Preparation of 1,4-Oxaselenin from AgNO3/LDA-Assisted Reaction of 3-Selena-4-pentyn-1-one as Potential Antitumor Agents

Article abstract of DOI:10.1021/ol015897z

(matrix presented) 1,4-Oxaselenins were synthesized from 3-selena-4-pentyn-1-ones by the use of AgNO₃ and LDA. One of the obtained oxaselenins, 2-(4-chlorophenyl)-6-phenyl-1,4-oxaselenin 5c, showed an inhibitory effect against the proliferation

Full text of DOI:10.1021/ol015897z

ORGANIC
LETTERS
2001
Vol. 3, No. 11
1705-1707
Preparation of 1,4-Oxaselenin from
AgNO /LDA-Assisted Reaction of
3
3-Selena-4-pentyn-1-one as Potential
Antitumor Agents
,†
Mamoru Koketsu,* Hyun Ok Yang,‡ Yong Man Kim,§ Michiko Ichihashi,† and
,†
Hideharu Ishihara*
Department of Chemistry, Faculty of Engineering, Gifu UniVersity, Gifu, 501-1193
Japan, and Department of Traditional Medicine, Asan Institute for Life Sciences and
Department of Obstetrics & Gynecology, College of Medicine, UniVersity of Ulsan,
388-1 Poongnap-dong, Songpa-ku, Seoul 138-736, Korea
koketsu@cc.gifu-u.ac.jp
Received March 27, 2001
ABSTRACT
1,4-Oxaselenins were synthesized from 3-selena-4-pentyn-1-ones by the use of AgNO and LDA. One of the obtained oxaselenins,
3
2-(4-chlorophenyl)-6-phenyl-1,4-oxaselenin 5c, showed an inhibitory effect against the proliferation of human cancer cells and inducing effects
on the early stage of apoptosis.
The literature shows many selenium-containing heterocyclic
compounds,1 and of these, many are potential pharmaceutical
agents.2 Among the oxaselenins, the syntheses of 1,3-
oxaselenin-2-one,3 1,2-oxaselenin,4 and 3,1-benzooxaselenin-
4-one5 have been extensively reported, while preparations
of 1,4-oxaselenins are much rarer.6 We have recently reported
that the reaction of alkynyl propargyl selenide with primary
amines afforded 2-imino-2H-5,6-dihydroselenines.7 The use
of alkynyl selenide is one of the most efficient methods for
the synthesis of heterocyclic compounds containing sele-
nium.8 Herein, we describe the preparation of three 1,4-
oxaselenins from 3-selena-4-pentyn-1-one by treatment of
2-bromoacetophenones with AgNO3 and LDA. We also
present their evaluation as potential antitumor agents.
(2) (a) Clement, I.; Lisk, D. J.; Ganther, H. E. Anticancer Res. 1998,
18, 4019. (b) May, S. W.; Pollock, S. H. Drugs 1998, 56, 959. (c) Koketsu,
M.; Ishihara, H.; Wu, W.; Murakami, K.; Saiki, I. Eur. J. Pharm. Sci. 1999,
9, 157. (d) Wu, W.; Murakami, K.; Koketsu, M.; Yamada, Y.; Saiki, I.
Anticancer Res. 1999, 19, 5375. (e) May, S. W. Expert Opin. InVest. Drugs
1999, 8, 1017. (f) Page, K.; Li, J.; Hodge, J. A.; Liu, P. T.; Hoek, T. L. V.;
Becker, L. B.; Pestell, R. G.; Rosner, M. R.; Hershenson, M. B. J. Biol.
Chem. 1999, 274, 22065. (g) Zhu, Z.; Jiang, W.; Ganther, H. E. Ip, C.;
Thompson, H. J. Biochem. Pharmacol. 2000, 60, 1467. (h) Cho, S. I.;
Koketsu, M.; Ishihara, H.; Matsushita, M.; Nairn, A. C.; Fukazawa, H.;
Uehara, Y. Biochim. Biophys. Acta 2000, 1475, 207. (i) Ostrovidov, S.;
Franck, P.; Joseph, D.; Martarello, L.; Kirsch, G.; Belleville, F.; Nabet, P.;
Dousset, B. J. Med. Chem. 2000, 43, 1762.
† Gifu University.
‡ Asan Institute for Life Sciences.
