Syntheses and cytotoxicity evaluation of bis(indolyl)thiazole, bis(indolyl)pyrazinone and bis(indolyl)pyrazine: Analogues of cytotoxic marine bis(indole) alkaloid

Article abstract of DOI:10.1016/S0968-0896(99)00290-4

2,4-Bis(3'-indolyl)thiazoles, 3,5-bis(3'-indolyl)-2(1H)pyrazinone and 3,6-bis(3'-indolyl)pyrazine were synthesized and evaluated for cytotoxic activity against diverse human cancer cell lines by the National Cancer Institute. These compounds demonstrated significant inhibitory effects in the growth of a range of cancer cell lines. 2,4-Bis(3'-indolyl)thiazole displayed selective cytotoxicity against certain leukemia cell lines with GI₅₀ values in the low micromolar range while the substituted derivatives showed a broad spectrum of cytotoxic activity. 3,5-Bis(3'-indolyl)-2(1H)pyrazinone and 3,6- bis[3'-(N-methyl-indolyl)]pyrazine possessed strong inhibitory activity against a wide range of human tumor cell lines. The mechanism of action remained unknown. The results suggested that 2,4-bis(3'-indolyl)thiazoles, 3,5-bis(3'-indolyl)-2(1H)pyrazinone and 3,6-bis[3'-(N-methyl-indolyl)] pyrazine offer potential as lead compounds for the discovery of anticancer agents. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(99)00290-4

Bioorganic & Medicinal Chemistry 8 (2000) 363±371
Syntheses and Cytotoxicity Evaluation of Bis(indolyl)thiazole,
Bis(indolyl)pyrazinone and Bis(indolyl)pyrazine: Analogues of
Cytotoxic Marine Bis(indole) Alkaloid
Biao Jiang* and Xiao-Hui Gu
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P.R. China
Received 28 June 1999; accepted 29 October 1999
AbstractÐ2,4-Bis(30-indolyl)thiazoles, 3,5-bis(30-indolyl)-2(1H)pyrazinone and 3,6-bis(30-indolyl)pyrazine were synthesized and
evaluated for cytotoxic activity against diverse human cancer cell lines by the National Cancer Institute. These compounds
demonstrated signi®cant inhibitory e€ects in the growth of a range of cancer cell lines. 2,4-Bis(30-indolyl)thiazole displayed selective
cytotoxicity against certain leukemia cell lines with GI50 values in the low micromolar range while the substituted derivatives
showed a broad spectrum of cytotoxic activity. 3,5-Bis(30-indolyl)-2(1H)pyrazinone and 3,6-bis[30-(N-methyl-indolyl)]pyrazine
possessed strong inhibitory activity against a wide range of human tumor cell lines. The mechanism of action remained unknown.
The results suggested that 2,4-bis(30-indolyl)thiazoles, 3,5-bis(30-indolyl)-2(1H)pyrazinone and 3,6-bis[30-(N-methyl-indolyl)] pyra-
zine o€er potential as lead compounds for the discovery of anticancer agents. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
ring. When evaluated for cytotoxicity in the NCI's in
vitro disease-oriented antitumor screen, the bis(indo-
le)alkaloids analogues were found to possess signi®cant
cytotoxic activities against human cancer cell lines with
GI50 values in the low micro-molar concentration range.
Cancer remains a major threat to the public health.
Natural products, especially marine natural products,
continue to be an important source of novel bio-active
chemotypes for anticancer drug development. A num-
ber of bis(indole)alkaloids have been isolated from the
marine environment over the past decade, which exhibit
various biological activities including antibacterial,
antiviral and cytotoxic activities.1,2 Nortopsentins A±C,
having a characteristic 2,4-bis(3-indolyl)imidazole skele-
ton, were isolated from the deep-water marine sponge
spongsorites ruetzleri (Fig. 1). Nortopsentins A±C
exhibited in vitro cytotoxicity against P388 cell: IC50(mg/
mL), 7.6, 7.8 and 1.7 respectively.3±6 Due to the inter-
esting biological activities and unique chemical struc-
tures of marine indolealkaloids and its low availability,
marine indolealkaloids as lead compounds for discovery
of new drugs have become an attractive ®eld in medic-
inal chemistry. In our e€ort to search for novel anti-
tumor compounds, we designed and synthesized
bis(indolyl) alkaloids in which the imidazole moiety of
the cytotoxic marine bis(indole) alkaloid nortopsentins
was replaced with a thiazole, pyrazinone or pyrazine
Results and Discussion
A general synthesis of 2,4-bis(30-indolyl)thiazoles is
shown in Scheme 1. Indole-3-carboxaldehydes (1), pre-
pared from the corresponding indole by the Vilsmeier
reaction, were transformed into indole-3-carbonitriles
(2) in good yields by treatment with diammonium
hydrogen phosphate, 1-nitropropane and acetic acid.7
Treatment of indole-3-carbonitrile (2) with H2S in pyri-
dine in the presence of triethylamine yielded indole-3-
carbothioamides (3) in good yields.8,9 3-Acetylindoles
(5) were prepared from N-toluenesulphonylindoles10 by
Friedel±Crafts acylation in excellent yields.11 Bromina-
tion of 5 with copper(II) bromide in re¯uxing CHCl3/
EtOAc12,13 a€orded the a-bromoketones 6 in moderate
yield. The centeral thiazole ring between the indolyl
groups was constructed by reaction of the correspond-
ing thioamide 3 and a-bromoketone 6 in re¯uxing
absolute ethanol for 0.5±1 h. The N-tosylated bis(3-
indolyl)thiazoles deposited from the reaction solution.
After ®ltration, the products were obtained in excellent
yields. Deprotection of the toluenesulfonyl group with
Keywords: alkaloiods; antitumor compounds; cytotoxins; substituent
e€ects.
