Discovery of New Antiproliferative Imidazopyrazole Acylhydrazones Able To Interact with Microtubule Systems. (27th April 2020)

• Record Type: Journal Article
• Authors: Brullo, Chiara; Rapetti, Federica; Alfei, Silvana; Maric, Irena; Rizzelli, Francesca; Mapelli, Marina; Rosano, Camillo; Viale, Maurizio; Bruno, Olga
• Is Part Of: ChemMedChem. Volume 15:Number 11(2020)
• Page Start: 961
• Page End: 969
• Publication Date: 2020-04-27
• Subjects: antiproliferative agents -- apoptosis -- cell cycle inhibition -- imidazo[1, 2-b]pyrazole acylhydrazones -- tubuline polymerization.; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000122
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Abstract : Two imidazopyrazole carbohydrazides were identified as potential anticancer drugs by preliminary screening of a large library of small molecules against NCI 60 panel cell lines. Further analyses showed their ability to induce apoptosis and affect cell‐cycle phases. Immunofluorescence analysis, tubulin polymerization assays and a docking study suggest that the mechanism of action involves the microtubule system.