Synthesis and cytotoxicity of 3-(hetarylthio)-1-propynyl-(trimethyl)silanes

Article abstract of DOI:10.1023/A:1020650224525

We have developed a two-step method for synthesis of 3-(hetarylthio)-1-propynyl(trimethyl)silanes from thiols in a phase-transfer catalysis system HC≡CCH₂Br-solid K₂CO₃-18-crown-6-toluene followed by reaction with n-BuLi-Me₃SiCl in ether or THF. We have observed that 3-[1,3-bis(trimethylsilyl)-2-propynyl] thioindole displays high cytotoxicity in HT-1080 and MG-22A tumor cell lines.

Full text of DOI:10.1023/A:1020650224525

Chemistry of Heterocyclic Compounds, Vol. 38, No. 7, 2002
SYNTHESIS AND CYTOTOXICITY
OF 3-(HETARYLTHIO)-1-PROPYNYL-
(TRIMETHYL)SILANES
R. Abele, E. Abele, K. Rubina, O. Dzenitis, P. Arsenyan, I. Shestakova, A. Nesterova,
I. Domracheva, J. Popelis, S. Grinberga, E. Lukevics
We have developed a two-step method for synthesis of 3-(hetarylthio)-1-propynyl(trimethyl)silanes from
thiols in a phase-transfer catalysis system HC≡CCH2Br–solid K2CO3–18-crown-6-toluene followed by
reaction with n-BuLi–Me3SiCl in ether or THF. We have observed that 3-[1,3-bis(trimethylsilyl)-2-
propynyl]thioindole displays high cytotoxicity in HT-1080 and MG-22A tumor cell lines.
Keywords: alkynes, heteroaromatic compounds, silicon-containing compounds, phase-transfer catalysis,
cytotoxicity.
Heteroaromatic sulfides are of interest as biologically active compounds [1]. In particular, high anti-
tumor activity and cytotoxicity have been established for pyridine [2-9], quinoline [10-16], indole [17-21],
benzothiazole [22], benzimidazole [23], uracil [24], and purine sulfides [25]. The results of a study of the anti-
tumor activity of different silanes have been summarized in [26]. We have established that heteroaromatic
sulfides of the type HetS(CH2)nSiR3 (n = 1,3) lower the blood cholesterol level and exhibit vasodilator
properties [27]. The cytotoxicity of heteroaromatic sulfides of the type HetSCH2C≡CSiMe3 was not studied
previously, and this is the objective of this work.
Br
H
HetS
H
Het SH
K2CO3 / 18-crown-6 /
PhMe
1–7
8–14
1) BuLi
HetS
SiMe3
2)Me3SiCl
15–21
We have developed
a
novel two-step method for synthesis of 3-(hetarylthio)-1-
propynyl(trimethyl)silanes from thiols. Heteroaromatic thiols 1-7, 22 in the system HC≡CCH2Br–solid K2CO3–
18-crown-6–toluene form hetaryl propargyl sulfides 8-14, 23 in up to 100% yields. The high efficiency of this
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV-1006; e-mail: abele@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 7, pp. 977-982, July, 2002. Original article submitted May 7, 2002.
0009-3122/02/3807-0867$27.00©2002 Plenum Publishing Corporation
867

phase-transfer catalysis system for alkylation of thiols has been demonstrated in [1, 27]. Consecutive reactions
of sulfides 8-14 with n-BuLi and Me3SiCl in ether lead to formation of 3-(hetarylthio)-1-
propynyl(trimethyl)silanes 15-21 in up to 83% yields (Tables 1-3).
Metalation of 3-(2-propynyl)thioindole 23 with butyllithium was carried out in THF due to problems
connected with the solubility of the dilithium salt of 23 in ether. Reaction of sulfide 23 with n-BuLi
(2.2 equivalents) in THF followed by treatment of the reaction mixture with excess of Me3SiCl leads to a
mixture of silylated products 24 and 25 (45:55). During their separation by column chromatography on silica
gel, N-desilylation of compounds 24 and 25 occurs. As a result, we isolated 3-(3-trimethylsilyl-2-
propynyl)thioindole 26 (18% yield) and 3-[1,3-bis(trimethylsilyl)-2-propynyl]thioindole 27 (22% yield).
