Y. Liu et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1639–1641
1641
We obtained the designed title compounds, but the
synthetic approach was rather long and had a ‘bottle-
neck’ step [compound 5 was obtained in lower yield
(almost 20%)]. Further improvements are underway.
4. Kramer, R. M.; Johansen, B.; Hession, C.; Pepinsky, R. B.
Adv. Prostaglandin Thromboxane Leuktriene Res. 1990, 20,
79.
5. Conrad, M.; Limpach, L. Ber. 1887, 20, 944.
6. Kaslow, C. E.; Lauer, W. H. Org. Synth. Coll. 1955, 3,
194.
A preliminary bioassay study in vitro showed that
compounds 11 and 12 displayed inhibition to Naja naja
sPLA2 with the IC50 of 10 mMin the system we used.
The IC50 of compound 10 was 1 mM, and it was also
shown to be active on an animal model (data not
shown). The concentration–velocity (maximum) curve
of compound 10 compared to a standard curve is shown
in Figure 2.
7. New compounds gave satisfactory structural data. Selected
1
physical data and H NMR data are as follows: 10: M S:m/z
308 (M+) calcd for C18H16N2O3 308. 34; 1H NMR (400 MHz,
CD3COCD3): 3.94 (s, 3H, –OCH3), 4.05 (s, 2H, –CH2–), 6.52
(br, 1H, –NH, disappears after D2O exchange), 7.15 (br, 1H,
–NH, disappears after D2O exchange), 7.22–7.28 (m, 4H, 3-H,
Ph-H), 7.32 (dd, 1H, J=9.4, 2.0 Hz 7-H), 7.44–7.52 (m, 2H,
Ph-H), 7.54 (d, J=2.0 Hz, 5-H), 7.59 (d, J=9.4 Hz, 8-H);
Anal (calcd) %: C: 70.11 (70.13); H: 5.23 (5.19); N: 9.11 (9.09).
12. m/z 294 (M+) calcd for C17H14N2O3 294.32; 1H NM R
(400 MHz, CD3COCD3): 3.84 (s, 3H, –OCH3) 7.22–7.28 (m,
3H, Ph-H), 7.29 (s, 1H, 3-H), 7.35 (dd, 1H, J=8.2, 1.9 Hz, 7-
H), 7.45–7.49 (m, 2H, Ph-H), 7.57 (d, 1H, J=1.9 Hz, 5-H),
7.60 (d, 1H, J=8.2 Hz, 8-H), 7.89 (br, 1H, –NH weakens after
D2O exchange), 8.29 (br, 1H, –NH2, weakens after D2O
exchange); Anal (calcd)%: C: 69.48 (69.39); H: 4.71 (4.76); N:
9.48 (9.52).
Conclusions
We have designed and synthesized novel quinoline-4-
acetamide compounds as non-structural analogues of
the phospholipidic substrate of PLA2s. Bioassay results
indicate that the compounds are potential inhibitors of
sPLA2.
8. Washburn, W. N.; Dennis, E. A. J. Am. Chem. Soc. 1990,
112, 2040.
9. Washburn, W. N.; Dennis, E. A.. J. Biol. Chem. 1991, 266,
5042.
10. Test condition in vitro: Re=1.6; CMC=0.29;
[SIBLINKS]=0.768 M; [Triton]=1.49 mM; T=22 ꢀC;
[PLA2]=7.5 mg/mL.
11. Scott, D. L.; White, S. P.; Browning, J. L.; Rosa, J. J.;
Gelb, M. H.; Sigler, P. B. Science 1991, 254, 1007.
12. Kuntz, I. D.; Blaney, J. M.; Oatley, S. J.; Langridge, R.;
Ferrin, T. E. J. Mol. Biol. 1982, 161, 269.
Acknowledgements
This work was supported by the 863 High Technology
Program of China (863-103-13-04-02) and the National
Natural Science Foundation of China.
13. Meng, E. C.; Kuntz, I. D.; Abraham, D. J.; Kellogg, G. E.
J. Comput.-Aided. Mol. Des. 1994, 8, 299.
14. Wang, R. X.; Liu, L.; Lai, L. H.; Tang, Y. Q. J. Mol.
Model. 1998, 4, 379.
15. Wang, R. X.; Gao, Y.; Lai, L. H. J. Mol. Model. 2000, 6,
498.
16. Arndt, F.; Eistert, B. Ber. 1935, 1, 38.
References and Notes
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2. Vadas, P. Biochim. Biophys. Acta 1997, 1346, 193.
3. Buchler, M.; Malfertheiner, P.; Schadlich, H.; Nevalainen,
T. J.; Friess, H.; Berger, H. G. Gastroenterology 1989, 97, 1521.