Synthesis and cytotoxicity of derivatives of di(3-indolyl) selenide

Article abstract of DOI:10.1023/B:COHC.0000040769.55088.e3

A method has been developed for the synthesis of di(3-indolyl) selenides. From indole and SeO₂. N-Alkyl derivatives of di(3-indolyl) selenide have been obtained in the two-phase system alkyl halide-solid K ₂CO₃ (or KOH)-18

Full text of DOI:10.1023/B:COHC.0000040769.55088.e3

Chemistry of Heterocyclic Compounds, Vol. 40, No. 6, 2004
SYNTHESIS AND CYTOTOXICITY OF
DERIVATIVES OF DI(3-INDOLYL) SELENIDE
E. Abele, J. Popelis, I. Shestakova, I. Domracheva, P. Arsenyan, and E. Lukevics
A method has been developed for the synthesis of di(3-indolyl) selenides. From indole and SeO . N-Alkyl
2
derivatives of di(3-indolyl) selenide have been obtained in the two-phase system alkyl halide–solid
K CO (or KOH)–18-crown-6–toluene. It was discovered that N-unsubstituted di(3-indolyl) selenides
2
3
possess high cytotoxicity on HT-1080 and MG-22A tumor cell lines.
Keywords: indole, selenides, phase-transfer catalysis, cytotoxicity.
Selenium-containing indoles are used in organic synthesis as intermediates for radical cyclization [1,2].
These indoles are used as biologically active compounds. It was shown recently that amides of
2
,2'-diselenobis(1H-indoles) actively inhibit tyrosine kinase [3,4]. On the other hand, derivatives of
benzoseleno[4,3-b]indole [5] are carcinogens [6]. Among recent studies it is necessary to note investigations on
routes of synthesis and properties of 1,2,5-selenadiazolo[3,4-e]indoles and their [3,4-f] and [3,4-g] isomers [7].
The classical method of synthesizing 3,3'-diindolyl diselenides is based on the selenocyanation of indole
with bis-seleno cyanide with subsequent treatment of the reaction mixture with KOH solution in methanol
[8-11]. Some work has been devoted to the synthesis of indole selenides. Previously
β-(3-indolyl)ethylselenoacetic acid was obtained from β-(3-indolyl)ethyl bromide and (HO CCH Se) [12]. In
2
2
2
addition 3,3'-diindolyl selenides were successfully synthesized by the reaction of indoles with SeO in benzene
2
[13]. Bisharmine selenides were obtained analogously [14]. The mass spectrometric investigation of indole
selenides has been described in detail in [15]. It has also been shown that di(1-methyl-3-indolyl) selenide in the
presence of Raney nickel gives biindolyl and indole.
Investigation of the cytotoxicity of derivatives of di(3-indolyl) selenides has not been carried out
previously and is the aim of the present work.
Di(3-indolyl) selenides 3, 4 were obtained from indole 1 and 2-methylindole 2 by the procedure reported
in [13]. In the reaction of 2-methylindole with SeO in boiling benzene after 2 h the author of [13] obtained di(2-
2
methyl-3-indolyl) triselenide (16%) and di(2-methyl-3-indolyl) diselenide (22%). Under similar conditions (4 h
in boiling benzene) we obtained di(2-methyl-3-indolyl) selenide (4) as the sole product, but in only 7% yield.
1
13
77
The structure of selenide 4 was confirmed by data of elemental analysis, and H, C, and Se NMR spectra. The
7
7
Se chemical shift for selenide 4 has a characteristic value (1287.29 ppm) for this class of compound.
Di(3-indolyl) selenide (3) in the system alkyl halide (R'X)–solid K CO (or KOH)–18-crown-6–toluene
2
3
forms the N-substituted selenides 5-8 in 28-38% yield (Tables 1-3). In the reaction of selenide 3 with
Br(CH ) Br in the system solid K CO –18-crown-6–toluene the mono N-alkylated product 9 was obtained in
2
5
2
3
3
0% yield. The cyclic product is not formed under these conditions.
_
_________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: abele@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 6, pp. 868-872, June, 2004. Original article submitted December 6, 2002.
7
42 0009-3122/04/4006-0742©2004 Plenum Publishing Corporation

