Y. Xia et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2891–2893
2893
Acknowledgements
R. M.; Tosini, S.; Skehan, P.; Scudiero, P. A.; Monks, A.;
Boyd, M. R. J. Natl. Cancer Inst. 1990, 82, 1113.
14. Melting points were determined on a Fisher-Johns melting
point apparatus without correction. 1H NMR spectra were
measured on a Bruker AC-300 spectrometer with TMS as
internal reference and CDDl3 or DMSO-d6 as solvent. Flash
chromatography was performed on silica gel (mesh 25–150
mm).
This investigation was supported by grant CA-17625
from the National Cancer Institute awarded to K. H.
Lee.
References and Notes
15. General procedure for the synthesis of 2-phenyl-4-quinolone
acetic acids and their esters. Methyl 2-aminophenylacetate (6)
(1.65 g, 10 mmol) was suspended in 8 g of polyphosphoric acid
(PPA). The mixture was warmed at 90–100 ꢁC, and 1.92 g (10
mmol) of ethyl benzoylacetate (7) was added dropwise. The
resulting mixture was further stirred for 1 h. After cooling,
water was added, then aqueous NaOH (10%) was added
slowly until pH=6 and the solution extracted with CHCl3.
The organic layer was dried over sodium sulfate and con-
centrated in vacuo. Chromatography using CHCl3/CH3OH
(30:1) as eluant afforded 2.93 g of compound 9, yield 65.5%;
1. Oyama, M.; Bastow, K. F.; Tachibana, Y.; Shirataki, Y.;
Yamaguchi, S.; Cragg, G. M.; Wu, T. S.; Lee, K. H. Bioorg.
Med. Chem. Submitted for publication.
2. Plowman, J.; Narayanan, V. L.; Dykes, D.; Szarvasi, E.;
Briet, P.; Yoder, O. C.; Paull, K. D. Cancer Treat. Rep. 1986,
70, 631.
3. Atassi, G.; Briet, P.; Berthelon, J. J.; Collonges, F. Eur. J.
Med. Chem. Chim. Ther. 1995, 20, 393.
4. Bibby, M. C.; Double, J. A. Anti-Cancer Drugs 1993, 4, 3.
5. Harris, S. R.; Thorgeirsson, U. P. Biochem. Biophy. Res.
Commun. 1997, 235, 509.
mp 76–78 ꢁC; H NMR (CDCl3) d 3.77 (s, 3H, CH3), 3.95 (s,
1
2H, CH2), 6.65 (s, 1H, H-3), 7.28 (m, 2H, H-6, H-7), 7.56 (m,
3H, H-30, H-40, and H-50), 7.82 (m, 2H, H-20, H-60), 8.34 (d,
1H, J=8.0 Hz, H-5), 10.1 (s, 1H, NH).
6. Murray, J. C.; Smith, K. A.; Stern, D. M. Eur. J. Cancer
1991, 27, 765.
7. Valenti, P.; Fabbri, G.; Rampa, A.; Bisi, A.; Gobbi, S.; Da
Re, P.; Carrara, M.; Sgevano, A.; Cima, L. Anti-Cancer Drug
Des. 1996, 11, 243.
8. Kuo, S. C.; Lee, H. Z.; Juang, J. P.; Lin, Y. T.; Wu, T. S.;
Chang, J. J.; Lednicer, D.; Paull, K. D.; Lin, C. M.; Hamel,
E.; Lee, K. H. J. Med. Chem. 1993, 36, 1146.
9. Li, L.; Wang, H. K.; Kuo, S. C.; Wu, T. S.; Lednicer, D.;
Lin, C.; Hamel, E.; Lee, K. H. J. Med. Chem. 1994, 37, 3400.
10. Li, L.; Wang, H. K.; Kuo, S. C.; Wu, T. S.; Lednicer, D.;
Lin, C.; Hamel, E.; Lee, K. H. J. Med. Chem. 1994, 37, 1126.
11. Xia, Y.; Yang, Z. Y.; Xia, P.; Bastow, K.; Tachibana, Y.;
Kuo, S. C.; Hamel, E.; Hackl, T.; Lee, K. H. J. Med. Chem.
1998, 41, 1155.
12. Fife, T. H.; Duddy, N. W. J. Am. Chem. Soc. 1983, 105, 74.
13. Tubulin polymerization assays were performed as descri-
bed in ref 11. Cytotoxic assays were performed as described in:
Rubinstein, L. V.; Shoemaker, R. H.; Paull, K. D.; Simo,
16. 2-Phenyl-4-quinolone-8-acetic acid (11). 2-Phenyl-4-quino-
lone-8-methyl acetate (9) (150 mg, 0.51 mmol) was suspended
in 50% aq EtOH (10 mL) containing NaOH (100 mg). The
mixture was heated under reflux for 2 h. After cooling, the
solution was slowly acidified with aqueous HCl. The pre-
cipitate was collected, and washed with water to provide 140
mg of 11, yield 98%; mp 238–240 ꢁC; H NMR (DMSO-d6) d
1
4.17 (s, 2H, CH2), 7.40 (s, 1H, H-3), 7.56 (m, 2H, H-6, H-7),
7.61–8.01 (m, 5H, aromatic), 8.14 (d, 1H, J=8.0 Hz, H-5),
11.9 (s, 1H, NH), 12.9 (s, 1H, COOH).
17. 2-(20-Fluorophenyl)-4-quinolone-8-acetic acid (12). Obtained
by hydrolysis of 10 with aqueous 50% EtOH containing
NaOH using the same synthetic procedure as for 11, yield
78.9%; mp 243–245 ꢁC; H NMR (DMSO-d6) d 4.07 (s, 2H,
1
CH2), 7.35 (s, 1H, H-3), 7.35–7.40 (m, 4H, H-6, H-7, H-30 and
H-50), 7.53–7.63 (m, 2H, H-40, H-60), 8.08 (d, 1H, J=9.0 Hz,
H-5), 12.0 (br s, 1H, NH), 12.4 (S, 1H, COOH).