S
SH
Br
1) BuLi
H
2) Me3SiCl
H
S
K2CO3 /
N
H
N
H
18-crown-6
23
22
SiMe3
S
SiO2
+
SiMe3
SiMe3
N
N
SiMe3
24
SiMe3
25
SiMe3
S
S
+
SiMe3
SiMe3
N
H
N
H
26
27
The biological activity of the compounds obtained were studied for two tumor cell lines: HT-1080
(human fibrosarcoma) and MG-22A (mouse hepatoma) (Table 4). The greatest cytotoxic effect is exhibited by
3-[1,3-bis(trimethylsilyl)-2-propynyl]thioindole (27), and specifically IC50 is 5 µg/ml (CV test) for fibrosarcoma
and 2 µg/ml (CV and MTT tests) for mouse hepatoma. We should note the very high level of NO generation for
the indole derivative 27 (900% for the HT-1080 line, and 300% for the MG-22A line).
TABLE 1. Synthesis of Hetaryl Propargyl Sulfides 8-14 and 3-(Hetarylthio)-
1-propynyl(trimethyl)silanes 15-21
Yield
Yield of
Thiol
Het
treaction, h
Sulfide
Silane
8-14, %
silanes, %
Ph
2-Pyridyl
2-Quinolyl
2-Pyrimidyl
6
4
8 [28]
9
78
95
15 [29]
16
65
54
83
23
51
1
2
3
4
5
9
70
10
17
6
10
100
91
11
12
18
19
1-Methyl-2-
imidazolyl
2-Benzoxazolyl
2-Benzthiazolyl
3
6
86
63
13
77
6
7
13
14
20
21
868

TABLE 2. 1H and 13C NMR Spectra of Alkynes 9-14, 16-21, 26, 27
13C NMR, δ, ppm
Het
1H NMR, δ, ppm, J (Hz)
Alkyne
SCH2C≡CR
2.18 (1H, t, J = 2.6, CH);
119.85 (C-5), 122.00 (C-3),
18.16 (CH2),
70.42 (≡CH),
80.06 (≡C)
9
3.95 (2H, d, J = 2.6, SCH2); 7.00, 7.18, 136.09 (C-4), 149.52 (C-6),
7.50 and 8.44 (4H, m, ring protons)
157.05 (C-2)
2.19 (1H, t, J = 2.8, CH);
120.33 (C-3), 125.52 (C-6),
17.91 (CH2),
70.48 (≡CH),
80.02 (≡C)
10
11
4.16 (2H, d, J = 2.8, SCH2); 7.22, 7.42, 126.07 (C-4a), 127.59 (C-5),
7.66, 7.92 (6H, m, ring protons)
128.11 (C-7), 129.76 (C-8),
135.70 (C-4), 148.17 (C-8a),
157.05 (C-2)
2.18 (1H, t, J = 2.6, CH);
4.00 (2H, d, J = 2.6, SCH2);
6.98 (1H, m, 5-H);
116.77 (C-5),
19.15 (CH2),
70.38 (≡CH),
79.49 (≡C)
157.28 (C-4 and C-6),
170 (C-2)
8.51 (2H, m and m, 4- and 6-H)
2.18 (1H, t, J = 2.6, CH);
122.80 (C-5), 129.59 (C-4),
23.14 (CH2),
71.77 (≡CH),
79.18 (≡C)
20.66 (CH2),
72.38 (≡CH),
77.86 (≡C)
12
13
3.67 (3H, s, CH3); 3.67 (2H, d, J = 2.6, 139.29 (C-2), 33.42 (NCH3)
SCH2); 6.9-7.2 (2H, m, ring protons)
2.30 (1H, t, J = 2.8, CH);
109.99 (C-6), 118.67 (C-5),
124.15 (C-7), 124.40 (C-4),
4.07 (2H, d, J = 2.8, SCH2);
7.26 (2H, m, 5- and 6-H); 7.45 and 7.62 141.74 (C-7a), 152.00 (C-3a),
(2H, m and m, 7- and 4-H)
162.99 (C-2)
2.29 (1H, t, J = 2.6, CH);
4.11 (2H, d, J = 2.6, SCH2);
7.2-7.9 (4H, m, ring protons)
121.02 (C-7), 121.75 (C-4),
124.47 (C-6), 126.11 (C-5),
135.40 (C-7a), 152.95 (C-3a),
164.51 (C-2)
21.52 (CH2),
72.28 (≡CH),
76.37 (≡C)
14
16
