Synthesis and antitumor evaluation of novel monoindolyl-4-trifluoromethylpyridines and bisindolyl-4-trifluoromethylpyridines

Article abstract of DOI:10.1016/S0960-894X(00)00704-6

A series of novel monoindolyl-4-trifluoromethylpyridines and bisindolyl-4-trifluoromethylpyridines was designed and synthesized as potential antitumor agents. They were evaluated for preliminary cytotoxic activity against P388 and A-549 cells with IC₅₀ values. 4-Trifluoromethyl-2,6-bis[3′-(N-tosyl-6′-methoxyl-indolyl)] pyridine was identified as the most potent in this series.

Full text of DOI:10.1016/S0960-894X(00)00704-6

Bioorganic & Medicinal Chemistry Letters 11 (2001) 475±477
Synthesis and Antitumor Evaluation of Novel
Monoindolyl-4-tri¯uoromethylpyridines and
Bisindolyl-4-tri¯uoromethylpyridines
Biao Jiang,* Xen-Nan Xiong, and Cai-Guang Yang
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
3
54 Fenglin Road, Shanghai 200032, People's Republic of China
Received 27 September 2000; accepted 2 December 2000
AbstractÐA series of novel monoindolyl-4-tri¯uoromethylpyridines and bisindolyl-4-tri¯uoromethylpyridines was designed and
synthesized as potential antitumor agents. They were evaluated for preliminary cytotoxic activity against P388 and A-549 cells with
0
0
IC50 values. 4-Tri¯uoromethyl-2,6-bis[3 -(N-tosyl-6 -methoxyl-indolyl)] pyridine was identi®ed as the most potent in this series.
#
2001 Elsevier Science Ltd. All rights reserved.
Introduction
that if a ¯uorine atom was introduced into indole alka-
loids, the resulting analogues might bring about signi®cant
biological consequence. A range of tri¯uoromethyl con-
taining indole alkaloids were designed and synthesized.
Marine indole alkaloids have emerged as an important
structural class based upon their high degree of biological
activities including antimicrobial, antiviral and antitumor
1
properties. A common structural feature of these kinds
In this communication, we wish to report the synthesis
of monoindolyl-4-tri¯uoromethylpyridines and bisindo-
lyl-4-tri¯uoromethylpyridines. Their preliminary cyto-
toxicity toward P388 and human tumor cell A-549 was
described.
of compounds incorporates an extra ®ve-, six- or seven-
membered heterocyclic ring with one or two indole
rings. Bis(indole) alkaloids, dragmacidin Dand nortop-
sentins A±C inhibited in vitro the growth of the P388
2
murine. Monoindole alkaloids, meridianins B±E
3
showed cytotoxity toward murine tumor cell lines. One
of the goals of our group is to develop novel antitumor
agents by using marine indole alkaloids as the lead
compounds. In a previous work, we have reported the
Chemistry
2-(3-Indolyl)-4-tri¯uoromethylpyridines and 2,6-bis(3-
indolyl)-4-tri¯uoromethylpyridines were conveniently
prepared by using the palladium catalyzed Suzuki cross-
coupling reaction of 3-indolylboronic acids with 4-tri-
¯uoromethyl-halogenopyridines.
4
synthesis of bis(indolyl)thiazoles, mono(indolyl)pyr-
imidines and bis(indolyl)pyrimidines, mono(indolyl)
5
pyrazines and bis(indolyl)pyrazines, bis(indolyl)pyrazi-
6
nones, which exhibited signi®cant cytotoxic activities
against a variety of human cancer cell lines in vitro.
These results promoted us to design new analogues with
further modi®cation of indole alkloids. On the basis of
the well-known feature that the ¯uorine atom as a
highly electronegative center alters signi®cantly the
physico-chemical properties of organic compounds,
thereby modifying biological activity, we anticipated
The synthetic route to the key intermediate 2-chloro-4-tri-
¯uoromethylpyridine 7 and 2,6-dichloro-4-tri¯uoromethyl-
pyridine 10 is shown in Scheme 1. Commercially avail-
able tri¯uoroacetate 1 was reacted with allylmagnesium
7
bromide to form tri¯uoromethyl-diallylcarbinol 3. Oxi-
dation of alcohol 3 with ozone a€orded dialdehyde 4,
which was cyclized in ammonia-saturated methanol
solution to yield pyridine 5. Oxidation of 4-tri¯uoro-
methylpyridine 5 with m-CPBA produced N-oxide 6,
which was chlorinated with thionyl chloride to give the
*
6
Corresponding author. Tel.: +86-21-64163300; fax: +86-21-
4166128; e-mail:
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00704-6