(3) Lucas, M. A.; Carl, H. S. J. Org. Chem. 1998, 63, 3032.
§ Department of Obstetrics & Gynecology, College of Medicine.
(1) (a) Ogawa, A.; Sonoda, N. ReV. Heteroat. Chem. 1994, 10, 43. (b)
Guziec, F. S., Jr.; Guziec, L. J. In ComprehensiVe Organic Functional Group
Transformations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.;
Pergamon: Oxford, 1995; Vol. 3, p 381. (c) Krief, A. In ComprehensiVe
Organometallic Chemistry; Abel, W. W., Stone, F. G. A., Wilkinson, G.,
Eds.; Pergamon: Oxford, 1995; Vol. 11, p 515. (d) Koketsu, M.; Hiramatsu,
S.; Ishihara, H. Chem. Lett. 1999, 485. (e) Back, T. G. Organoselenium
Chemistry: A Practical Approach; Oxford University Press: U.K., 1999.
(f) Koketsu, M.; Suzuki, N.; Ishihara, H. J. Org. Chem. 1999, 64, 6473.
(g) Wirth, T. Organoselenium Chemistry. Modern DeVelopments in Organic
Synthesis; Springer, 2000.
(4) Kataoka, T.; Watanabe, S.; Yamamoto, K.; Yoshimatsu, M.; Tanabe,
G.; Muraoka, O. J. Org. Chem. 1998, 63, 6382.
(5) Okuma, K.; Kojima, K.; Kaneko, I.; Tsujimoto, Y.; Ohta, H.;
Yokomori, Y. J. Chem. Soc., Perkin Trans. 1 1994, 2151.
(6) These examples were for 1,4-oxaselenins with different structures
from different starting materials. Reported as 3,5-disubstituted 2,5-dihydro-
1,4-oxaselenin; (a) Migalina, Y. V.; Staninets, V. I.; Lendel, V. G.; Balog,
I. M.; Palyulin, V. A.; Koz′min, A. S.; Zefirov, N. S. Khim. Geterotsikl.
Soedin. 1977, 58; Chem. Abstr. 1977, 86, 189862x. Reported as 3,5-
disubstituted 1,4-oxaselenin: (b) Migalina, Y. V.; Lendel, V. Y.; Staninets,
V. I. Ukr. Khim. Zh. (Russ. Ed.) 1980, 46, 640; Chem. Abstr. 1980, 93,
204592z.
10.1021/ol015897z CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/21/2001

The synthesis of 5-phenyl-3-selena-4-pentyn-1-ones 4a-c
using lithium phenylselenorate 2 was achieved by the
following one-pot procedure (Scheme 1). Bromoacetophe-
from its 1H NMR spectra, which showed a 1J(77Se-1H) value
of J ) 21.6 Hz at the H3 and H5 protons of product 5a.
Other combinations of AgNO3, Cu(I)I, LDA, and n-BuLi
gave no identifiable products. Only the corresponding starting
material could be isolated (runs 2-4). Though copper(I) has
been commonly used to catalyze cyclizations10 and the
substitutions of nonactivated aryl bromides or iodides,11 it
did not provide the desired product in the present reaction.
It was anticipated that activation of alkyne by silver-induced
nucleophilic attack of the oxygen in 4a was followed by
dehydrogenated by LDA to afford 5a. Similarly, the use of
one base only (e.g., LDA, n-BuLi, NaH, or EtONa) also only
gave mixtures instead of 5a (runs 5, 7, and 8) or provided
no products other than recovered starting material (runs 6
and 9). Next, we investigated various reaction conditions to
improve the yield of 5a from the treatment with AgNO3 and
LDA (Table 2). The addition of AgNO3 at 0 °C followed by
Scheme 1
nones 3a-c were added to the lithium phenylethyneseleno-
late 2 in THF, generated in situ from phenylacetylene 1 and
elementary selenium, and stirred at -78 °C for 1 h. Three
5-phenyl-3-selena-4-pentyn-1-ones, 4a-c, were obtained in
high yield. Several attempts to determine the optimal
activator for the preparation of 2,6-diphenyl-1,4-oxaselenin
5a from 1,5-diphenyl-3-selena-4-pentyn-1-one 4a showed
that the best result was obtained from the combination of
AgNO39 and LDA (Table 1). In this procedure, AgNO3 was
Table 2. Investigations of Optimal Condition for the
Preparation of 1,4-Oxaselenin
run
temp (°C)
conditions
yield (%)a
1
2
3
4
5
6
0
0
0
0
rt
rt
-78 °C/1 h f -20 °C/3 h
-78 °C/1 h f 0 °C/3 h
-78 °C/6 h
0 °C/2 h
-78 °C/1 h f -20 °C/3 h
-78 °C/1 h f 0 °C/3 h
52
37
7
13
35
21
Table 1. Evaluation of Activators for Optimizing the
Preparation of 2,6-Diphenyl-1,4-oxaselenin 5a from
1,5-Diphenyl-3-selena-4-pentyn-1-one 4a
a Isolated yield.