0.05 (9H, s, SiMe3); 3.91 (2H, s, CH2); 119.61 (C-5), 121.85 (C-3),
-0.24 (SiMe3),
19.41 (CH2),
87.41 (≡CSi),
101.36 (SC≡)
6.90, 7.13, 7.41 and 8.35 (4H, m, ring
protons)
135.88 (C-4), 149.29 (C-6),
157 (C-2)
0.06 (9H, s, SiMe3); 4.12 (2H, s, CH2); 120.32 (C-3), 125.44 (C-6),
-0.12 (SiMe3),
19.22 (CH2),
87.68 (≡CSi),
101.37 (SC≡)
17
7.14, 7.34, 7.60 and 7.83 (6H, m, ring
protons)
126.01 (C-4a), 127.59 (C-5),
128.06 (C-7), 129.72 (C-8),
135.59 (C-4), 148.15 (C-8a),
157.52 (C-2)
0.13 (9H, s, SiMe3); 3.97 (2H, s, CH2); 116.67 (C-5),
-0.20 (SiMe3),
20.42 (CH2),
87.59 (≡CSi),
100.82 (SC≡)
-0.68 (SiMe3),
24.49 (CH2),
88.35 (≡CSi),
100.59 (SC≡)
-0.29 (SiMe3),
21.92 (CH2),
89.81 (≡CSi),
98.92 (SC≡)
-0.24 (SiMe3),
22.93 (CH2),
89.90 (≡CSi),
99.39 (SC≡)
18
19
20
21
26
27
6.98 (1H, m, 5-H);
157.22 (C-4 and C-6),
171.20 (C-2)
8.52 (2H, m, 4- and 6-H)
0.11 (9H, s, SiMe3); 3.70 (2H, s, CH2); 122.61 (C-5), 129.46 (C-4),
3.74 (3H, s, NCH3); 6.97 and 7.11 (2H, 139.10 (C-2), 33.35 (NCH3)
both d, J = 0.6, ring protons)
0.13 (9H, s, SiMe3); 4.11 (2H, s, CH2); 109.94 (C-6), 118.61 (C-5),
7.2-7.6 (4H, m, ring protons)
124.08 (C-7), 124.36 (C-4),
141.83 (C-7a), 151.98 (C-3a),
163.22 (C-2)
0.16 (9H, s, SiMe3); 4.16 (2H, s, CH2); 121.02 (C-7), 121.76 (C-4),
7.1-7.9 (4H, m, ring protons)
124.07 (C-6), 124.46 (C-5),
126.12 (C-7a), 135.50 (C-3a),
153.05 (C-2)
0.05 (9H, s, SiMe3); 3.36 (2H, s, CH2); 111.43 (C-5), 119.44 (C-4),
-0.19 (SiMe3),
26.14 (CH2),
88.19 (≡CSi),
102.92 (SC≡)
7.1-7.4 and 7.80 (5H, m, ring protons); 119.44 (C-6), 120.52 (C-3),
8.37 (1H, br. s, NH)
122.66 (C-7), 129.32 (C-3a),
130.35 (C-7a), 136.13 (C-2)
0.05 and 0.22 (18H, s and s, SiMe3);
106.80 (C-5), 111.29 (C-4),
-2.99
3.02 (1H, s, CH); 7.2-7.4 and 7.82 (5H, 119.69 (C-6), 120.35 (C-3),
(CHSi(CH3)3),
0.07 (SiMe3),
29.87 (CH2),
87.33 (≡CSi),
106.50 (SC≡)
m, ring protons); 8.22 (1H, br. s, NH)
122.53 (C-7), 129.45 (C-3a),
132.88 (C-7a), 136.13 (C-2)
869

TABLE 3. Mass Spectra of Alkynes 9-14, 16-21, 23-27
Alkyne
m/z (Irel, %)
148 (100, M+), 117 (28),104 (24), 83 (17), 79 (47), 69 (17), 57 (14), 51 (40)
198 (100, M+), 167 (10), 129 (17)
9
10
11
12
13
14
16
17
18
19
149 (100, M+), 123 (12), 118 (14), 84 (9), 80 (13), 69 (12), 57 (14), 53 (18)
152 (100, M+), 137 (41), 113 (37), 106 (17), 72 (100), 55 (8)
189 (98, M+), 160 (18), 150 (43), 122 (100), 63 (10)
205 (100, M+), 173 (15), 166 (32), 160 (13), 129 (13), 122 (17), 108 (34), 102 (10) 69 (10)
220 (97, M+), 206 (100), 191 (14), 168 (21), 162 (10), 138 (13), 83 (17), 73 (14)
271 (18, M+), 256 (40), 198 (100), 180 (8), 128 (17), 101 (7), 73 (10)
