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 GI50 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.

Department of Chemical Biology and Genetics Centre of the Region Haná for Biotechnological and Agricultural Research Faculty of Science Palacký University Šlechtitelů 27 CZ 78371 Olomouc Czech Republic

Department of Organic Chemistry Kaunas University of Technology Radvilėnų pl 19 LT 50254 Kaunas Lithuania

Division of Drug Synthesis Department of Pharmaceutical Chemistry University of Vienna Althanstrasse 14 A 1090 Vienna Austria

Laboratory of Growth Regulators Centre of the Region Haná for Biotechnological and Agricultural Research Palacký University and Institute of Experimental Botany ASCR Šlechtitelů 27 CZ 78371 Olomouc Czech Republic

Laboratory of Growth Regulators Centre of the Region Haná for Biotechnological and Agricultural Research Palacký University and Institute of Experimental Botany ASCR Šlechtitelů 27 CZ 78371 Olomouc Czech Republic; Department of Chemical Biology and Genetics Centre of the Region Haná for Biotechnological and Agricultural Research Faculty of Science Palacký University Šlechtitelů 27 CZ 78371 Olomouc Czech Republic

References provided by Crossref.org

Synthesis and Characterization of New Pyrano[2,3-c]pyrazole Derivatives as 3-Hydroxyflavone Analogues

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Convenient Synthesis of N-Heterocycle-Fused Tetrahydro-1,4-diazepinones

Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2H-pyrazolo[4,3-c]pyridines