Discovery of New Antiproliferative Imidazopyrazole Acylhydrazones Able To Interact with Microtubule Systems |
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Authors: | Prof Chiara Brullo Dr Federica Rapetti Prof Silvana Alfei Dr Irena Maric Dr Francesca Rizzelli Dr Marina Mapelli Dr Camillo Rosano Dr Maurizio Viale Prof Olga Bruno |
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Affiliation: | 1. Department of Pharmacy, University of Genoa, V.le Benedetto XV, 3, 16132 Genova, Italy;2. Department of Pharmacy, University of Genoa, V.le Cembrano, 4, 16148 Genova, Italy;3. IRCCS Ospedale Policlinico San Martino, U.O. Cellular Oncology, L.go. R. Benzi, 10, 16132 Genova, Italy;4. European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy;5. IRCCS Ospedale Policlinico San Martino, Proteomics and Mass Spectrometry Unit, L.go. R. Benzi, 10, 16132 Genova, Italy;6. IRCCS Ospedale Policlinico San Martino, U.O. Biotherapy, L.go. R. Benzi, 10, 16132 Genova, Italy |
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Abstract: | Even though immunotherapy has radically changed the search for anticancer therapies, there are still many different pathways that are open to intervention with traditional small molecules. To expand our investigation in the anticancer field, we report here a new series of compounds in which our previous pyrazole and imidazopyrazole scaffolds are linked to a differently decorated phenyl ring through an acylhydrazone linker. Preliminary tests on the library were performed at the National Cancer Institute (USA) against the full NCI 60 cell panel. The best compounds among the imidazopyrazole series were then tested by immunofluorescence staining for their inhibition of cell proliferation, apoptosis induction, and their effect on the cell cycle and on microtubules. Two compounds, in particular 4-benzyloxy-3-methoxybenzyliden imidazopyrazole-7-carbohydrazide showed good growth inhibition, with IC50 values in the low-micromolar range, and induced apoptosis. Both compounds altered the cell-cycle phases with the appearance of polyploid cells. Immunofluorescence analysis evidenced microtubules alterations; tubulin polymerization assays and docking studies suggested the tubulin system to be the possible, although not exclusive, target of the new acylhydrazone series reported here. |
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Keywords: | antiproliferative agents apoptosis cell cycle inhibition imidazo[1 2-b]pyrazole acylhydrazones tubuline polymerization |
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