221 (100, M+), 207 (97), 168 (19), 163 (14), 131 (12), 96 (8), 83 (23), 73 (17), 53 (13)
224 (100, M+), 209 (92), 191 (33), 171 (87), 165 (34), 151 (13), 141 (10), 133 (15),
119 (15), 113 (33), 96 (15), 83 (45), 72 (37), 55 (17)
260 (100, M+), 246 (42), 208 (25), 176 (17), 150 (25), 122 (40), 96 (17), 83 (47), 73 (20)
277 (100, M+), 262 (43), 244 (17), 186 (13), 166 (21), 108 (22), 83 (18), 73 (17)
186 (100, M+), 154 (7), 115 (9), 93 (6)
20
21
23
24
25
331 (23, M+), 220 (100), 73 (54), 45 (9)
403 (27, M+), 330 (20), 298 (27), 286 (11), 261 (27), 246 (23), 220 (100), 183 (22),
73 (54)
259 (24, M+), 186 (23), 148 (100), 121 (9), 73 (9)
26
27
331 (35, M+), 258 (100), 242 (19), 226 (22), 183 (42), 174 (58), 148 (39), 73 (59)
Quinoline derivative 17 and indole derivative 26 also displayed high cytotoxicity for the MG-22A line
(1 µg/ml, MTT test).
TABLE 4. Cytotoxic Activity in vitro of Silanes 15-21*
Cell lines
Com-
pound
HT-1080
IC50, µg/ml
MG-22A
IC50, µg/ml
NO, CV *2
NO, CV
CV
MTT
CV
MTT
44
27
24
27
57
42
77
35
36
36
31
500
83
150
28
100
13
250
900
35
25
3
24
18
1
91
83
500
73
14
500
13
15
16
17
18
19
20
21
26
27
28
87
11
14
21
13
3
*
50
3
3
3
3
*
*
*
*
9
5
14
11
3
2
1
2
200
300
_______
* IC50 is the concentration killing 50% of the cells; CV is staining by crystal
violet;
MTT
is
staining
by
3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide.
*2 NO concentration, % (CV staining).
*3 No cytotoxic activity.
870

EXPERIMENTAL
The 1H and 13C NMR spectra were recorded on a Varian 200 Mercury spectrometer (200 and 50 MHz)
in CDCl3, internal standard hexamethyldisiloxane. The mass spectra were recorded on a GC-MS HP 6890
chromatograph/mass spectrometer with ionizing electron energy 70 eV. GLC analysis was carried out on a
Chrom-5 chromatograph with flame-ionization detector and glass column (1.2 × 3 mm), packed with 5%
OV-101 on Chromosorb W-HP (80-100 mesh). The carrier gas was nitrogen (60 cm3/min). The analysis
temperature was varied over the range 180-250°C, depending on the composition of the reaction mixture.
Thiophenol (1), 2-mercaptopyridine (2), 2-mercaptoquinoline (3), 2-mercaptopyrimidine (4), 2-mercapto-1-
methylimidazole (5), 2-mercaptobenzoxazole (6), 2-mercaptobenzothiazole (7), and 18-crown-6 (Acros) were
used without additional purification. Propargyl bromide and trimethylchlorosilane were distilled before the
experiment. 3-Mercaptoindole was obtained from indole in the system iodine–KI–NH2CSNH2–H2O, as
described in the literature [30]. Diethyl ether and THF were distilled over sodium and benzophenone.