SeO2
Se
R
N
N
N
H
H
R
R
H
1
, 2
3, 4
R'X, 18-crown-6
K CO / PhMe
Se
3
2
3
N
N
R'
R'
5–8
Br(CH ) Br, 18-crown-6
2
5
K CO
2
3
Se
N
H
N
CH (CH ) Br
2
2 4
9
1
, 3 R = H; 2, 4 R = Me; 5 R' = Me; 6 R' = PhCH ; 7 R' = 2-MeC H CH ; 8 R' = Me Si(CH ) .
2 6 4 2 3 2 3
In the synthesis of 6, 7 X = Br; 5, 8 X = I
The biological activity of the obtained compounds was investigated on two tumor cell lines, viz.
HT-1080 (human fibrosarcoma) and MG-22A (mouse hepatoma) (Table 4). Di(3-indolyl) selenide (3) possesses
the greatest cytotoxic effect. This compound shows an IC50 of 1 µg/ml (CV test) for the fibrosarcoma and
2
µg/ml (CV and MTT tests) for the mouse hepatoma. The methyl-substituted selenide 4 also showed a similar
activity. The N-alkyl derivatives of selenide 3 showed low cytotoxicity. The high level of NO generation by
selenide 3 should be noted (450% in the HT-1080 line and 400% in the MG-22A line).
EXPERIMENTAL
1
13
77
The H, C, and Se NMR spectra were recorded on a Varian 200 Mercury spectrometer (200, 50, and
3
9 MHz respectively) in CDCl (in DMSO-d for compounds 3 and 4), internal standard was HMDS. For the
3
6
7
7
Se NMR spectra the internal standard was SeO (δ 1275.5 ppm). Indole, 2-methylindole, selenium dioxide,
2
methyl iodide, benzyl bromide, 2-methylbenzyl bromide, and 18-crown-6 (Acros) were used without further
purification. 3-Iodopropyl(trimethyl)silane was obtained by the Grignard reaction [16,17]. Di(3-indolyl) selenide
(
3) was obtained from indole and SeO in benzene as described in [13].
2
TABLE 1. Interphase Catalyzed Alkylation of Di(3-indolyl) Selenide 3
Found, %
Calculated, %
H
Reaction Pro-
Empirical
formula
——————
Yield,
%
R'X
mp, °C
time, h
duct
C
N
MeI
7
8
5
6
7
8
C
C
C
C
18
30
32
28
H
16
H
24
H
28
H
40
N
2
N
2
N
2
N
2
Se
63.46 4.74
.71 4.75
8.10
8.25
160-162
38
3
PhCH
2
Br
Se
73.22 4.81
3.31 4.92
5.65 >300 (dec.) 28
5.70
5.26
5.39
4.84
5.18
7
2
-MeC
6
H
4
CH
2
Br
14
10
Se
73.71 5.44
3.97 5.43
168-169
33
7
Me
3
Si(CH Br
2
)
3
SeSi
2
61.04 7.38
2.30 7.46
69-70
28
6
7
43

1
13
TABLE 2. Data of H and C NMR Spectra for Selenides 3-8
1
3
С NMR spectra, δ, ppm
1
Selenide
Н NMR, δ, ppm (J, Hz)
Indole
R'
3
7.04, 7.33 and 7.66 (10H, all m,
ring protons); 11.28 (2H, br. s, NH)
98.94, 111.75, 119.36,
19.44, 121.52, 129.40,
—
1
30.52, 136.19
4
2.59 (6H, s, CH
and 7.54 (8H, all m, ring protons);
1.24 (2H, br. s, NH)
3
); 6.96, 7.21
18.26 (CH ), 102.74,
115.88, 123.90, 124.37,
125.88, 135.76, 140.56,
3
—
1
1
44.47
5
6
3.66 (6H, s, CH
and 7.81 (10Н, m, ring protons)
3
); 7.13-7.22
99.55, 109.26, 119.79, 32.77 (CH
120.36, 121.91, 130.28,
3
)
1
33.64, 137.03
5.20 (4H, s, CH
2
); 7.0-7.3 and 7.77
99.98, 109.81, 120.02, 50.10 (CH
2
), 126.79,
(20Н, m and m, ring protons)
120.53, 122.12, 130.49, 127.65, 128.76,
32.98, 137.03 136.75 (all Ph)
1
7
8
2.22 (6H, s, CH
3
); 5.18 (4H, s, CH
2
);
99.82, 109.64, 119.98, 19.02 (CH ), 48.15
120.51, 122.04, 130.20, (CH ), 109.73,
132.68, 136.82 126.64, 127.51,
3
7
.13-7.24 and 7.75 (18Н, m and m,
2
ring protons)
1
27.89, 130.27,
135.74 (all Ph)
-0.05 (18H, s, Si(CH
SiCH ); 1.75 (4H, m, CH
.99 (4H, t, J = 7.2, NCH
and 7.84 (10Н, m and m, ring protons)
3
)
3
); 0.44 (4H, m, 99.19, 109.45, 119.64, -1.81 (SiMe
CH CH ); 120.45, 121.72, 130.36, (SiCH ), 24.89
); 7.09-7.28 132.64, 136.40 (CH CH CH ),
49.65 (NCH
3
), 13.91
2
2
2
2
2
3
2
2
2
2
2
)
Di(2-methyl-3-indolyl) Selenide (4). A suspension of 2-methylindole 2 (7.86 g, 30 mmol) and SeO2
(
4.40 g, 39.6 mmol) in benzene (90 ml) was refluxed for 5 h. The reaction mixture was filtered, and the filtrate
was evaporated to 20 ml on a rotary evaporator. Hexane was added to turbidity of the reaction mixture. The
product was twice recrystallized at 4°C from benzene–hexane. The yield of compound 4 was 0.70 g (7%).
7
7
Se NMR spectrum, δ, ppm: 1287.29.
TABLE 3. Mass Spectra of Selenides 4-8
Selenide
m/z (Irel, %)*
340 [M] (37), 338 (17), 260 (95), 245 (16), 243 (17), 217 (13), 209 (29),
+
4
2
8
07 (13), 131 (95), 130 (100), 122 (16), 117 (9), 115 (14), 103 (60), 102 (35),
9 (25), 78 (50), 77 (70), 65 (32), 63 (37)
+
5
6
7
340 [M] (13), 338 (7), 260 (100), 245 (30), 130 (38), 122 (10), 89 (15),
7
7 (15), 71 (15), 69 (15), 63 (10), 61 (14)
+
492 [M] (20), 412 (100), 321 (95), 204 (25), 177 (8), 130 (11), 102 (11),
9
7 (12), 91 (95), 89 (35), 77 (24), 71 (17), 69 (25), 65 (72)
+
520 [M] (19), 440 (100), 414 (3), 367 (10), 335 (92), 231 (19), 221 (52),
2
7
18 (20), 117 (12), 106 (77), 105 (90), 103 (68), 91 (12), 89 (15), 79 (75),
7 (70), 69 (11), 65 (14), 63 (13)
+
8
540 [M] (8), 462 (16), 461 (45), 460 (100), 359 (17), 231 (17), 157 (20),
1
30 (54), 97 (12), 95 (19), 83 (15), 75 (15), 73 (75), 71 (16), 69 (19)
_
*
______
Ions having m/z >60 and I >10% are shown. For selenium-containing
rel
8
0
fragments ions with the Se isotope are given.
7
44

