Pro‑apoptotic activity of novel synthetic isoxazole derivatives exhibiting inhibitory activity against tumor cell growth <em>in&nbsp;vitro</em>

Lampronti,Ilaria; Simoni,Daniele; Rondanin,Riccardo; Baruchello,Riccardo; Scapoli,Chiara; Finotti,Alessia; Borgatti,Monica; Tupini,Chiara; Gambari,Roberto

doi:10.3892/ol.2020.12002

Pro‑apoptotic activity of novel synthetic isoxazole derivatives exhibiting inhibitory activity against tumor cell growth in vitro

Authors:
- Ilaria Lampronti
- Daniele Simoni
- Riccardo Rondanin
- Riccardo Baruchello
- Chiara Scapoli
- Alessia Finotti
- Monica Borgatti
- Chiara Tupini
- Roberto Gambari
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Affiliations: Department of Life Sciences and Biotechnology, Ferrara University, I‑44121 Ferrara, Italy, Department of Chemical and Pharmaceutical Sciences, Ferrara University, I‑44121 Ferrara, Italy
Published online on: August 24, 2020 https://doi.org/10.3892/ol.2020.12002
Article Number: 151
Copyright: © Lampronti et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

In order to develop potential anticancer agents stimulating apoptosis, novel 3,4‑isoxazolediamide and 4,5,6,7‑tetrahydro‑isoxazolo‑[4,5‑c]‑pyridine derivatives have been synthetized. The original structures of geldanamycin and radicicol, which are known natural heat shock protein (HSP) inhibitors, were deeply modified because both of them exhibit several drawbacks, such as poor solubility, hepatotoxicity, intrinsic chemical instability or deprivation of the in vivo activity. This novel class of synthetic compounds containing the isoxazole nucleus exhibited potent and selective inhibition of HSP90 in previous studies. Biological assays (focusing on in vitro antiproliferative effects and pro‑apoptotic activity) in human erythroleukemic K562 cells (as a model system referring to tumor cells grown in suspension), glioblastoma U251‑MG and glioblastoma temozolomide (TMZ)‑resistant T98G cell lines (two model systems referring to tumor cells grown attached to the flask), were performed. Almost all isoxazole derivatives demonstrated significant antiproliferative and pro‑apoptotic activities, showing induction of both early and late apoptosis of K562 cells. Different effects were observed on the glioma U251‑MG and T98G cells, depending on the structure of the analogues. Antiproliferative and pro‑apoptotic activities in K562 cells were associated with the activation of the erythroid differentiation program. The present study demonstrated that 3,4‑isoxazolediamide and 4,5,6,7‑tetrahydro‑isoxazolo‑[4,5‑c]‑pyridine derivatives should be considered for in vivo studies focusing on the development of anticancer drugs acting, at least partially, via activation of apoptosis.

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