476
B. Jiang et al. / Bioorg. Med. Chem. Lett. 11 (2001) 475±477
ꢀ
ꢀ
Scheme 1. Reagents and conditions: (a) Mg, THF, 50 C, 3 h, 92%; (b) O
d) MCPBA, CH Cl , rt, 10 h, 73%; (e) SOCl , re¯ux, 3 h, 42%; (f) 30% H
re¯ux, 10 h, 30%.
3
, CH
2
Cl
, HCOOH, 70 C, 10 h, 68%; (g) NH
2
/MeOH, À78 C, 24 h, 90%; (c) NH
3
/MeOH, re¯ux, 24 h, 70%;
ꢀ
ꢀ
(
2
2
2
2
O
2
2
CONH
2
, 200 C, 8 h; (h) POCl
3
,
desired 2-chloro-4-tri¯uoromethylpyridine 7.8 Dialde-
hyde 4 was re¯uxed with 30% hydrogen peroxide in
formic acid to produce diacid 8. Heating the diacid 8 with
kis(triphenylphosphine) palladium and aqueous sodium
carbonate in MeOH or DME under re¯uxing (Scheme 3).
12
9
urea at high temperature led to imide 9. Chlorination of
imide 9 with phosphorus oxychloride under re¯uxing
Suzuki coupling of 7 with 1.1 mol equiv of N-tosyl-3-
indolylboronic acid 14 produced 2-indolyl-4-tri¯uoro-
12
methyl pyridines (26±31) in good yields (Scheme 4).
1
0
a€orded 2,6-dichloro-4-tri¯uoromethylpyridine 6.
The synthesis of 2,6-dichloro-3-cyano-4-tri¯uoro-
methylpyridine is depicted in Scheme 2. Hydroxypyridine
product 12 was synthesized from ethyl 4,4,4-tri¯uoro-
acetoacetate 11 and cyanoacetamide by adapting a lit-
Pharmacological Results and Discussion
The prepared indolylpyridine compounds have been
submitted to Shanghai Institute of Materia Medica for
testing their cytotoxicity. The preliminary cytotoxicity
1
1
erature method. Chlorination of hydroxypyridine 12
with phosphorous oxychloride at 180 C gave 2,6-di-
ꢀ
chloro-3-cyano-4-tri¯uoromethylpyridine 13.
Finally the desired 2,6-bis(3-indolyl)-4-tri¯uoromethyl
pyridines (15±25) were prepared, respectively, by Suzuki
cross-coupling reaction of 2,6-dichloro-4-tri¯uoro-
methylpyridine 10 or 2,6-dichloro-3-cyano-4-tri¯uoro-
methylpyridine 13 with 2.2 molar equiv of N-tosyl-3-
indolylboronic acid 14 in the presence of 10% tetra-
Scheme 2. Reagents and conditions: (a) cyanoacetamide, CH
ꢀ
3
ONa,
3 4 2 3
Scheme 4. Reagents and conditions: (a) Pd(PPh ) , Na CO , benzene,
MeOH, 85±92%.
ꢀ
MeOH, 60 C, 8 h, 63%; (b) POCl
3
, 140 C, 18 h, 80%.
3 4 2 3
Scheme 3. Reagents and conditions: (a) Pd(PPh ) , Na CO , benzene, MeOH or DME, 40±65%.

