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

0082517 - ÚEB 2007 RIV FR eng J - Journal Article
Kryštof, Vladimír - Moravcová, Daniela - Paprskářová, Martina - Barbier, P. - Peyrot, V. - Hlobilková, Alice - Havlíček, Libor - Strnad, Miroslav
Synthesis and biological activity of 8-azapurine and pyrazolo[4,3-d]pyrimidine analogues of myoseverin.
[Syntéza a biologické aktivity 8-azapurinového a pyrazolo[4,3-d]pyrimidinového analogu myoseverinu.]
European Journal of Medicinal Chemistry. Roč. 41, - (2006), s. 1405-1411. ISSN 0223-5234. E-ISSN 1768-3254
R&D Projects: GA ČR GA301/05/0418; GA ČR GP204/03/D231
Institutional research plan: CEZ:AV0Z50380511
Keywords : Myoseverin * Purine * Tubulin
Subject RIV: CE - Biochemistry
Impact factor: 2.187, year: 2006

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.

Byla porovnána biologická aktivita známého purinového inhibitoru polymerace tubulinu – myoseverinu - a jeho 8-azapurinového a pyrazolo[4,3-d]pyrimidinového analogu v testu inhibice syntézy tubulinu, inhibice CDK1 a pritinádorové aktivitě na lidských nádorových buněčných liniích. Pyrazolo[4,3-d]pyrimidinový isomer myoseverinu má vedle inhibičních účinků na syntézu tubulinu (IC50=16microM) i vlastnosti inhibitoru CDK1 (IC50=4microM).
Permanent Link: http://hdl.handle.net/11104/0146054