General Procedure for Obtaining Hetaryl Propargyl Sulfides (8-14, 23). Propargyl bromide (2.7 ml,
30 mmol) were added to a suspension of thiol 1-7, 22 (20 mmol), 18-crown-6 (0.132 g, 0.5 mmol), powdered
K2CO3 (4.14 g, 30 mmol) in toluene (20 ml). The reaction mixture was stirred for 4-10 h at 20°C and then
filtered, and the filtrate was evaporated down on a rotary evaporator. The residue was purified by column
chromatography (eluent hexane–ethyl acetate in different ratios) and compounds 8-14, 23 were obtained (see
Tables 1-3).
General Procedure for Obtaining 3-(Hetarylthio)-1-propynyl(trimethyl)silanes (15-21). 2.5 M
solution of n-BuLi in hexane (4.4 ml, 11 mmol) was added to a solution of hetaryl propargyl sulfide 8-14
(10 mmol) in dry diethyl ether (40 ml) at 0°C, and the reaction mixture was stirred for 3 h at 20°C under a
nitrogen atmosphere. Then trimethylchlorosilane (1.9 ml, 15 mmol) were added, and the reaction mixture was
refluxed for 3 h and then washed with a saturated aqueous solution of ammonium chloride (2 × 30 ml), and the
organic layer was dried with MgSO4; the ether was evaporated off under reduced pressure. The residue was
purified by column chromatography (eluent hexane–ethylacetate in different ratios). As a result, compounds
15-21 were obtained (see Tables 1-3).
Silylation of 3-(2-Propynyl)thioindole (23). 3-(3-Trimethylsilyl-2-propynyl)-thioindole (26), and
3-[1,3-Bis(trimethylsilyl)-2-propynyl]thioindole (27). n-BuLi (4.0 ml, 10 mmol, 2.5 M in hexane) was added
to a solution of compound 23 (1.03 g, 5.5 mmol) in tetrahydrofuran (50 ml) at 0°C, and the reaction mixture was
stirred for 3 h at 20°C under a nitrogen atmosphere. Then trimethylchlorosilane (1.74 ml, 13.6 mmol) were
added and the reaction mixture was refluxed for 3 h, then washed with a saturated aqueous solution of
ammonium chloride (2 × 30 ml); the organic layer was dried with MgSO4, the ether was evaporated off under
reduced pressure. The residue, consisting of compounds 24 and 25 was purified by column chromatography
(eluent hexane–ethylacetate, 10:1). As a result, we obtained compounds 26 (0.25 g, 18% yield) and 27 (0.40 g,
22%) (see Tables 2 and 3).
REFERENCES
1.
2.
E. Abele, K. Rubina, R. Abele, I. Sleiksha, and E. Lukevics, Khim. Geterotsikl. Soedin., 1197 (1999).
F. P. Invidiata, S. Grimaudo, P. Giammanco, and L. Giammanco, Farmco, 46, 1489 (1991); Chem.
Abstr. 116:187514 (1992).
3.
4.
Varvaresou, A. Papadaki-Valiraki, and Th. Siatra-Papastaikoudi, Bioorg. Med. Chem. Lett., 6, 861
(1996).
K. Tomita, K. Chiba, S. Kashimoto, K. Shibamori, and Y. Tsuzuki, PCT Int. Appl. WO Pat. 9534559;
Chem. Abstr. 124:289559 (1996).
871

5.
6.
7.
M. Gielen, A. Bouhdid, E. R. T. Tiekink, D. de Vos, and R. Willem, Metal Based Drugs, 3, 75 (1996).
A. Gangjee, Yu. Zhu, and S. F. Queener, J. Med. Chem., 41, 4533 (1998).
A. P. Krapcho, S. N. Haydar, S. Truong-Chiott, M. P. Hacker, E. Menta, and G. Beggiolin, Bioorg. Med.
Chem. Lett., 10, 305 (2000).
8.