LDA at -78 °C, stirring for 1 h, and furtherstirring at -20
°C for 3 h gave 5a in the highest yield (run 1). For the
addition of AgNO3, 0 °C provided better yields than room
temperature (runs 1 and 5 or 2 and 6). For LDA addition,
both higher and lower temperature failed to improve the
yields (runs 1-4). Three 1,4-oxaselenins, 5a-c, were
obtained from the corresponding 5-phenyl-3-selena-4-pentyn-
1-ones 4a-c in 35-53% yield (Scheme 2), respectively.
According to Baldwin’s rules for ring closure,12 the present
reaction is a faVored 6-End-Digonal system, which affords
a six-membered ring heterocyclic product. For comparison,
a AgNO3 or Cu(I)I (0 °C/1 h)/ LDA or n-BuLi (-78 °C/1 h f 0 °C/3
h). b -78 °C/1 h f rt/20 h. c -78 °C/1 h f -0 °C/5 h. d -78 °C/6 h. e 0
°C/3 h.
added to a THF solution of 1,5-diphenyl-3-selena-4-pentyn-
1-one 4a at 0 °C, and the mixture was stirred for 1 h.
Subsequently, LDA was added at -78 °C, and the mixture
was stirred for 1 h, warmed to 0 °C, and further stirred for
3 h. This condition afforded 2,6-diphenyl-1,4-oxaselenin 5a
in a 37% yield (run 1). The structure of 5a was determined
(10) (a) Yu, Y.; Yamanaka, M.; Nakamura, E. Org. Lett. 1999, 1, 407.
(b) Iwamatsu, S.; Matsubara, K.; Nagashima, H. J. Org. Chem. 1999, 64,
9625. (c) Campo, F. D.; Laste´coue`res, D.; Vincent, J.-M. Verlhac, J.-B. J.
Org. Chem. 1999, 64, 4969. (d) Fitzgerald, J. P.; Nanda, H.; Fitzgerald, P.
Yee, G. T. J. Org. Chem. 2000, 65, 2222. (e) Garc´ıa-Frutos, E. M.;
Ferna´ndez-La´zaro, F.; Maya, E. M.; Va´zquez, P.; Torres, T. J. Org. Chem.
2000, 65, 6841. (f) Erdelmeier, I.; Tailhan-Lomont, C.; Yadan, J.-C. J. Org.
Chem. 2000, 65, 8152. (g) Nagashima, H.; Isono, Y.; Iwamatsu, S. J. Org.
Chem. 2001, 66, 315.
(11) (a) Suzuki, H.; Shinoda, M. Synthesis 1977, 640. (b) Suzuki, H.;
Miyoshi, K.; Shinoda, M. Bull. Chem. Soc. Jpn. 1980, 53, 1765. (c) Lindley,
J. Tetraherdon 1984, 40, 1433. (d) Peng, S.; Qing, F.-L.; Li, Y.-Q.; Hu,
C.-M. J. Org. Chem. 2000, 65, 694.
(7) Koketsu, M.; Kanoh, M.; Itoh, E.; Ishihara, H. J. Org. Chem., in
press.
(8) (a) Shimada, K.; Akimoto, S.; Itoh, H.; Nakamura, H.; Takikawa,
Y. Chem. Lett. 1994, 1743. (b) Shimada, K.; Akimoto, S.; Takikawa, Y.;
Kabuto, C. Chem. Lett. 1994, 2283. (c) Murai, T.; Ezaka, T.; Kanda, T.;
Kato, S. Chem. Commun. 1996, 1809. (d) Watanabe, S.; Mori, E.; Nagai,
H.; Kataoka, T. Synlett 2000, 49.