*Corresponding author. Tel.: +86-21-6416-3300; fax: +86-21-6416-
6128; e-mail: jiangb@pub.sioc.ac.cn
0968-0896/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(99)00290-4

364
B. Jiang, X.-H. Gu / Bioorg. Med. Chem. 8 (2000) 363±371
antitumor screen14±16 against approximately a panel of
60 human tumor cell lines derived from leukemia, non-
small-cell lung cancer, colon cancer, CNS cancer, mela-
noma, ovarian cancer, renal cancer, prostate cancer and
breast cancer. The results are shown in Table 1 as GI50
values. All compounds exhibited cytotoxic activities
against a variety of human cancer cell lines. The com-
pound 7 selectively exhibited in vitro cytotoxicities
against leukemia and ovarian cancer cell lines, a€ording
GI50 of 3.27 mM in K562, 5.31 mM in Molt-4 and
8.14 mM in IGROV1 assay. In the other human tumor
cell line assay, the GI50 of compound 7 exceeded 100
mM. To test the possibility that substitutes in the indole
ring might result in a potency increase, most of the 2,4-
bis(3-substituted-indolyl)thiazoles showed broad e€ects
on tumor cell lines from the leukemia, colon cancer,
CNS cancer and breast cancer panels while unsub-
stituted counterpart 7 brought out highly selective
activity against leukemia cell lines and IGROV1 ovarian
cancer cell lines. The position of bromine in the indole
ring plays an important role in cytotoxicity. Dibromi-
nated compound 16 e€ectively exhibited MCF 7 of
breast cancer, a€ording the GI50 of 0.888 mM. The
compound 17, masked the NH in indolyl ring with
methyl group, resulted in decreased activity against leu-
kemia cell lines. Changing one indolyl ring for pyridinyl
ring, 20 has detrimental e€ect on activities against
certain colon cancer, ovarian cancer, prostate cancer,
Figure 1.
NaOH in re¯uxing methanol a€orded the 2,4-bis(3-
indolyl)thiazoles 7±16.
2,4-Bis[30-(N-methylindolyl)]thiazole (17) was synthe-
sized from 7 in 83% yield by reaction with an excess of
iodomethane in acetone in the presence of anhydrous
potassium carbonate. 2-(20-Pyridinyl)-4-[30-(50-bromo-
noindolyl)] thiazole 20 was synthesized as shown in
Scheme 2. Commercially available 2-cyanopyridine (18)
was converted to 2-thioamide (19) with H2S and tri-
ethylamine in methanol. Carbothioamide (19) was con-
densed with 3-(a-bromoacetyl)-5-bromo-indole 6b in
re¯uxing ethanol and subsequent N-detosylation with
NaOH, 20 was obtained in 86% yield (Scheme 2).
The prepared indolylthiazole compounds were evaluated
for cytotoxicity in the NCI's in vitro disease-oriented
Scheme 1. Conditions and reagents: (a) (NH4)2HPO4, CH3CH2CH2NO2, HOAc, re¯ux; (b) H2S, Et3N; (c) Ac2O, AlCl3, CH2Cl2, 0 ꢀC-rt; (d) CuBr2,
CHCl3±EtOAc (1:1), re¯ux; (e) EtOH, re¯ux; (f) NaOH, MeOH, re¯ux.

B. Jiang, X.-H. Gu / Bioorg. Med. Chem. 8 (2000) 363±371
365
Scheme 2.
Table 1. Inhibition of in vitro tumor cell growth by prepared indolyl thiazoles
Cell line
Cytotoxicity (GI50 in mM)a
7
8
9
10
11
12
13
14
15
16
17
20
Leukemia
CCRF-CEM
HL-60(TB)
K-562
MOLT-4
RPMI8226
NDb
ND
3.27
5.31
ND
14.6
ND
18.8
19.9
19.4
10.9
ND
5.61
31.2
12.2
10.1
0.95
4.69
5.80
11.4
2.11
2.43
1.96
1.41
1.97
2.40
2.76
1.94
1.75
1.95
27.7
ND
15.2
23.0
27.1
2.58
3.76
2.13
1.55
2.24
2.66
4.13
1.74
2.95
2.03
2.99
3.86
2.15
2.26
1.84
>100
>100
11.2
14.1
20.8
5.35
1.96
2.98
3.56
5.04
Non-small cell lung cancer
NCI-226
NCIH322M
NCI-H460
EKVX
>100
>100
>100
>100
14.4
16.7
16.1
15.6
24.4
18.9
7.31
29.5
3.3
18.4
16.4
28.6
2.10
2.01
2.55
ND
3.14
1.99
1.93
ND
45.4
70.8
23.2
32.1
2.48
2.51
2.31
0.48
2.24
3.09
1.58
0.29
7.23
2.99
2.00
0.55
32.2
24.5
26.5
ND
8.91
13.0
4.05
3.99
Colon cancer
HCT-15
SW-620
>100
>100
15.2
16.5
17.8
25.6
8.50
12.5
1.81
1.52
2.51
2.14
7.54
7.00
2.70
3.57
0.81
5.50
2.84
2.89
>100
59.4
8.05
14.6
CNS cancer
SF-295
SF-268
SNB-19
U21
33.6
ND
>100
>100
14.6
18.3
17.8
17.9
9.23
32.1
41.87
28.1
4.81
1.98
1.52
2.11
2.10
2.71
2.44
3.75
2.30
73.5
26.0
>100
25.0
4.56
2.69
2.60
3.34
ND
13.8
10.5
5.07
ND
1.80
3.34
3.00
23.5
58.2
42.6
32.4
2.57
13.7
4.03
10.4
ND
17.2
15.3
Ovarian cancer
IGROV1
OVCAR-5
8.14
>100
13.0
16.1
30.5
37.1
14.4
23.6
1.85
1.96
1.70
2.14
81.5
42.7
2.96
2.16
4.61
3.44
2.43
2.35
27.0
95.9
19.9
26.1
Renal cancer
786-0
A498
>100
>100
ND
18.0
17.0
22.4
19.9
25.7
7.62
15.9
23.2
18.4
2.28
1.92
1.81
1.95
2.48
1.69
27.4
89.4
11.9
1.50
2.19
2.42
3.89
7.43
2.03
2.21
2.40
1.66
17.2
12.6
14.1
6.04
3.99
2.31
RXF 393
Prostate cancer
PC-3
DU-145
>100
>100
15.6
18.8
16.9
14.9
15.3
18.4
2.02
2.29
2.57
2.61
10.4
>100
4.16
3.74
3.49
5.46
2.81
2.03
21.9
42.9
8.53
14.1
Breast cancer
MCF7
MDAMB435
MDA-N
T-47D
>100
33.1
83.0
>100
>100
16.7
14.9
19.2
24.8
18.3
27.2
25.6
31.5
23.9
73.8
6.46
4.34
2.94
16.2
41.1
2.13
2.53
1.88
3.27
2.71
2.70
2.27
2.09
2.90
10.6
54.1
7.70
8.27
59.3
67.3
0.88
4.54
2.86
3.33
1.24
4.36
14.6
6.84
4.12
1.46
3.82
3.97
3.77
1.76
1.41
45.5
26.4
24.9
28.1
56.3
10.3
46.3
23.7
5.54
>100
BT-549
Melanoma
LOX IWVI
MALME-3M
M14
SK-MEL-2
SK-MEL-28
SK-MEL-5
21.8
15.5
16.9
14.2
ND
14.2
14.9
6.55
>100
32.4
37.5
7.74
11.3
ND
10.6
68.8
32.0
28.5
1.97
1.28
1.61
1.81
3.02
1.76
1.69
1.72
1.63
1.98
3.05
1.63
64.1
17.5
>100
19.1
>100
>100
2.32
1.45
2.86
3.25
9.84
2.82
2.41
1.50
5.49
7.30
1.36
5.13
1.87
2.83
2.77
2.91
4.96
3.36
36.4
19.0
26.7
38.8
61.5
26.9
5.52
19.1
13.5
21.7
64.2
12.9
>100
>100
>100
>100
ND
23.7
aData obtained from NCI's in vitro disease-oriented tumor cells screen.
bNot determined.

