J. P. Rappai et al. / Bioorg. Med. Chem. Lett. 19 (2009) 764–765
765
of furans.17 When we applied this protocol for the oxidation of 3-
bromo-2,4,6-triphenylfuran, (E)-2-bromo-1,3,4-triphenylbut-2-
40000
35000
30000
25000
20000
15000
10000
5000
ene-1,4-dione 3 was generated in excellent yields.19 The furanon-
es, 2-acetoxy-2,4,5-triphenyl-2H-furan-3-one 4 and 2-methoxy-
2,4,5-triphenyl-2H-furan-3-one 5, were prepared according to
the reported procedures.15 It may be noted that different substit-
uents may be introduced on any of the aryl groups or at the 2-po-
sition of the furanone ring system. Thus, the improved procedure
developed by us has paved way to the generation of several
3(2H)-furanones in multigram quantities.
The antitumor activity of these furanones was evaluated via
both in vivo and in vitro methods. Oral administration of com-
pounds 4 and 5 to tumor bearing mice showed a significant de-
crease in the tumor growth (Fig. 1). This suggests that the
furanones efficiently inhibit tumor cell proliferation in vivo.20
The anti-proliferate effect of these compounds was studied
using DLA cells. These in vitro experiments showed that the pres-
ence of compounds 4 and 5 significantly reduced the proliferation
of DLA cells (Figs. 2 and 3).21
In conclusion, we synthesized two triaryl 3(2H)-furanones and
evaluated their antitumor activity. Both the in vivo and in vitro
studies showed that these compounds were active against tumor
cell proliferation.
0
Control
10
20
50
5
100
200
Concentration of compound in microgram / mL
Figure 3. Effect of compound 5 on DNA synthesis of DLA cell line (in vitro).
Acknowledgments
This work was supported by DST, Government of India, in the
form of Research Grant No. SP/S1/G-23/2000.
J.P.R. and V.R. acknowledge CSIR, India, for financial assistance.
References and notes
0.7
1. (a) Ley, S. V.; Cox, L. R.; Meek, G. Chem. Rev. 1996, 96, 423; (b) Negishi, E.;
Kotora, M. Tetrahedron 1997, 53, 6707; (c) Collins, I. J. Chem. Soc., Perkin Trans. 1
1998, 1869; (d) Collins, I. J. Chem. Soc., Perkin Trans. 1 1999, 1377.
2. Perold, G. W.; Muller, J. C.; Ourisson, G. Tetrahedron 1972, 28, 5797.
3. Nineham, A. W.; Raphel, R. A. J. Chem. Soc. 1949, 118.
0.6
4. Dal Pozzo, A.; Danci, A.; Meneghini, E. Bull. Chim. Farm. 1974, 113.
5. Felman, S. W.; Jirkovsky, I. L.; Memoli, K. A. US Patent No. US 5314913, 1992.
6. Lee, J.; Choe, I.; Kim, H.; Choe, K. Korean Patent No. KR 119908, 1994.
7. Koga, T.; Moro, K.; Matsudo, T. J. Agric. Food. Chem. 1998, 46, 946.
8. Rebstock, T. L.; Sell, H. M. J. Chem. Soc. 1952, 74, 274.
9. Iino, Y.; Tanaka, A.; Yamashita, K. Agric. Biol. Chem. 1972, 36, 2505.
10. Kupchan, S. M.; Eakin, M. A.; Thomas, A. M. J. Med. Chem. 1971, 14, 1147.
11. (a) Shin, S. S.; Noh, M. S.; Byun, Y. J.; Choi, J. K.; Kim, J. Y.; Lim, K. M.; Ha, J. Y.;
Kim, J. K.; Lee, C. H.; Chung, S. Bioorg. Med. Chem. Lett. 2001, 11, 165; (b) Shin, S.
S.; Byun, Y.; Lim, K. M.; Choi, J. K.; Lee, K. W.; Moh, J. H.; Kim, J. K.; Jeong, Y. S.;
Choi, Y. H.; Koh, H. J.; Park, Y. H.; Oh, Y. I.; Noh, M. S.; Chung, S. J. Med. Chem.
2004, 47, 792.
12. Smeds, A.; Vartiainen, T.; Maki-Paakkanen, J.; Kroberg, L. Environ. Sci. Technol.
1997, 31, 1033.
13. Chimichi, S. O.; Boccalini, M. O.; Cosimelli, B.; Dall’Acqua, F.; Viola, G.
Tetrahedron 2003, 59, 5215.
14. Lutz, R. E.; Tyson, W. R.; Sanders, A. G.; Fink, C. K. J. Am. Chem. Soc. 1934, 56,
2679.
15. Kuhn, L. P.; Lutz, R. E.; Bauer, C. R. J. Am. Chem. Soc. 1950, 72, 5058.
16. Lutz, R. E.; McGinn, C. E. J. Am. Chem. Soc. 1942, 64, 2585.
17. Rappai, J. P.; Prathapan, S.; Vishnu Unni, M. V.; Unnikrishnan, P. A. Synth.
Commun. 2007, 37, 569.
Control
Compund 4
Compund 5
0.4
0.5
0.3
0.2
0.1
0
18. Procedure for the synthesis of compound 2. Dry HBr(g) was passed through a
solution of 1,2,4-triphenylbut-2-ene-1,4-dione 1 (9.4 g, 30 mmol) in acetic acid
for about 30 min. The solid that separated out was filtered and purified by
recrystallization from a 1:1 mixture of methanol and chloroform to yield 3-
bromo-2,4,5-triphenylfuran 2 (7.8 g, 70%). Its spectral and analytical data were
found to be identical to the one reported in the literature.14
Days after tumor inoculation
Figure 1. Antitumor activity of compounds 4 and 5 (1 mg/kg of body weight)
(in vivo).
19. Procedure for the synthesis of compound 3. A mixture of 3-bromo-2,4,5-
triphenylfuran 2 (3.75 g, 10 mmol), aqueous acetic acid (10 mL, 80%, v/v) and
ammonium nitrate (1.3 g, 12.5 mmol) was heated at reflux for 90 min. The
reaction mixture was cooled, diluted with cold water and filtered. The solid
that separated out was filtered and purified by recrystallization from methanol
35000
30000
25000
20000
15000
10000
5000
0
to yield (E)-2-bromo-1,3,4-triphenylbut-2-ene-1,4-dione
3 (2.9 g, 74%). Its
spectral and analytical data were identical to those reported in the
literature.14,15
20. Inbred male Swiss albino mice (6 mices/group) were used to study the in vivo
antitumor activity of compounds
4 and 5. Solid tumor was induced by
subcutaneous injection of 1 Â 106 Daltons Lymphoma Ascites (DLA) cells. After
seven days of tumor induction, experimental groups received the compounds
(1 mg/kg body weight) orally while controls received sterile phosphate buffer
saline. Tumor development was measured after each three days using vernier
calipers and tumor volume calculated.
21. The DLA (1 Â 106) cells were cultured in vitro in presence of test compounds 4
and 5 with concentrations varying from 10 to 200 lg. Thymidine (0.01 lCi)
Control
10
20
50
100
200
was added to all the plates. One set was kept as control. After 24 h of
incubation, cells were separated by centrifugation. Cells were digested
overnight using sodium hydroxide. Radioactivity was measured by using a
liquid scintillation counter.
Concentration of compound 4 in microgram / mL
Figure 2. Effect of compound 4 on DNA synthesis of DLA cell line (in vitro).