J. P. Dumas, T. K. Joe, H. C. E. Kluender, W. Lee, D. Nagarathnam, R. N. Sibley, N. Su, S. J. Boyer,
and J. A. Dixon, PCT Int. Appl. WO Pat. 0123375; Chem. Abstr. 134:266326 (2001).
Y. Tsuzuki, K. Chiba, and K. Hino, Tetrahedron: Assym., 12, 1793 (2001).
W. O. Foye, S. H. An, and T. J. Maher, J. Pharm. Sci., 73, 1168 (1984).
D. T. Chu, J. J. Plattner, L. Klein, and L. L. Shen, Eur. Pat. 424802; Chem. Abstr. 115:136090 (1991).
Y. Ito, H. Kato, S. Yasuda, N. Yagi, T. Yoshida, and T. Suzuki, Jpn. Pat. 04117388; Chem. Abstr.
117:111597 (1992).
9.
10.
11.
12.
13.
14.
Y. Ito, H. Kato, S. Yasuda, T. Yoshida, Y. Yamamoto, and M. Ueshima, Jpn. Pat. 0570467; Chem.
Abstr. 119:139203 (1993).
Y. Ito, H. Kato, S. Yasuda, T. Yoshida, and Y. Yamamoto, Jpn. Pat. 04356491; Chem. Abstr. 119:95504
(1993).
15.
16.
Y. H. Choi, A. Park, F. J. Schmitz, and I. van Altena, J. Natur. Prod., 56, 1431 (1993).
M. Flores, A. Fracesch, P. Gallego, J. L. Chicharro, M. Zarzuelo, C. Fernandez, and I. Manzanares, PCT
Int. Appl. WO Pat. 0177115; Chem. Abstr. 135:304055 (2001).
17.
18.
K. W. Bair, Canad. Pat. 2012626; Chem. Abstr. 117:26549 (1992).
J. H. Van Maarseveen, P. H. H. Hermkens, E. De Clercq, J. Balzarini, H. W. Scheeren, and C. G. Kruse,
J. Med. Chem., 35, 3223 (1992).
19.
20.
21.
22.
J. J. Bhatt, B. R. Shah, H. P. Shah, P. B. Trivedi, N. K. Undavia, and N. C. Desai, Indian J. Chem., 33B,
189 (1994).
S. Ikeda, U. Kimura, T. Ashizawa, K. Gomi, H. Saito, M. Kasai, J. Kanazawa, K. Sasaki, E. Nukui,
M. Okabe, and S. Sato, US Pat. 5952355; Chem. Abstr. 131:2286546 (1999).
C. Chin, R. L. Tolman, M. Q. Nguyen, and R. Holcomb, PCT Int. Appl. WO Pat. 0102394; Chem. Abstr.
134:86237 (2001).
R. C. Schnur, R. J. Gallaschun, D. H. Singleton, M. Grissom, D. E. Sloan, P. Goodwin, P. A. McNiff,
A. F. J. Fliri, and F. M. Mangano, J. Med. Chem., 34, 1975 (1991).
E.-S. A. Ibrahim, A.-M. M. E. Omar, and M. A. Khalil, J. Pharm. Sci., 69, 1348 (1980).
J. Okada, K. Nakano, H. Miyake, and S. Yasufuku, Chem. Pharm. Bull., 30, 91 (1982).
K. Tsujihara, N. Harada, M. Oohashi, T. Kashida, and K. Oda, Jpn. Pat. 05194517; Chem. Abstr.
120:164209 (1994).
E. Lukevics and L. Ignatovich, Appl. Organometal. Chem., 6, 113 (1992).
K. Rubina, E. Abele, P. Arsenyan, R. Abele, M. Veveris, and E. Lukevics, Metal Based Drugs, 8, 85
(2001).
Kh. Filipova, Yu. L. Frolov, G. S. Liashenko, V. B. Modonov, N. A. Ivanova, I. D. Khalikhman,
M. G. Voronkov, and N. S. Vyazankin, Izv. Akad. Nauk SSSR, Ser. Khim., 1847 (1986).
J. B. Baudin, S. A. Julia, and R. Lorne, Bull. Soc. Chim. France, 440 (1992).
R. L. N. Harris, Org. Synth., 53, 1834 (1973).
23.
24.
25.
26.
27.
28.
29.
30.
872