TABLE 4. Cytotoxic Activity of Selenides 3-8 in vitro
Cell lines
HT-1080
MG-22A
Compound
IC50
CV*
*
IC50
,
NO100%
CV*
NO
100% CV
2
3
4
IC50* CV IC50* MTT
MTT*
3
4
5
6
7
8
1
4
2
450
300
53
6
2
2
2
3
400
250
10
12
26
5
5
23
*
*
*
*
*
*
*
*
5
5
5
5
5
5
5
5
*
*
218
13
5
5
*
*
12
18
5
5
*
*
20
_
*
*
*
*
*
______
Concentration µg/ml causing death of 50% cells.
2
Staining with Crystal Violet.
Staining with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide.
NO concentration (%) (CV staining).
3
4
5
No cytotoxic activity.
General Procedure for Interphase Catalysed Alkylation of Di(3-indolyl) Selenide (3)*. The
appropriate alkyl halide (2.2 mmol) was added to a suspension of compound 3 (0.311 g, 1 mmol), 18-crown-6
(
(
0.026 g, 0.1 mmol), and powdered KOH (0.224 g, 4 mmol) [in the synthesis of compound 8 powdered K CO3
0.552 g, 4 mmol) was used] in toluene (10 ml). The reaction mixture was stirred at room temperature (100°C for
2
compound 8) for 8-14 h, filtered, and the filtrate was evaporated on a rotary evaporator. The residue was purified
by column chromatography (eluent was hexane–ethyl acetate in various concentrations), and compounds 5-8
were obtained (Tables 1-3).
1
-(5-Bromopentyl)-3-[(3-indolyl)seleno]indole (9). 1,5-Dibromopentane (0.14 ml, 1 mmol) was added
to a suspension of compound 3 (0.311 g, 1 mmol), 18-crown-6 (0.026 g, 0.1 mmol), and powdered K CO (0.414
2
3
g, 4 mmol) in toluene (10 ml). The reaction mixture was stirred at 100°C for 40 h, filtered, and the filtrate
evaporated on a rotary evaporator. The residue was purified by column chromatography (eluent hexane–ethyl
1
acetate, 1:0.3), and compound 9 (0.14 g, 30%) was obtained having mp 138-142°C. H NMR spectrum, δ, ppm
(
J, Hz): 1.2-1.8 [8H, m, Br(CH ) ]; 3.99 (2H, t, J = 5.6, NCH ); 6.18 (1H, s, NH); 7.20-7.33 and 7.95 (10H, m,
2 4 2
ring protons).
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