Discovery of New Antiproliferative Imidazopyrazole Acylhydrazones Able To Interact with Microtubule Systems

C. Brullo, F. Rapetti, S. Alfei, I. Maric, F. Rizzelli, M. Mapelli, C. Rosano, M. Viale, O. Bruno

Research output: Contribution to journal › Article › peer-review

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. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Original languageEnglish
Pages (from-to)961-969
Number of pages9
JournalChemMedChem
Volume15
Issue number11
DOIs
Publication statusPublished - 2020

Keywords

  • antiproliferative agents
  • apoptosis
  • cell cycle inhibition
  • imidazo[1,2-b]pyrazole acylhydrazones
  • tubuline polymerization.
  • 5 amino 1 (2 hydroxy 2 phenylethyl) n' (3 benzyloxy 4 methoxybenzylidene) 1h pyrazole 4 carbohydrazide
  • 5 amino 1 (2 hydroxy 2 phenylethyl) n' (3 benzyloxybenzylidene) 1h pyrazole 4 carbohydrazide
  • 5 amino 1 (2 hydroxy 2 phenylethyl) n' (3 methoxy 4 phenoxybenzylidene) 1h pyrazole 4 carbohydrazide
  • 5 amino 1 (2 hydroxy 2 phenylethyl) n' (3 phenoxybenzylidene) 1h pyrazole 4 carbohydrazide
  • 5 amino 1 (2 hydroxy 2 phenylethyl) n' (3,4 dimethoxybenzylidene) 1h pyrazole 4 carbohydrazide
  • 5 amino 1 (2 hydroxy 2 phenylethyl) n' (4 benzyloxy 3 methoxybenzylidene) 1h pyrazole 4 carbohydrazide
  • 5 amino 1 (2 hydroxy 2 phenylethyl) n' (4 benzyloxybenzylidene) 1h pyrazole 4 carbohydrazide
  • 5 amino 1 (2 hydroxy 2 phenylethyl) n' (4 fluoro 3 phenoxybenzylidene) 1h pyrazole 4 carbohydrazide
  • 5 amino 1 (2 hydroxy 2 phenylethyl) n' (4 methoxy 3 phenoxybenzylidene) 1h pyrazole 4 carbohydrazide
  • 5 amino 1 (2 hydroxy 2 phenylethyl) n' (4 phenoxybenzylidene) 1h pyrazole 4 carbohydrazide
  • antineoplastic agent
  • benzylidene derivative
  • colchicine
  • hydrazide derivative
  • imidazole derivative
  • n' (3 benzyloxy 4 methoxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
  • n' (3 benzyloxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
  • n' (3 methoxy 2 phenoxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
  • n' (3 methoxy 4 phenoxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
  • n' (3 phenoxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
  • n' (3,4 dimethoxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
  • n' (4 benzyloxy 3 methoxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
  • n' (4 benzyloxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
  • n' (4 methoxy 3 phenoxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
  • n' (4 phenoxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
  • nocodazole
  • pyrazole derivative
  • tubulin
  • unclassified drug
  • vinblastine
  • 786-O cell line
  • A-549 cell line
  • A2780 cell line
  • antiproliferative activity
  • Article
  • cancer inhibition
  • cell cycle G0 phase
  • cell cycle G1 phase
  • cell cycle G2 phase
  • cell cycle M phase
  • cell cycle S phase
  • cell interaction
  • cell proliferation
  • controlled study
  • drug efficacy
  • drug mechanism
  • drug potency
  • drug synthesis
  • drug targeting
  • female
  • HT-29 cell line
  • human
  • human cell
  • IC50
  • immunofluorescence
  • IMR-32 cell line
  • LC50
  • LOX-IMVI cell line
  • male
  • MDA-MB-435 cell line
  • MDA-MB-453 cell line
  • microtubule
  • microtubule assembly
  • multinuclear cell
  • NCI-H460 cell line
  • OVCAR-3 cell line
  • OVCAR-4 cell line
  • PC-3 [Human prostate carcinoma] cell line
  • preliminary data
  • priority journal
  • proapoptotic activity
  • SF295 cell line
  • SF539 cell line
  • SK-BR-3 cell line
  • SNB-75 cell line
  • structure activity relation
  • SW620 cell line
  • T-47D cell line
  • tubulin polymerization assay
  • U-251MG cell line

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