TY - JOUR
T1 - Discovery of New Antiproliferative Imidazopyrazole Acylhydrazones Able To Interact with Microtubule Systems
AU - Brullo, C.
AU - Rapetti, F.
AU - Alfei, S.
AU - Maric, I.
AU - Rizzelli, F.
AU - Mapelli, M.
AU - Rosano, C.
AU - Viale, M.
AU - Bruno, O.
N1 - Export Date: 2 March 2021
CODEN: CHEMG
Correspondence Address: Brullo, C.; Department of Pharmacy, V.le Benedetto XV, 3, Italy; email: brullo@difar.unige.it
Chemicals/CAS: colchicine, 64-86-8; nocodazole, 31430-18-9; vinblastine, 865-21-4
Funding details: National Cancer Institute, NCI
Funding text 1: The authors thank NCI, Division of Cancer Treatment Diagnosis (USA), for screening the title compounds during the Developmental Therapeutic Program (DPI) and Dr. R. Raggio, Dr. M. Anzaldi, and O. Gagliardo for technical support.
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PY - 2020
Y1 - 2020
N2 - 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
AB - 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
KW - antiproliferative agents
KW - apoptosis
KW - cell cycle inhibition
KW - imidazo[1,2-b]pyrazole acylhydrazones
KW - tubuline polymerization.
KW - 5 amino 1 (2 hydroxy 2 phenylethyl) n' (3 benzyloxy 4 methoxybenzylidene) 1h pyrazole 4 carbohydrazide
KW - 5 amino 1 (2 hydroxy 2 phenylethyl) n' (3 benzyloxybenzylidene) 1h pyrazole 4 carbohydrazide
KW - 5 amino 1 (2 hydroxy 2 phenylethyl) n' (3 methoxy 4 phenoxybenzylidene) 1h pyrazole 4 carbohydrazide
KW - 5 amino 1 (2 hydroxy 2 phenylethyl) n' (3 phenoxybenzylidene) 1h pyrazole 4 carbohydrazide
KW - 5 amino 1 (2 hydroxy 2 phenylethyl) n' (3,4 dimethoxybenzylidene) 1h pyrazole 4 carbohydrazide
KW - 5 amino 1 (2 hydroxy 2 phenylethyl) n' (4 benzyloxy 3 methoxybenzylidene) 1h pyrazole 4 carbohydrazide
KW - 5 amino 1 (2 hydroxy 2 phenylethyl) n' (4 benzyloxybenzylidene) 1h pyrazole 4 carbohydrazide
KW - 5 amino 1 (2 hydroxy 2 phenylethyl) n' (4 fluoro 3 phenoxybenzylidene) 1h pyrazole 4 carbohydrazide
KW - 5 amino 1 (2 hydroxy 2 phenylethyl) n' (4 methoxy 3 phenoxybenzylidene) 1h pyrazole 4 carbohydrazide
KW - 5 amino 1 (2 hydroxy 2 phenylethyl) n' (4 phenoxybenzylidene) 1h pyrazole 4 carbohydrazide
KW - antineoplastic agent
KW - benzylidene derivative
KW - colchicine
KW - hydrazide derivative
KW - imidazole derivative
KW - n' (3 benzyloxy 4 methoxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
KW - n' (3 benzyloxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
KW - n' (3 methoxy 2 phenoxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
KW - n' (3 methoxy 4 phenoxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
KW - n' (3 phenoxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
KW - n' (3,4 dimethoxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
KW - n' (4 benzyloxy 3 methoxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
KW - n' (4 benzyloxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
KW - n' (4 methoxy 3 phenoxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
KW - n' (4 phenoxybenzylidene) 2 phenyl 2,3 dihydro 1h imidazo[1,2 b]pyrazole 7 carbohydrazide
KW - nocodazole
KW - pyrazole derivative
KW - tubulin
KW - unclassified drug
KW - vinblastine
KW - 786-O cell line
KW - A-549 cell line
KW - A2780 cell line
KW - antiproliferative activity
KW - Article
KW - cancer inhibition
KW - cell cycle G0 phase
KW - cell cycle G1 phase
KW - cell cycle G2 phase
KW - cell cycle M phase
KW - cell cycle S phase
KW - cell interaction
KW - cell proliferation
KW - controlled study
KW - drug efficacy
KW - drug mechanism
KW - drug potency
KW - drug synthesis
KW - drug targeting
KW - female
KW - HT-29 cell line
KW - human
KW - human cell
KW - IC50
KW - immunofluorescence
KW - IMR-32 cell line
KW - LC50
KW - LOX-IMVI cell line
KW - male
KW - MDA-MB-435 cell line
KW - MDA-MB-453 cell line
KW - microtubule
KW - microtubule assembly
KW - multinuclear cell
KW - NCI-H460 cell line
KW - OVCAR-3 cell line
KW - OVCAR-4 cell line
KW - PC-3 [Human prostate carcinoma] cell line
KW - preliminary data
KW - priority journal
KW - proapoptotic activity
KW - SF295 cell line
KW - SF539 cell line
KW - SK-BR-3 cell line
KW - SNB-75 cell line
KW - structure activity relation
KW - SW620 cell line
KW - T-47D cell line
KW - tubulin polymerization assay
KW - U-251MG cell line
U2 - 10.1002/cmdc.202000122
DO - 10.1002/cmdc.202000122
M3 - Article
VL - 15
SP - 961
EP - 969
JO - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
IS - 11
ER -