366
B. Jiang, X.-H. Gu / Bioorg. Med. Chem. 8 (2000) 363±371
melanoma and breast cancer cell lines, but it has little
e€ect on activities against certain leukemia, and renal
cancer cell lines.
treatment with sodium azide in re¯uxing aqueous ace-
tone23 a€orded the azidoketone 22 in 34% overall yield.
a-Azidoketone 22 was hydrogenated over 10%Pd/C in
methanol containing a few drops of glacial acetic acid at
room temperature for 24 h to o€er 3,5-bisindolyl pyra-
zine 23 in 74% yield.24 Attempting to synthesize 23 by
treatment of a-azidoketone 22 with triphenylphosphine
or tributylphosphine25 resulted in recovery of the start-
ing material.
Compound 7 was then evaluated in a hollow ®ber cell
assay,17 recently developed at the National Cancer
Institute, wherein tumor cells are cultivated in hollow
®bers through encapsulation/implantation technology.
This assay is intended to provide a preliminary indica-
tion of the potential for compounds to exhibit in vivo
antineoplastic activity in xenograft models. The cell
lines used in the assay were LOX, UACC-62, MDA-
MB-435, MDA-MB-231, COLO205, SW620, SF-295,
U251, OVCAR-3, OVCAR-5, NCI-H23 and NCI-
H522. The test doses were 150 and 100 mg/kg/ingestion
given IP once daily for 4 days. The results suggested
that compound 7 was inactive in vivo.
Azidoketone 22 was hydrogenated over 10% Pd/C in
methanol containing concentration hydrochloric acid to
a€ord 3-(a-aminoacetyl)indole hydrochloride salt 26.
Reaction of 26 with 3-indolylglyoxylic chloride 2526 in
CH2Cl2 and Et3N yielded compound 27 in 67% yield.
In accordance with reported methods applying for
synthesis of the central pyrazinone ring, such as,
treatment of 27 with ammonium acetate in re¯uxing
ethanol,27 or in re¯uxing acetic acid9 failed to give com-
pound 28. Tried to search other synthetic process, ®nally,
central pyrazinone ring was successfully constructed by
treatment of 27 in excess of ammonia at 60±80 ꢀC under
50 psi pressure for three days. The desired product 28 was
obtained in the form of a brown solid in 62% yield.
Nortopsentins have a structure of ®ve-member ring of
imidazole attached by two indolyl groups. The thiazole
analogues of nortopsentin prepared above, also showed
the cytotoxic activities. Several pyrazine compounds has
been proved to be potent antitumor agents.18,19 In the
family of marine bisindole alokoilds, antitumor active
dragmacidin d isolated from spongosorites sp. has a
chemical structure of a central six-membered ring of
pyrazinone linked with two indolyl groups and show
antiviral activities.20,21 We planned to synthesize the
pyrazine and pyrazinone analogues bearing bisindole.
Thus, 3,6-bis(30-indolyl)pyrazine and 3,5-bis(30-indolyl)-
2(1H)pyrazinone were designed and synthesized as shown
in Scheme 3. Reaction of indole with chloroacetyl
chloride in toluene containing pyridine,22 followed by
As shown in Table 2, in spite of the fact that compound
23 showed weakness of cytotoxicity, its N-methylated
derivative 24 possessed very strong inhibitory activity
against all cell lines with GI50 values below 10 mM. The
GI50 values of 24 were respectively 0.72, 0.248, 0.058,
0.287, and 0.29 mM against NCI-H322M lung, HCT-15
and KM12 colon, SK-MEL-5 melanoma, and MCF 7
Scheme 3. Reagents and conditions: (a) (ClCH2COCl, pyridine, toluene, 60 ꢀC, 36%; (b) NaN3, acetone/H2O, re¯ux, 98%; (c) H2, 5%Pd/C, EtOH,
AcOH (trace) rt; (d) (COCl)2, CH2Cl2 rt; (e) H2, 10% Pd/C, MeOH, 35%HCl, 87%; (f) Et3N, CH2Cl2, rt, 67%; (g) liq. NH3, MeOH, 60±80 ꢀC, 62%.

B. Jiang, X.-H. Gu / Bioorg. Med. Chem. 8 (2000) 363±371
367
Table 2. Inhibition of tumor cell growth in vitro by compound 23, 24
and 28 (GI50 in mM)a,b
internal standard. J values were given in Hz. Infrared
spectra were taken on a Shimadzu IR-440 spectrometer.
Mass spectra (MS) and high-resolution mass spectra
(HRMS) were run respectively on a Finnigan 4021 GC
MS/DC and Varian MAT 21 instrument with an ionis-
ing voltage of 70eV.
Cells/compounds
23
28
24
Leukemia
K-562
SR
2.97
3.99
18.8
30.0
7.19
3.14
Non-small cell lung cancer
NCI-H522
NCI-H322M
General procedure for synthesis of indole-3-carbonitrile
(2). A mixture of indole-3-carbaldehyde (10 mmol),
diammonium hydrogen phosphate (7.0 g, 53 mmol),
1-nitropropane (30 mL, 340 mmol) and acetic acid (10
mL) was re¯uxed for 16 h. The reaction mixture was
turned to dark red from pale-yellow. The solvent was
removed under reduced pressure, and water (200 mL)
was added to the dark residue. After a short time, crude
indole-3-carbonitrile precipitated rapidly. The solid was
®ltered and recrystallized from acetone±hexane to yield
fairly pure indole-3-carbonitrile (2).