B. Jiang et al. / Bioorg. Med. Chem. Lett. 11 (2001) 475±477
Table 1. In vitro cytotoxicity against the P388 and A-549 cell lines
P388
477
A-549
a
b
Concn
mM)
100
10
1
0.1
CTX P388
IC50 (mM)
100
10
1
0.1
CTX A-549
IC50 (mM)
(
15
16
17
18
21
22
23
24
26
27
29
31
14.7
8.9
13.8
99.9
8.2
1.3
Ð
3.8
49.9
32.6
15.6
2.2
23.5
15.1
5.0
92.8
Ð
5.7
3.5
10.1
Ð
20.9
10.0
7.0
Ð
3.7
1.7
15.7
8.1
9.3
Ð
>100
>100
>100
4.3
>100
>100
>100
>100
>100
>100
>100
>100
69.3
49.2
41.7
97.1
70.6
48.1
17.7
21.2
68.4
98.0
51.8
35.9
27.6
32.0
22.2
45.7
9.6
27.6
25.2
13.3
30.5
20.6
14.1
9.9
36.7
30.7
7.1
37.5
25.8
16.7
35.5
9.8
23.8
25.0
33.0
29.2
38.9
24.5
16.9
23
>100
>100
1.7
28.8
17.4
18.8
24.4
26.7
35.0
32.8
19.7
23.2
Ð
78
3.1
1.7
5.1
Ð
9.7
Ð
>100
>100
>100
25
4.1
>100
>100
9.1
10.5
17.8
Ð
21.9
Ð
Ð
Ð
Ð
a
Cytotoxicity (CTX) against murine leukemia cells (P388) was measured by the microculture tetrazolium-formazan method.
CTX against human lung cancer cells (A-549) was measured by the sulforhodamine B dye-staining method.
b
screening results agaist murine leukemia cells P388 and
human lung tumor cells A-549 are shown in Table 1 as
IC50 values.
References and Notes
1
. (a) Nishizawa, Y. Nature 1984, 308, 693. (b) Nishizawa,
Y. Science 1986, 233, 305. (c) Nishizawa, Y. Nature 1988,
34, 661. (d) Stewart, A. F.; Schultz, G. Cell 1987, 50, 1109.
e) Wu, H. Y.; Shyy, S. H.; Wang, J. C.; Liu, L. F. Cell 1988,
Compounds 15, 16, 21, 22, 23, 24, 29, and 31 were inactive
against P388 and A-549 tumor cells. Compounds 15 and
3
(
2
6 were inactive against P388 cells and showed weak
53, 433. (f) Merino, A.; Madden, K. R.; Lane, W. S.; Champoux,
J. J.; Deinberg, D. Nature 1993, 365, 227.
2. (a) Wright, A. E.; Pomponi, S. A.; Cross, S. S.; McCarthy,
P. J. Org. Chem. 1992, 57, 4772. (b) Tsujii, S.; Rinehart, K. L.
J. Org. Chem. 1988, 53, 5446.
cytotoxicity toward A-549. Compound 27 was inactive
agaist P388 cells and showed cytotoxicity toward A-549
with IC50 value of 4.1 mM. Compound 18 exhibited good
inhibitory activities against P388 cell lines with IC values
5
0
Â
3. Franco, L. H.; Jo€e, E. B. K.; Puricelli, L.; Tatian, M.;
Seldes, A. M.; Palermo, J. A. J. Nat. Prod. 1998, 61, 1130.
of 4.3 mM and A-549 cell lines with IC50 values of 1.7 mM.
4
1
5
6
. Gu, X. H.; Wang, X. Z.; Jiang, B. Bioorg. Med. Chem. Lett.
999, 9, 569.
. Jiang, B.; Gu, X.-H. Bioorg. Med. Chem. 2000, 8, 363.
. (a) Jiang, B.; Yang, C.-G. Heterocycles 2000, 53, 1489. (b)
In conclusion, we have designed and synthesized the
tri¯uoromethyl containing indolylpyridines. The pre-
liminary screening shows that 4-tri¯uoromethyl-2,6-
bis[3 -(N-tosyl-6 -methoxylindolyl)]pyridine 18 was
identi®ed as the most potent in this series.
0
0
Jiang, B.; Gu, X. H. Heterocycles 2000, 53, 1559.
7. Pellissier, H.; Wilmouth, S.; Santelli, M. Tetrahedron Lett.
1
8
996, 37, 5107.
. Hojo, M.; Masuda, R.; Kokuryo, Y.; Shioda, H.; Matsuo,
S. Chem. Lett. 1976, 499.
. Crockett, G. C.; Swanson, B. J.; Anderson, D. R.; Koch,
T. H. Syn. Commun. 1981, 11, 447.
0. Nishiyama, R.; Fujikawa, K.; Yokomichi, I.; Tsujii, Y.;
Nishimura, S. EP 42,696, 1981; Chem. Abstr. 1982, 96, 181147.
Acknowledgements
9
The authors express deep thanks to Dr. Jian Ding, Dr.
Dong Xiao and their colleagues of the Shanghai Insti-
tute of Materia Medica for conducting the in vitro dis-
ease-oriented primary antitumor screen. This work was
®nancially supported by a grant from the Shanghai
Municipal Committee of Science and Technology.
1
1
1. Grozinger, K. G. WO patent 22532, 1992; Chem. Abstr.
992, 118, 191556.
12. Compounds 15±25 and 26±31 were fully characterized by
1
1
9
1
13
F NMR, H NMR, C NMR, MS, HRMS and IR spectra.