Synthesis and biological activity of 8-azapurine and pyrazolo[4,3-d]pyrimidine analogues of myoseverin

Eur J Med Chem. 2006 Dec;41(12):1405-11. doi: 10.1016/j.ejmech.2006.07.004. Epub 2006 Sep 22.

Abstract

The trisubstituted purine myoseverin has been recently identified as a novel inhibitor of microtubule assembly. To analyze the effects of modifying its heterocyclic skeleton, we prepared 8-azapurine and pyrazolo[4,3-d]pyrimidine analogues of myoseverin and compared their biological activities. Rearrangement of nitrogen atoms in the heterocycle changes the affinity of the compounds to purified tubulin, as demonstrated by the results of polymerization assays, and affects the proliferation of cancer cell lines. Surprisingly, compound E2GG, a pyrazolo[4,3-d]pyrimidine analogue of myoseverin, displayed inhibitory activity towards both tubulin polymerization and the activity of cyclin-dependent kinases 1, 2 and 7. Such a dual specificity-inhibitor offers a starting point for developing a novel class of antiproliferative agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Magnetic Resonance Spectroscopy
  • Purines / chemical synthesis*
  • Purines / pharmacology*
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / pharmacology*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacology*

Substances

  • Purines
  • Pyrazoles
  • Pyrimidines
  • myoseverin
  • pyrazolo(3,4-d)pyrimidine
  • triazolopyrimidinone