6.79
15.5
28.5
41.7
1.94
0.72
Colon cancer
HCT-15
KM 12
11.1
4.96
4.90
58.6
74.2
18.9
0.248
0.058
2.07
SW-620
CNS cancer
SF-295
SF-539
4.53
8.62
20.2
23.5
1.87
NDc
Melanoma
SK-MEL-5
Ovarian cancer
IGROV1
13.4
50.1
0.287
12.93
6.57
30.9
>100
5.66
2.81
Indole-3-carbonitrile (2a). Yield 68%; mp 178.8±
179.4 ꢀC; UV (95%EtOH) lmax 217, 270, 278, 285 nm;
IR (KBr) nmax 3224 (NH), 2228 (CꢁN) cm 1; 1H NMR
(DMSO-d6) d 8.32 (s, 1H), 7.91 (m, 1H), 7.83 (m, 1H),
7.56±7.47 (m, 2H); MS (EI) m/z 142 (M+).
OVCAR-4
Renal cancer
RXF 393
CAKI-1
2.73
3.28
26.7
74.8
2.17
5.77
Breast cancer
MCF7
MDA-MB-435
MDA-N
10.2
3.29
2.47
6.60
25.0
19.1
0.29
1.16
1.21
5-Bromoindole-3-carbonitrile (2b). Yield 67%; mp 191.1±
191.7 ꢀC; UV (MeOH) lmax 218, 234, 278 nm; IR (KBr)
1
nmax 3289 (NH), 2218 (CꢁN) cm 1; H NMR (DMSO-
aData obtained from NCI's in vitro disease-oriented tumor cells
screen.
bGI50 is the molar concentration causing 50% growth inhibition of
tumor cells. Compounds with GI50>100 mM are considered inactive.
cND=not determined.
d6) d 12.39 (br, 1H), 8.31 (d, J=1.9 Hz, 1H), 7.79 (d,
J=2.5 Hz, 1H), 7.48 (d, J=8.6 Hz, 1H), 7.41 (dd,
J=1.8 and 8.6 Hz, 1H); MS (EI) m/z 222/220 (M+).
6-Bromoindole-3-carbonitrile (2c). Yield 81%; mp 186.2±
1
186.5 ꢀC; IR (KBr) nmax 3255 (NH), 2221 (CꢁN) cm
;
breast cancer cell line. Compound 28 demonstrated
strong inhibitory e€ects against a variety of tumor cell
lines, including leukemia, non-small cell lung cancer,
colon cancer, CNS cancer, ovarian cancer, renal cancer,
and breast cancer cell lines with GI50 values between 1
and 10 mM, but it displayed inhibitory e€ects weaker
than that of melanoma cell lines.
1H NMR (DMSO-d6) d 12.31 (br, 1H), 8.28 (s, 1H),
7.75 (m, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.36 (dd, J=1.7
and 8.5 Hz, 1H); MS (EI) m/z 222/220 (M+).
6-Methoxyindole-3-carbonitrile (2d). Yield 72%; mp
173.6±174.2 ꢀC dec; UV (MeOH) lmax 220, 270, 290 nm;
IR (KBr) nmax 3256 (NH), 2837, 2223 (CN) cm 1; H
1
NMR (DMSO-d6) d 11.98 (br, 1H, NH), 8.10 (d, J=2.6
Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.03 (d, J=2.3 Hz,
1H), 6.89 (dd, J=2.3 and 8.7 Hz, 1H), 3.80 (s, 3H,
OCH3); MS (EI) m/z 172 (M+).
COMPARE computations28 were performed on the
NCI screening data for all of the synthesized bis(indole)
alkaloid compounds, and all were negative (Pearson
correlation coecients<0.6) against the NCI ``Standard
Agent'' database. This suggested that these compounds
probably act a mechanism di€erentiating those of the
Standard Agents.
General procedure for synthesis of indole-3-thioamide
(3). H2S gas was bubbled into a mixture of indole-3-
carbonitrile 2 (10 mmol), pyridine (20 mL) and tri-
ethylamine (2 mL, 14 mmol) for 1 h. The resultant
reaction mixture was sealed and stirred for two days at
room temperature. The mixture was poured onto ice-
cooled water (100 mL). The orange±yellow precipitate
was collected by ®ltration, washed with water and dried
under reduce pressure to a€ord 3.
In conclusion, we have synthesized a series of novel 2,4-
bis(30-indolyl)thiazoles, 3,6-bis(30-indolyl)pyrazine and
3,5-bis(30-indolyl)-2(1H)pyrazinone. The compounds
demonstrated powerful inhibitory e€ects in vitro in the
growth of a wide variety of human tumor cell lines and
would promise as lead compounds for further develop-
ment of indole alkaloid anticancer agents.
Indole-3-carbothioamide (3a). Yield 68%; mp 148.6±
152.2 ꢀC; UV (MeOH) lmax 212, 252, 276, 324 nm; IR
(KBr) nmax 3386, 3276, 3180, 1623, 1529, 1442, 1365,
1133 cm 1; 1H NMR (DMSO-d6) d 11.79 (br, 1H), 8.96
(br, 1H), 8.82 (br, 1H,), 8.62 (m, 1H), 8.09 (d, J=2.9
Hz, 1H), 7.43 (m, 1H), 7.15 (m, 2H); MS (EI) m/z 176
(M+).
Experimental
1
Mp was uncorrected. H NMR spectra were recorded
on a Bruker AM-300 spectrometer with Me4Si as an

368
B. Jiang, X.-H. Gu / Bioorg. Med. Chem. 8 (2000) 363±371
5-Bromoindole-3-carbothioamide (3b). Yield 58%; mp
240.8±241.2 ꢀC; UV (MeOH) lmax 218, 234, 278 nm. IR
(KBr) nmax 3381, 3190, 1623, 1525, 1435, 1295, 1191,
1117 cm 1; 1H NMR (DMSO-d6) d 11.95 (br, 1H), 9.01
(br, 1H), 8.94±8.90 (m, 2H), 8.14 (d, J=2.1 Hz, 1H),
7.42 (d, J=8.6 Hz, 1H), 7.3 (dd, J=2.0 and 8.6 Hz); MS
(EI) m/z 254/256 (M+).
IR (KBr) nmax 1671, 1595, 1537, 1437, 1380, 1294, 1191
cm 1; 1H NMR (CDCl3) d 8.49 (d, J=1.9 Hz, 1H), 8.18
(s, 1H), 7.81 (d, J=8.3 Hz, 2H), 7.79 (d, J=8.7 Hz,
1H), 7.46 (dd, J=1.9 and 8.8 Hz, 1H), 7.29 (d, J=8.3
Hz, 2H), 2.55 (s, 3H), 2.37 (s, 3H); MS (EI) m/z 392/390
(M+).
