Imidazo[4,5-b]pyridine derived tubulin polymerization inhibitors: Design, synthesis, biological activity in vitro and computational analysis (CROSBI ID 312302)
Prilog u časopisu | izvorni znanstveni rad | međunarodna recenzija
Podaci o odgovornosti
Boček, Ida ; Hok, Lucija ; Persoons, Leentje ; Daelemans, Dirk ; Vianello, Robert ; Hranjec, Marijana
engleski
Imidazo[4,5-b]pyridine derived tubulin polymerization inhibitors: Design, synthesis, biological activity in vitro and computational analysis
Imidazo[4, 5-b]pyridine derived acrylonitriles were synthesized and explored for their in vitro antiproliferative effect on a diverse human cancer cell line panel. Three compounds, 20, 21 and 33, showed strong activity in the submicromolar range (IC50 0.2–0.6 μM), and were chosen for further biological experiments. Immunofluorescence staining and tubulin polymerization assays confirmed tubulin as the main target, but excluded its colchicine-binding site as a potential interacting unit. This was supported by the computational analysis, which revealed that the most potent ligands act on the extended colchicine site on the surface between interacting tubulin subunits, where they interfere with their polymerization and reveal pronounced antitumor properties. In addition, lead molecule 21 potently inhibited cancer cell migration, while it did not affect the viability of normal cells even at the highest concentration tested (100 μM).
acrylonitriles ; amination ; antiproliferative activity in vitro ; imidazo[4, 5-b]pyridine ; docking simulations ; molecular dynamic simulations ; tubulin polymerization
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Podaci o izdanju
127
2022.
106032
13
objavljeno
0045-2068
1090-2120
10.1016/j.bioorg.2022.106032
Povezanost rada
Biologija, Kemija, Temeljne medicinske znanosti