Bulletin of the Korean Chemical Society

Korean Chemical Society (대한화학회)
권호 표지
DOI QR코드

DOI QR Code

Solid-phase Synthesis and Preliminary Evaluation of 1,6,8-Trisubstituted Tetrahydro-2H-pyrazino[1,2-a]pyrimidine-4,7-diones as a NF-kB Inhibitor

  • Kim, Jin-Woong (Medicinal Chemistry Research Center, Korea Institute of Science and Technology) ;
  • Cho, Jung-Hyuck (Medicinal Chemistry Research Center, Korea Institute of Science and Technology) ;
  • Han, Tae-hee (Hawon Pharm. Co.) ;
  • Lee, Jong-Baek (Department of Chemical Engineering, Dongeui University) ;
  • Oh, Chang-Hyun (Medicinal Chemistry Research Center, Korea Institute of Science and Technology)
  • Published : 2006.04.20
Download PDF
⟨ Previous Next ⟩

Abstract

The solid-phase synthesis of new series of 1,6,8-trisubstituted tetrahydro-2H-pyrazino[1,2-a]pyrimidine-4,7-diones as bicyclic $\beta$-turn mimetics is described. Their NF-kB inhibition activities were tested and the effect of substituents on bicyclic ring was investigated. Among the prepared compounds, the fluorobenzyl and methoxybenzyl group substituted compounds 26 and 27 at C-1 and C-8 position showed more inhibitory activities than the others. Tested at a concentration of 10 uM, these two compounds showed a 60% inhibition against the target NF kB 549.

Keywords

References

  1. Haefner, B. Drug discovery today 2002, 7, 653 https://doi.org/10.1016/S1359-6446(02)02309-7
  2. Karin, M.; Cao, Y.; Greten, F. R.; Li, Z.-W. Nat. Rev. Cancer 2002, 2, 301 https://doi.org/10.1038/nrc780
  3. O'Byrne, K. J.; Dalgleish, A. G. Br. J. Cancer 2001, 85, 473 https://doi.org/10.1054/bjoc.2001.1943
  4. Balkwill, F.; Mantovani, A. Lancet. 2001, 357, 539 https://doi.org/10.1016/S0140-6736(00)04046-0
  5. Baxter, A.; Brough, S.; Faull, A.; Johnstone, C.; Mcinally, T. WO0158890
  6. Ritzeler, O.; Stilz, H. U.; Neises, B.; Bock, W. J.; Walser, A.; Flynn, G. A. WO0100610
  7. Ritzeler, O.; Stilz, H. U.; Neises, B.; Jaehne, G.; Habermann, J. WO0130774
  8. Kahn, M. Synlett. 1993, 11, 821
  9. Souers, A. J.; Virgilio, A. A.; Schürer, S. S.; Ellman, J. A.; Kogan, T. P.; Ankener, H. W.; Vanderslice, P. Bioorg. Med. Chem. Lett. 1998, 8, 2297 https://doi.org/10.1016/S0960-894X(98)00416-8
  10. Souers, A. J.; Virgilio, A. A.; Rosenquist, A.; FenuikJ. A.; Ellman, A. J. Am. Chem. Soc. 1999, 121, 1817 https://doi.org/10.1021/ja983742p
  11. Masakatsu, E.; Lee, M. S.; Hiroshi, N.; Marcin, S.; Scott, L.; Kahn, M. J. Am. Chem. Soc. 1999, 121, 12204 https://doi.org/10.1021/ja992203x
  12. Masakatsu, E.; Lee, M. S.; Richard, Y. W.; Shea, J. P.; Marcin, S.; Scot, L.; Kahn, M. J. Med. Chem. 2002, 45, 1395 https://doi.org/10.1021/jm0155897
  13. Masakatsu, E.; Lee, M. S.; Stasiak, M.; Kahn, M. Tetrahedron Lett. 2001, 42, 1237 https://doi.org/10.1016/S0040-4039(00)02248-6
  14. Kee, K. S.; Jois, D. S. Current Pharmaceutical Design 2003, 9, 1209 https://doi.org/10.2174/1381612033454900
  15. Kahn, M. Ed. Tetrahedron 1993, 49, Symposia 50, 3433 https://doi.org/10.1016/S0040-4020(01)90205-4
  16. Hanessian, S.; McNaughton-Smith, G.; Lombart, H. G.; Lubell, W. D. Tetrahedron 1997, 53, 12789 https://doi.org/10.1016/S0040-4020(97)00476-6
  17. Gillespie, P.; Cicariello, J.; Olson, G. L. Biopolymers 1997, 43, 191 https://doi.org/10.1002/(SICI)1097-0282(1997)43:3<191::AID-BIP2>3.0.CO;2-Q
  18. Hanessian, S.; Huynh, H. K.; Reddy, G. V.; McNaughton-Smith, G.; Ernst, B.; Sweeley, C. Bioorg. Med. Chem. Lett. 1998, 8, 2803 https://doi.org/10.1016/S0960-894X(98)00500-9
  19. Fink, B. E.; Kym, P. R.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1998, 120, 4334 https://doi.org/10.1021/ja974023y
  20. Hirschmann, R.; Hynes, J.; Cichy-Knight, M. A.; Pietranico-Cole, S.; Smith, A. B. J. Med. Chem. 1998, 41, 1382 https://doi.org/10.1021/jm9800346
  21. Jeong, D.-W.; Yoo, M.-H.; Kim, T. S.; Kim, J.-H.; Kim, I. Y. The J. of Biol. Chem. 2002, 277, 17871 https://doi.org/10.1074/jbc.M200808200

Cited by

  1. Solution-phase Synthesis and Preliminary Evaluation of 1,6,8-Trisubstituted Tetrahydro-2H-pyrazino[1,2-a]pyrimidin-4,7-dione Derivatives as a NF-kB Inhibitor vol.27, pp.12, 2006, https://doi.org/10.5012/bkcs.2006.27.12.2087
  2. An efficient synthesis of (E)-(2-arylpyrazino[1,2-a]pyrimidine-4-ylidene)acetonitriles and cyanomethyl appended pyrimidines vol.48, pp.4, 2006, https://doi.org/10.1016/j.tetlet.2006.11.136
  3. Research developments in the syntheses, anti-inflammatory activities and structure-activity relationships of pyrimidines vol.11, pp.11, 2006, https://doi.org/10.1039/d0ra10657g