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

• Published in: European journal of medicinal chemistry Vol. 41; no. 12; pp. 1405 - 1411
• Main Authors: Kryštof, Vladimír, Moravcová, Daniela, Paprskářová, Martina, Barbier, Pascale, Peyrot, Vincent, Hlobilková, Alice, Havlíček, Libor, Strnad, Miroslav
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 01.12.2006; Elsevier
• Subjects: Antineoplastic agents; Biochemistry; Biochemistry, Molecular Biology; Biological and medical sciences; Chemical Sciences; Chemistry, Medicinal; Cyclin-dependent kinase; Cytoskeleton; General aspects; Life Sciences; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Medical sciences; Medicinal Chemistry; Myoseverin; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Purine; Purines - chemical synthesis; Purines - pharmacology; Pyrazoles - chemical synthesis; Pyrazoles - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Science & Technology; Tubulin; Cyclin-dependent kinase; Cytoskeleton; Purine; Tubulin; Myoseverin; CELLS; PROTEIN; cytoskeleton; myoseverin; MICROTUBULE ASSEMBLY INHIBITORS; tubulin; DEPENDENT KINASE INHIBITOR; OLOMOUCINE; TRIAZINE; IN-VITRO; purine; cyclin-dependent kinase; BRAIN; Antineoplastic agent; Human; Flow cytometry; Purine derivatives; Enzyme; Transferases; Antitubulin; In vitro; Biological activity; Signal transduction; Cell line; Protein kinase; Cell cycle; Immunofluorescence; Chemical synthesis; Antimitotic; Cyclin dependent kinase; Tumor cell
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2006.07.004

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. [Display omitted] To analyze the effects of modifying heterocyclic skeleton of myoseverin, its 8-azapurine and pyrazolo[4,3- d]pyrimidine analogues were prepared and compared in biochemical and biological assays.