Synthesis and anti-mitotic activity of 2,4- or 2,6-disubstituted- and 2,4,6-trisubstituted-2H-pyrazolo[4,3-c]pyridines

0489492 - ÚEB 2019 RIV FR eng J - Článek v odborném periodiku
Milišiunaitė, V. - Arbačiauskienė, E. - Řezníčková, Eva - Jorda, Radek - Malínková, V. - Žukauskaitė, Asta - Holzer, W. - Šačkus, A. - Kryštof, Vladimír
Synthesis and anti-mitotic activity of 2,4- or 2,6-disubstituted- and 2,4,6-trisubstituted-2H-pyrazolo[4,3-c]pyridines.
European Journal of Medicinal Chemistry. Roč. 150, APR 25 (2018), s. 908-919. ISSN 0223-5234. E-ISSN 1768-3254
Grant CEP: GA MŠMT(CZ) LO1204
Institucionální podpora: RVO:61389030
Klíčová slova: Apoptosis * G2/M cell cycle arrest * Pyrazole * Structure-activity relationships
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 4.833, rok: 2018

An efficient synthetic route for the synthesis of 2H-pyrazolo[4,3-c]pyridines, primarily varying by the substituents at the 2-, 4- and 6-positions, is described here. A Sonogashira-type cross-coupling reaction was employed to yield 3-alkynyl-1H-pyrazole-4-carbaldehydes, ethanones and propanones from the corresponding 1H-pyrazol-3-yl trifluoromethanesulfonates. Subsequent treatment of the coupling products with dry ammonia afforded a versatile library of 2H-pyrazolo[4,3-c] pyridines, which were then evaluated for their cytotoxicity against K562 and MCF-7 cancer cell lines. The most potent of these compounds displayed low micromolar GI 50 values in both cell lines. Active compounds induced dose-dependent cell-cycle arrest in mitosis, as shown by flow cytometric analysis of DNA content and phosphorylation of histone H3 at serine-10. Moreover, biochemical assays revealed increased activities of caspases-3/7 in treated cells, specific fragmentation of PARP-1, and phosphorylation of Bcl-2, collectively confirming apoptosis as the mechanism of cell death.
Trvalý link: http://hdl.handle.net/11104/0283900