3-Acetyl-6-bromo-N-(toluenesulfonyl)indole (5c). Yield
85%; mp 166.0±166.9 ꢀC; UV (MeOH) lmax 210, 276
nm; IR (KBr) nmax 1674, 1598, 1536, 1477, 1378, 1361,
6-Bromoindole-3-carbothioamide (3c). Yield 58%; mp
193.2±193.6 ꢀC dec; IR (KBr) nmax 3348, 3176, 1627,
1
1
1447, 1408, 1365, 1204, 1147 cm 1; H NMR (DMSO-
1196, 1183 cm 1; H NMR (CDCl3) d 8.20 (d, J=8.5
d6) d 11.87 (br, 1H), 9.05 (brs, 1H), 8.92 (br, 1H), 8.61
(d, J=8.7 Hz, 1H), 8.10 (d, J=2.3 Hz, 1H), 7.64 (d,
J=1.5 Hz, 1H), 7.28 (dd, J=8.7 and 1.5 Hz, 1H); MS
(EI) m/z 256/254 (M+).
Hz, 1H), 8.16 (s, 1H), 8.11 (d, J=1.6 Hz, 1H), 7.84 (d,
J=8.5 Hz, 2H), 7.45 (dd, J=1.6 and 8.6 Hz, 1H), 7.33
(d, J=8.3 Hz, 2H), 2.56 (s, 3H), 2.40 (s, 3H); MS (EI)
m/z 393/391 (M+).
6-Methoxyindole-3-carbothioamide (3d). Yield 72%; mp
240 ꢀC dec; UV (MeOH) nmax, 220, 270, 290 nm; IR
(KBr) nmax 3256 (NH), 3200, 2837, 1630, 1510, 1435,
1133 cm 1; 1H NMR (DMSO-d6) d 11.18 (br, 1H), 9.01
(br, 2H), 8.08 (d, J=2.6 Hz, 1H), 7.49 (d, J=8.6 Hz,
1H), 7.23 (d, J=2.3 Hz, 1H), 7.01 (dd, J=2.3 and 8.7
Hz, 1H), 3.80 (s, 3H, OCH3); MS (EI) m/z 172 (M+).
3-Acetyl-6-methoxy-N-(toluenesulfonyl)indole (5d). Yield
87%; mp 128.2±128.9 ꢀC; UV (MeOH) lmax 230 nm; IR
(KBr) nmax 1668, 1615, 1492, 1382, 1279, 1249, 1168
cm 1; 1H NMR (CDCl3) d 8.18 (d, J=8.8 Hz, 1H), 8.10
(s, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.43 (d, J=2.3 Hz,
1H), 7.28 (d, J=8.8 Hz, 2H), 6.95 (dd, J=2.3 and 8.8
Hz, 1H), 3.87 (s, 3H), 2.54 (s, 3H), 2.37 (s, 3H); MS (EI)
m/z 343 (M+).
Pyridinyl-2-thioamide (19). Compound 19 was prepared
in same procedure as 3 in yield 69%; mp 137.2±
General procedure for synthesis of N-(toluenesulfonyl)-3-
(2-bromoacetyl) indole (6). To a suspension solution of
copper (II) bromide (1.92 g, 8.57 mmol) in ethyl acetate
(25 ml) was added a solution of 3-acetyl-N-(toluene-
sulfonyl)indoles (7 mmol) in chloroform (25 mL). The
mixture was re¯uxed with vigorous stirring for 10 h.
When the reaction was cooled to room temperature, the
solid was ®ltered. After removal of solvent under
reduced pressure, the crude product was puri®ed by
column chromatography to give (6).
137.4 ꢀC; IR (KBr) nmax 3349, 3149, 1602, 1581, 1441,
1275, 1146 cm
1
;
1H NMR (DMSO-d6) d 10.16 (br,
1H), 9.92 (br, 1H), 8.61 (m, 1H), 8.53 (m, 1H), 7.98 (m,
1H), 7.60 (m, 1H); MS (EI) m/z 138 (M+).
General procedure for synthesis of 3-acetyl-N-(toluene-
sulfonyl) indoles (5a±d). To a solution of indole
(80 mmol) in toluene (80 mL) was added Bu4NHSO4
(1.88 g, 5.55 mmol), 50% aqueous KOH (100 mL) and
p-CH3C6H4SO2Cl (20.4 g in 200 mL toluene) and the
mixture stirred at ambient temperature for 3 h. The
organic layer was separated, washed with H2O, dried
over Na2SO4, concentrated under reduced pressure, and
the crude product was crystallized form 95% ethanol.
N-(Toluenesulfonyl)-3-(2-bromoacetyl)indole (6a). Yield
55%; mp 126.6±127.4 ꢀC; UV (MeOH) lmax 206, 234,
294 nm; IR (KBr) nmax 1669, 1535, 1479, 1446, 1390,
1337, 1294, 1191 cm 1; 1H NMR (CDCl3) d 8.35 (s, 1H),
8.31 (m, 1H), 7.96±7.93 (m, 1H), 7.86 (d, J=8.4 Hz, 2H),
7.44±7.34 (m, 2H), 7.31 (d, J=8.3 Hz, 2H), 4.36 (s, 2H,
CH2Br), 2.38 (s, 3H, CH3); MS (EI) m/z 393/391 (M+).
To a suspension solution of AlCl3 (20.5 g, 154 mmol) in
CH2Cl2 (300 mL) was added acetic anhydride (8.0 mL,
85 mmol) at ambient temperature for 30 min. A solu-
tion of N-(toluenesulfonyl) indole (6.8 g, 25 mmol) in
CH2Cl2 (40 mL) was added dropwise. The mixture was
stirred at ambient temperature for 16 h and poured into
ice (200 g). The aqueous layer was extracted with
CH2Cl2. The organic extracts were washed with satu-
rated NaHCO3, brine and dried over Na2SO4. After
removal of the solvent, the crude product was recrys-
tallized with MeOH to give pure 3-acetyl-N-(toluene-
sulfonyl)indole 5.
N-Toluenesulphonyl-5-bromo-3-(2-bromoacetyl)indole
(6b). Yield 56%; mp 164±164 ꢀC; UV (MeOH) lmax
214, 292 nm; IR (KBr) nmax 1691, 1593, 1493, 1391,
1
1294, 1193 cm 1; H NMR (CDCl3) d 8.45 (d, J=2.0
Hz, 1H), 8.33 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.80 (d,
J=8.7 Hz, 1H), 7.48 (dd, J=2.0 and 8.8 Hz, 1H), 7.30
(d, J=8.3 Hz, 2H), 4.32 (s, 2H), 2.38 (s, 3H); MS (EI)
m/z 473/469 (M+).
