of mice was estimatꢀ
[(1ꢀBenzylindolꢀ3ꢀyl)sulfonyl]acetic acid (5а) was synthesized
from acid 4g (2.97 g, 0.01 mol). The product was isolated in
a yield of 3.03 g.
2ꢀ[(1ꢀBenzylindolꢀ3ꢀyl)sulfonyl]propionic acid (5b) was synꢀ
thesized from acid 3j (3.11 g, 0.01 mol). The product was isolated
in a yield of 3.08 g.
2ꢀ[(1ꢀBenzylindolꢀ3ꢀyl)sulfonyl]butanoic acid (5c) was synꢀ
thesized from acid 3k (3.25 g, 0.01 mol). The product was isolatꢀ
ed in a yield of 4.01 g.

Indolꢀ3ꢀylsulfonylalkanecarboxylic acids
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 12, December, 2010
2245
ed. Healthy pubescent mice, viz., hybrids (CBAхC57BL/6)F1
(CBF1), both male and female, 8—10 weeks age, with the body
weight 18—20 g, were used. The scatter in groups by the initial
weight of the body did not exceed 10%. Reference and tested
animals of the same age were obtained simultaneously from one
breeding nursery. Before and during experiments, the reference
and tested animals were contained in a vivarium on a standard
food allowance. All tests were carried out at the same time (in the
morning). Tests were carried out according to the rules accepted
by the European Convention for the Protection of Animals
(Strasbourg, 1986) and approved by the Committee on Biomedꢀ
ical Ethics of the Research Institute of Clinical Immunology of
the Russian Academy of Medical Sciences.
Studies of the spontaneous and Con Аꢀinduced proliferation of
spleen cells. Spleen cells in mice were cultured in roundꢀbottom
trays for immunologic reaction (Linbro) at 37 °С under СО2
(5%) and air (95%) atmosphere. The absolute number of cells
introduced into a well was 200 000. The cells were stimulated by
mitogens, namely, concanavalin A (Con A, Sigma). The mitoꢀ
gen concentration was selected by preliminary titration and used
in the optimal dose, being for Con A 2 μg mL–1. The compounds
in three doses (3, 30, and 300 mg kg–1) were introduced into
wells simultaneously with mitogens. The proliferative activity of
the cells was estimated by the inclusion of Н3ꢀthymidine into
DNA of dividing cells. A label was introduced 16 h before the
end of cultivation an amount of 1 μCi into each well of the tray.
For this purpose, the basic solution of Н3ꢀthymidine was
first dissolved in RPMIꢀ1640 medium to a concentration of
100 μCi mL–1, and then 10 μL of the solution was added to each
well of the tray. After the end of incubation, the cells were colꢀ
lected on glassꢀfiber filters (Flow Lab) using a Harvester apparaꢀ
tus (Titertek). The filters were dried and placed into vials for
scintillation counting; radioactivity was counted in a toluene
scintillator (4 g of diphenyloxazole, 0.1 g of diphenyloxazolylꢀ
benzene per liter of toluene) in a Delta liquid scintillation counter
(USA). The results were expressed in pulse min–1 of included
thymidine per 2•105 cells. The data averaged over triplet are
presented. The data were processed by the nonꢀparametric Wilꢀ
coxon—Mann—Whitney U test.
Dokl. Akad. Nauk SSSR, 2003, 391, 410 [Dokl. Biol. Sci.
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6. M. G. Voronkov, A. N. Mirskova, O. P. Kolesnikova, O. T.
Kudaeva, V. L. Limonov, V. A. Kozlov, Abstrs of Int. Symp.
on Advances in Synthetic, Combinatorial and Medicinal Chemꢀ
istry, Moscow, 2004, 143.
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125 [Dokl. Biol. Sci. (Engl. Transl.), 2009, 428, 398].
11. A. N. Mirskova, S. N. Adamovich, R. G. Mirskov, M. G.
Voronkov, Dokl. Akad. Nauk, 2010, 433, 710 [Dokl. Biol. Sci.
(Engl. Transl.), 2010, 433, 244].
12. M. G. Voronkov, M. K. Nurbekov, S. N. Bobkova, L. K.
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M. G. Voronkov, Zh. Org. Khim., 1984, 20, 634 [J. Org.
Chem. USSR (Engl. Transl.), 1984, 20]; T. V. Nefedova,
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This work was financially supported by the Presidium
of the Russian Academy of Sciences (Program No. 21
"Fundamental Sciences for Medicine").
15. T. V. Nefedova, V. B. Kazimirovskaya, A. A. Ivanova, A. A.
Bryuzgin, S. A. Guseva, A. N. Mirskova, G. G. Levkovskaya,
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Received November 10, 2010;
in revised form November 23, 2010