(12) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734. (b)
Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.; Silberman, L.; Thomas,
R. C. J. Chem. Soc., Chem. Commun. 1976, 736.
(9) The use of other Ag(I) reagents could not improve the yield of 5a.
1706
Org. Lett., Vol. 3, No. 11, 2001

Compound 5c showed the greatest growth inhibition with
IC50s of 45.1 and 37.5 µM, respectively. Compounds 5a and
5b exhibited only weak inhibitory activities, with IC50s of
>100 µM. All three compounds showed no inhibitory effects
on proliferation of HeLa cells (Table 3). To determine the
mechanism of cytotoxicity for 5, the inducing effect of the
early stage of apoptosis was studied by the method of
combined annexin V-FITC and PI labeling with flow
cytometric analysis on SK-OV-3 cells. As we predicted, 5a
and 5b did not show any inducing effect of apoptosis on
cancer cells at doses of 15-60 µM. Compound 5c showed
inducing effects on the early stage of apoptosis of 11%, 15%,
and 19% at doses of 15, 30, and 60 µM, respectively. These
results showed that a 4-chlorophenyl group at the C2 position
of 5 was more effective than a 4-methoxyphenyl group or
an unsubstituted 4-phenyl group at showing cytotoxicity and
apoptosis induction against the cancer cells. These facts also
suggest that chlorination on the phenyl group at the C2
position is important for the cytotoxic activity. On the basis
of these data, further structure-activity relationship studies
are needed.
Scheme 2
a ring closure of propargyloxime would yield isoxazole,13
a
five-membered ring compound, by a 5-Exo-Digonal system.
The reason was thought to be the different character of the
linkers (e.g., trajectories, bond angles, and length of the
linking chain) between selenium and nitrogen atom.
The antitumor effects of the three 1,4-oxaselenins 5a-c
were also investigated.14 The proliferative inhibitory effects
of 5a-c against human uterine cervical cancer cells, such
as SiHa and HeLa cells, and human ovarian cancer cell, SK-
OV-3, are shown in Table 3. All three selenium compounds
exhibited growth inhibition against SiHa and SK-OV-3 cells.
In conclusion, we have demonstrated a novel method of
preparing 1,4-oxaselenins from 5-phenyl-3-selena-4-pentyn-
1-ones by treatment with AgNO3 and LDA and a useful basis
for the development of potential antitumor agents based on
1,4-oxaselenin.
Table 3. 1,4-Oxaselenin 5 Induced Cytotoxicity against
Human Tumor Cell Lines in Vitroa
IC50 (µM)
human tumor cells
5a
5b
5c
Supporting Information Available: Synthetic procedures
for the compounds prepared in this Letter, including spectral
characterization. Condition of cancer cell culture and assay
systems for the measurement of antitumor effects of com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
SK-OV-3 (ovarian cancer cell)
SiHa (uterine cervical cancer cell)
HeLa (uterine cervical cancer cell)
>100 >100 37.5 ( 6.8
>100 >100 45.1 ( 9.1
b
b
b
a Dose-dependent inhibitory effect of 5 on the growth of SK-OV-3, SiHa,
and HeLa cells. The cancer cells (1 × 104 cells per well) were seeded into
96-well plates and preincubated for 24 h. The complete medium was
removed and replaced with a serum-free media, and the cultured cells were
treated with various concentrations (10-60 µM) of 5 in the serum-free
medium for 24 h. Then, aliquots of the cultured medium were transferred
to new plates and the amount of lactate dehydrogenase (LDH) estimated
on a cytotox-96 equipped with a 490 nm ELISA reader. Data from three
independent cultures (triplicate wells for each condition) are expressed at
the mean (SD. b No inhibition.
OL015897Z
(13) Short, K. M.; Ziegler, C. B., Jr. Tetraheron Lett. 1993, 34, 75.
(14) (a) Koh, J. Y.; Choi, S. W. J. Neurosci. Methods 1987, 20, 83. (b)
Vermes, I.; Haanen, C. Steffens-Nakken, H.; Reutelingsperger. C. J.
Immunol. Methods 1995 184, 39. (C) Vermes, I.; Haanen, C. Steffens-
Nakken, H.; Reutelingsperger. C. J. Immunol. Methods 2000 243, 167.
Org. Lett., Vol. 3, No. 11, 2001
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