N-Toluenesulphonyl-6-bromo-3-(2-bromoacetyl)indole
(6c). Yield 63%; mp 159±160 ꢀC. UV (MeOH) lmax
240, 290 nm; IR (KBr) nmax 1687, 1537, 1378, 1292,
3-Acetyl-N-(toluenesulfonyl)indole (5a). Yield 94%; mp
148.1±150.3 ꢀC; UV (MeOH) nmax 206, 2588 nm; IR
(KBr) nmax 1670, 1595, 1540, 1478, 1445, 1381, 1192
1
1188 cm 1; H NMR (CDCl3) d 8.31 (s, 1H), 8.17 (d,
1
cm 1; H NMR (CDCl3) d 8.33 (m, 1H), 8.22 (s, 1H),
J=8.5 Hz, 1H), 8.13 (d, J=1.6 Hz, 1H), 7.86 (d, J=8.5
Hz, 2H), 7.50 (m, 1H), 7.40±7.34 (m, 3H), 4.36 (s, 2H,
CH2Br), 2.41 (s, 3H, CH3); MS (EI) m/z 473/469 (M+).
7.95±7.83 (m, 3H), 7.38±7.32 (m, 4H), 2.58 (s, 3H), 2.38
(s, 3H); MS (EI) m/z 313 (M+).
3-Acetyl-5-bromo-N-(toluenesulfonyl)indole (5b). Yield
91%; mp 166.8±167.3 ꢀC; UV (MeOH) lmax, 216, 276 nm;
N-Toluenesulphonyl-6-methoxy-3-(2-bromoacetyl)indole
(6d). Yield 58%; mp 156.4±156.8 ꢀC; UV (MeOH) lmax

B. Jiang, X.-H. Gu / Bioorg. Med. Chem. 8 (2000) 363±371
369
236 nm; IR (KBr) nmax 1688, 1540, 1390, 1292, 1190
(br, 1H, NH), 11.55 (br, 1H, NH), 8.31 (d, J=8.5 Hz,
1H), 8.18 (m, 2H), 8.03 (s, 1H), 7.68 (m, 25H), 7.40±7.27
(m, 3H); 13C NMR (DMSO-d6) d 162.40, 150.94,
138.43, 134.55, 130.27, 128.64, 128.41, 126.73, 124.64,
124.37, 123.52, 123.23, 122.93, 116.02, 115.72, 115.41,
112.39, 111.85, 107.91; MS (EI) m/z 475/471 (M+);
HRMS calcd. for C19H11Br2N3S 470.9041, found
470.9052.
1
cm 1; H NMR (DMSO-d6) d 8.68 (s, 1H), 8.09±7.97
(m, 3H), 7.49±7.39 (m, 3H), 7.00 (m, 1H), 4.67 (s, 2H),
3.84 (s, 3H), 2.34 (s, 3H); MS (EI) m/z 423/421 (M+).
General procedure for preparation of 2,4-bis(30-indolyl)-
thiazoles (7±16). A suspension of the indole-3-thio-
amide 3 (5 mmol) and 3-(2-bromoacetyl)-N-(toluene-
sulphonyl) indole 6 (5 mmol) in absolute ethanol (25 mL)
was re¯uxed at 80±90 ꢀC for about 30 min. A precipitate
deposited from the reaction mixture. The solid was ®l-
tered and treated with 10% sodium hydroxide in
methanol. The resulting mixture was re¯uxed for 3 h.
After removal of solvent, the mixture was extracted with
ether and washing with water and dried over Na2SO4.
After evaporation of the solvent, the residue was pur-
i®ed by ¯ash chromatography to a€ord corresponding
2,4-bis(30-indolyl)thiazole.
2-(30-Indolyl)-4-[30-(50-bromoindolyl)]thiazole (11). Yield
84%, mp 213.2±214.4 ꢀC (dec.); UV (MeOH) lmax 220,
1
266 nm; H NMR (DMSO-d6) d 11.73 (br, 1H, NH),
11.60 (br, 1H, NH), 8.52 (d, J=1.7 Hz, 1H), 8.41 (m,
1H), 8.13 (d, J=2.3 Hz, 1H), 8.05 (d, J=1.9 Hz, 1H),
7.65 (s, 1H), 7.53 (m, 1H), 7.50 (d, J=8.4 Hz, 1H),
7.33±7.23 (m, 2H); MS (EI) m/z 394/392 (M+).
2,4-Bis[30-(50-bromoindolyl)]thiazole (12). Yield 72%; mp
238.7±239.5 ꢀC; UV (MeOH) lmax 218, 266 nm; 1H
NMR (DMSO-d6) d 11.85 (br, 1H, NH), 11.57 (br,
1H, NH), 8.57 (d, J=1.9 Hz, 1H), 8.48 (d, J=1.8 Hz,
1H), 8.35 (d, J=2.4 Hz, 1H), 8.02 (d, J=1.9 Hz, 1H),
7.67 (s, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.47 (d, J=8.6
Hz, 1H), 7.38 (dd, J=1.9 and 8.6 Hz, 1H), 7.31 (dd,
J=1.91 and 8.6 Hz, 1H); MS (EI) m/z 475/471 (M+);
HRMS calcd. for C19H11Br2N3S 470.9040, found
470.9036.
2,4-Bis(30-indolyl)thiazole (7). Yield 88%; mp 289.2±
289.8 ꢀC; UV (95%EtOH) lmax 226, 274 nm; IR (KBr)
nmax 3388, 3123 (NH), 1675, 1616, 1575, 1475, 1427,
1
1333, 1259, 1097 cm 1; H NMR (DMSO-d6) d 11.74
(br, 1H, NH), 11.39 (br, 1H, NH), 8.37 (m, 1H), 8.22
(m, 1H), 8.14 (m, 1H), 7.6 (m, 1H), 7.53±7.47 (m, 2H),
7.26±7.16 (m, 4H); 13C NMR (DMSO-d6) d 161.76,
150.54, 136.65, 136.5, 126.39, 126.22, 124.66, 124.39,
122.36, 121.55, 120.71, 120.45, 120.18, 119.7, 112.16,
111.35, 110.84, 105.95; MS (EI) m/z 315 (M+); HRMS
calcd. for C19H13N3S 315.0831, found 315.0829.
