Synthesis and biological activity of 8-azapurine and pyrazolo[4,3-d]pyrimidine analogues of myoseverin.
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.
Krystof
Vladimír
V
Laboratory of Growth Regulators, Faculty of Science, Palacký University & Institute of Experimental Botany AS CR, Slechtitelů 11, 783 71 Olomouc, Czech Republic. krystof@prfholnt.upol.cz
Moravcová
Daniela
D
Paprskárová
Martina
M
Barbier
Pascale
P
Peyrot
Vincent
V
Hlobilková
Alice
A
Havlícek
Libor
L
Strnad
Miroslav
M
D009682:Magnetic Resonance Spectroscopy; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*
D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; C407365:myoseverin; C014175:pyrazolo(3,4-d)pyrimidine; C015008:triazolopyrimidinone