2-[30-(60-Bromoindolyl)]-4-[30-(60-methoxylindoly)]thiazole
(13). Yield 73%; mp 275.8±276.7 ꢀC (dec.); UV (MeOH)
lmax 228, 282 nm; IR (KBr) nmax 3401, 3120, 1629,
2(30-Indolyl)-4-[30-(60-bromoindolyl)]thiazole (8). Yield
82%; mp 256.7±257.4 ꢀC; UV (95% EtOH) lmax 210,
260 nm; IR (KBr) nmax 3442, 3215, 1617, 1578, 1474,
1232, 1134 cm 1; 1H NMR (DMSO-d6) d 11.78 (br, 1H,
NH), 11.56 (br, 1H, NH), 8.35 (m, 1H), 8.21 (d, J=8.6
Hz, 1H), 8.16 (d, J=2.5 Hz, 1H), 8.03 (d, J=2.1 Hz,
1H), 7.67 (d, J=1.6 Hz, 1H), 7.65 (s, 1H), 7.52 (m, 1H),
7.37 (s, 1H), 7.31 (d, J=1.8 Hz, 1H), 7.28±7.22 (m, 2H);
13C NMR (DMSO-d6) d 162.06, 149.78, 137.51, 136.63,
126.57, 125.73, 124.90, 124.52, 122.42, 122.03, 120.79,
120.38, 114.46, 114.33, 112.24, 111.47, 110.66, 106.63;
MS (EI) m/z 395/393 (M+); HRMS calcd. for
C19H12BrN3S 393.9837, found 393.9799.
1567, 1503, 1450, 1404, 1330, 1248, 1158 cm
;
1H
1
NMR (DMSO-d6) d 11.84 (br, 1H, NH), 11.18 (br, 1H,
NH), 8.33 (d, J=8.7 Hz, 1H), 8.16 (d, J=2.1 Hz, 1H),
8.06 (d, J=8.7 Hz, 1H), 7.79 (d, J=1.5 Hz, 1H), 7.72
(d, J=1.51 Hz, 1H), 7.56 (s, 1H), 7.39 (dd, J=1.8 and
8.5 Hz, 1H), 6.99 (d, J=2.2 Hz, 1H), 6.83 (dd, J=2.3
and 8.7 Hz, 1H), 3.82 (s, 3H); 13C NMR (DMSO-d6) d
161.09, 155.69, 150.69, 137.44, 137.27, 127.22, 127.05,
123.56, 123.34, 122.23, 120.67, 119.04, 115.00, 114.71,
111.21, 110.99, 106.01, 94.87, 55.16; MS (EI) m/z 425/
423 (M+); HRMS calcd. for C20H14BrN3OS 423.0219,
found 423.0206.
2-[30-(60-Bromoindolyl)]-4-[30-(50-bromoindolyl)]thiazole
(14). Yield 75%; mp 253.4±235.9 ꢀC (dec.); UV
(MeOH) lmax 218, 268 nm; 1H NMR (DMSO-d6) d
11.80 (br, 1H, NH), 11.57 (br, 1H, NH), 8.47 (d, J=1.4
Hz, 1H), 8.35 (d, J=8.5 Hz, 1H), 8.15 (d, J=2.1 Hz,
1H), 8.04 (d, J=1.8 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H),
7.66 (s, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.37 (dd, J=1.7
and 8.5 Hz, 1H), 7.32 (dd, J=1.8 and 8.6 Hz, 1H); 13C
NMR (DMSO-d6) d 164.44, 149.94, 137.45, 135.24,
127.33, 126.53, 126.06, 125.88, 124.00, 123.44, 123.38,
122.58, 122.17, 115.03, 114.78, 113.82, 112.39, 110.91,
110.86; MS (EI) m/z 475/471 (M+); HRMS calcd. for
C19H11Br2N3S 474.8999, found 474.8964.
2-[30-(60-Bromoindolyl)]-4-(30-indolyl)thiazole (9). Yield
76%; mp 261.0±262.3 ꢀC (dec.); UV (95%EtOH) lmax
228, 280 nm; IR (KBr) nmax 3390, 3122 (NH), 1670,
1544, 1456, 1423, 1333, 1292, 1235, 1147, 1021 cm 1; 1H
NMR (DMSO-d6) d 11.87 (br, 1H, NH), 11.42 (br, 1H,
NH), 8.34 (d, J=8.56 Hz, 1H), 8.21±8.17 (m, 2H), 8.00
(s, 1H), 7.7 (s, 1H), 7.63 (s, 1H), 7.48 (m, 1H), 7.39 (dd,
1H), 7.20±7.16 (m, 2H); 13C NMR (DMSO-d6) d 161.11,
150.59, 137.41, 136.62, 127.23, 124.81, 124.64, 123.53,
122.24, 121.48, 120.03, 119.65, 114.97, 114.67, 111.82,
111.19, 110.95, 106.22; MS (EI) m/z 395/393 (M+);
HRMS calcd. for C19H12BrN3S 395.9993, found
395.9953.
2-[30-(60-methoxylindolyl)]-4-(30-indolyl)thiazole (15).
Yield 75%; mp 241.6±242.3 ꢀC (dec.); UV (MeOH)
2,4-Bis[30-(60-bromoindolyl)]thiazole (10). Yield 78%; mp
>300 ꢀC; UV (95%EtOH) lmax 232, 270 nm; IR (KBr)
nmax 3539, 3206 (NH), 1615, 1579, 1473, 1331, 1294,
l
max 226, 284 nm; IR (KBr) nmax 3388, 3121, 1633, 1544,
1456, 1301, 1250 cm 1; 1H NMR (DMSO-d6) d 11.73 (s,
1H, NH), 11.18 (s, 1H, NH), 8.36 (m, 1H), 8.13 (d,
1
1120, 1098, 1055 cm 1; H NMR (DMSO-d6) d 11.87

370
B. Jiang, X.-H. Gu / Bioorg. Med. Chem. 8 (2000) 363±371
J=2.5 Hz, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.85 (d, 1H),
7.55 (s, 1H), 7.52 (m, 1H), 7.25 (m, 2H), 6.98 (d, J=2.3
Hz, 1H), 6.82 (dd, J=8.7 and 2.3 Hz, 1H); MS (EI) m/z
345 (M+); HRMS calcd. for C20H15N3OS 345.0936,
found 345.0920.
2-(30-Indolyl)-N-[2-(30-indolyl)-2-oxo-ethyl]-2-oxo-aceto-
mide (27). To a solution of 3-(2-amino-acetyl)-indole
(90 mg, 0.71 mmol) and triethyl amine (0.4 mL, 2.85
mmol) in CH2Cl2 (20 mL) was added indolyl glyoxylic
chloride (190 mg, 0.91 mmol) at 0 ꢀC. The mixture was
stirred over night. After work up as usual, the crude
product was puri®ed by chromatography on silica gel
to a€ord 27 (165 mg, 67%). Mp. 264±265 ꢀC; UV
2-[30 -(50 -Bromoindolyl)]-4-[30 -(60 -bromoindolyl)]thiazole
(16). Yield 74%; mp 240.5±241.4 ꢀC; UV (MeOH) lmax
232, 268 nm; IR (KBr) nmax 3429, 3205, 1616, 1542,
(95%EtOH) lmax 208, 242, 396 nm; IR (KBr) nmax 3386,
1
1
1416, 1329, 1287, 1242 cm 1; H NMR (DMSO-d6) d
3337, 2927, 2675, 2645, 1583, 1497, 1336 cm
;
1H
11.89 (br, 1H, NH), 11.48 (br, 1H, NH), 8.56 (d, J=1.9
Hz, 1H), 8.23 (d, J=8.6 Hz, 1H), 8.18 (d, J=2.3 Hz,
1H), 7.98 (d, J=1.7 Hz, 1H), 7.69 (d, J=1.7 Hz, 1H),
7.63 (s, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.37 (dd, J=1.9
and 8.6 Hz, 1H), 7.27 (dd, J=1.8 and 8.5 Hz, 1H); 13C
NMR (DMSO-d6) d 161.43, 149.98, 137.42, 137.25,
135.28, 135.12, 127.87, 127.70, 126.06, 125.45, 124.89,
123.83, 122.78, 122.34, 121.95, 114.47, 114.20, 113.30,
110.30; MS (EI) m/z 475/471 (M+); HRMS calcd. for
C19H11Br2N3S 470.9040, found 470.9049.
NMR (300 MHz, DMSO-d6) d 8.47 (t, J=5.75, 5.92 Hz,
1H, NH), 8.38 (d, J=1.95 Hz, 1H), 8.04 (d, J=2.37 Hz,
1H), 7.82 (m, 1H), 7.737 (m, 1H), 7.12±7.04 (m, 2H),
6.85 (m, 2H), 6.79 (m, 2H), 4.19 (d, J=3.77 Hz, 2H);
MS (EI) m/z: 345 (M+).
3,5-Bis(30-indolyl)-2(1H)pyrazinone (28). Compound 27
(150 mg, 0.43 mmol) in methanol (5 mL) was added to
liquid ammonia (10 mL) in autoclave. The mixture was
heated at 80 ꢀC for 3 days. After evaporation of
ammonia, the crude product was chromatography on
silica gel to a€ord 28 (65 mg, 63%). Mp >300 ꢀC; UV
(95%EtOH) lmax 274, 402 nm; IR (KBr) nmax 3555,
3410, 2920, 1640, 1619, 1531, 1499, 1455, 1418, 1332,
2-(20-Pyridinyl)-4-[30-(50-bromoindolyl)]thiazole (20).
Yield 86%; mp 229.3±230.4 ꢀC; UV (MeOH) lmax 232,
266 nm; IR (KBr) nmax 1567, 1479, 1453, 1433, 1278,
1228 cm 1; 1H NMR (DMSO-d6) d 11.67 (br, 1H, NH),
8.67 (m, 1H), 8.42 (d, J=1.5 Hz, 1H), 8.27 (d, J=7.9
Hz, 1H), 8.07 (d, J=2.2 Hz, 1H), 8.04 (dd, J=1.5 and
7.8 Hz, 1H), 7.99 (s, 1H), 7.54±7.46 (m, 2H), 7.32 (dd,
J=1.8 and 8.6 Hz, 1H); 13C NMR (DMSO-d6) d 167.42,
151.73, 150.58, 149.7, 137.75, 135.23, 126.40, 126.24,
126.07, 124.96, 124.18, 122.43, 118.99, 113.86, 113.14,
112.52, 110.48; MS (EI) m/z 354/356 (M+).
1
1237, 1161 cm 1; H NMR (300 MHz, DMSO-d6) d
12.27 (s, 1H, CONH), 11.64 (s, 1H, NH), 11.35 (s, 1H,
NH), 8.90 (s, 1H), 8.79 (d, J=7.69 Hz, 1H), 8.04 (d,
J=7.87 Hz, 1H), 7.85 (s, 1H), 7.52±7.47 (m, 3H), 7.24±
7.08 (m, 4H); 13C NMR (DMSO-d6) d 153.62, 150.31,
136.82, 136.67, 136.25, 131.31, 131.14, 129.97, 125.98,
124.50, 123.20, 122.56, 122.15, 121.40, 120.43, 119.89,
119.89, 119.33, 116.24, 113.33, 111.83; HRMS calcd. for
C20H14N4O 326.1167, found 326.1178.
2,4-Bis(30-N-methylindolyl)thiazole (17). A mixture of
2,4-bis(30-indolyl)thiazole 7 (149 mg, 0.473 mmol),
iodomethane (1 mL) and anhydrous potassium carbon-
ate (354 mg, 2.5 mmol) in dry acetone (10 mL) was
re¯uxed for 16 h. Additional iodomethane (1 mL) and
potassium carbonate (354 mg, 2.5 mmol) were added
and then re¯uxed for overnight. After evaporation of
the solvent, water (10 mL) added. The mixture was
extracted with ether. The extracts were washed with
saturated brine, dried over sodium sulfate. After work-
ing up, the crude product was puri®ed by ¯ash chro-
matography to give 17 (135 mg, 83%). Mp 174.2±
Acknowledgements
We thank Dr. B. L. Robeson, C. P. Starks, Dr. A. B.
Mauger, Dr. M. Holligshead, Dr. E. A. Sausville, Dr. V.
L. Narayanan and their colleagues of the NCI Devel-
opmental Therapeutics Program for conducting the in
vitro disease-oriented primary antitumor screen and
hollow ®ber assay. This work was ®nancially supported
by grant from Shanghai Municipal Committee of Science
and Technology.
174.6 ꢀC; UV (MeOH) lmax 228, 298 nm; IR (KBr) nmax
1
1612, 1566, 1477, 1417, 1330, 1240 cm
;
1H NMR
(DMSO-d6) d 8.39 (m, 1H), 8.22 (d, 1H), 8.16 (s, 1H),
7.8 (s, 1H), 7.58 (s, 1H), 7.57±7.51 (m, 2H), 7.34±7.18
(m, 4H), 3.90 (s, 3H), 3.89 (s, 3H); MS (EI) m/z 343
(M+); HRMS cald. for C21H17N3S 343.1144, found
343.1145.
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