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New Succinimides with Potent Anticancer Activity: Synthesis, Activation of Stress Signaling Pathways and Characterization of Apoptosis in Leukemia and Cervical Cancer Cells

Based on previously identified dicarboximides with significant anticancer and immunomodulatory activities, a series of 26 new derivatives were designed and synthesized by the Diels–Alder reaction between appropriate diene and maleimide or hydroxymaleimide moieties. The resulting imides were function...

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Autores principales: Cieślak, Marcin, Napiórkowska, Mariola, Kaźmierczak-Barańska, Julia, Królewska-Golińska, Karolina, Hawrył, Anna, Wybrańska, Iwona, Nawrot, Barbara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122671/
https://www.ncbi.nlm.nih.gov/pubmed/33919224
http://dx.doi.org/10.3390/ijms22094318
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author Cieślak, Marcin
Napiórkowska, Mariola
Kaźmierczak-Barańska, Julia
Królewska-Golińska, Karolina
Hawrył, Anna
Wybrańska, Iwona
Nawrot, Barbara
author_facet Cieślak, Marcin
Napiórkowska, Mariola
Kaźmierczak-Barańska, Julia
Królewska-Golińska, Karolina
Hawrył, Anna
Wybrańska, Iwona
Nawrot, Barbara
author_sort Cieślak, Marcin
collection PubMed
description Based on previously identified dicarboximides with significant anticancer and immunomodulatory activities, a series of 26 new derivatives were designed and synthesized by the Diels–Alder reaction between appropriate diene and maleimide or hydroxymaleimide moieties. The resulting imides were functionalized with alkanolamine or alkylamine side chains and subsequently converted to their hydrochlorides. The structures of the obtained compounds were confirmed by 1H and 13C NMR and by ESI MS spectral analysis. Their cytotoxicity was evaluated in human leukemia (K562, MOLT4), cervical cancer (HeLa), and normal endothelial cells (HUVEC). The majority of derivatives exhibited high to moderate cytotoxicity and induced apoptosis in K562 cells. Microarray gene profiling demonstrated upregulation of proapoptotic genes involved in receptor-mediated and mitochondrial cell death pathways as well as antiapoptotic genes involved in NF-kB signaling. Selected dicarboximides activated JNK and p38 kinases in leukemia cells, suggesting that MAPKs may be involved in the regulation of apoptosis. The tested dicarboximides bind to DNA as assessed by a plasmid DNA cleavage protection assay. The selected dicarboximides offer new scaffolds for further development as anticancer drugs.
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spelling pubmed-81226712021-05-16 New Succinimides with Potent Anticancer Activity: Synthesis, Activation of Stress Signaling Pathways and Characterization of Apoptosis in Leukemia and Cervical Cancer Cells Cieślak, Marcin Napiórkowska, Mariola Kaźmierczak-Barańska, Julia Królewska-Golińska, Karolina Hawrył, Anna Wybrańska, Iwona Nawrot, Barbara Int J Mol Sci Article Based on previously identified dicarboximides with significant anticancer and immunomodulatory activities, a series of 26 new derivatives were designed and synthesized by the Diels–Alder reaction between appropriate diene and maleimide or hydroxymaleimide moieties. The resulting imides were functionalized with alkanolamine or alkylamine side chains and subsequently converted to their hydrochlorides. The structures of the obtained compounds were confirmed by 1H and 13C NMR and by ESI MS spectral analysis. Their cytotoxicity was evaluated in human leukemia (K562, MOLT4), cervical cancer (HeLa), and normal endothelial cells (HUVEC). The majority of derivatives exhibited high to moderate cytotoxicity and induced apoptosis in K562 cells. Microarray gene profiling demonstrated upregulation of proapoptotic genes involved in receptor-mediated and mitochondrial cell death pathways as well as antiapoptotic genes involved in NF-kB signaling. Selected dicarboximides activated JNK and p38 kinases in leukemia cells, suggesting that MAPKs may be involved in the regulation of apoptosis. The tested dicarboximides bind to DNA as assessed by a plasmid DNA cleavage protection assay. The selected dicarboximides offer new scaffolds for further development as anticancer drugs. MDPI 2021-04-21 /pmc/articles/PMC8122671/ /pubmed/33919224 http://dx.doi.org/10.3390/ijms22094318 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cieślak, Marcin
Napiórkowska, Mariola
Kaźmierczak-Barańska, Julia
Królewska-Golińska, Karolina
Hawrył, Anna
Wybrańska, Iwona
Nawrot, Barbara
New Succinimides with Potent Anticancer Activity: Synthesis, Activation of Stress Signaling Pathways and Characterization of Apoptosis in Leukemia and Cervical Cancer Cells
title New Succinimides with Potent Anticancer Activity: Synthesis, Activation of Stress Signaling Pathways and Characterization of Apoptosis in Leukemia and Cervical Cancer Cells
title_full New Succinimides with Potent Anticancer Activity: Synthesis, Activation of Stress Signaling Pathways and Characterization of Apoptosis in Leukemia and Cervical Cancer Cells
title_fullStr New Succinimides with Potent Anticancer Activity: Synthesis, Activation of Stress Signaling Pathways and Characterization of Apoptosis in Leukemia and Cervical Cancer Cells
title_full_unstemmed New Succinimides with Potent Anticancer Activity: Synthesis, Activation of Stress Signaling Pathways and Characterization of Apoptosis in Leukemia and Cervical Cancer Cells
title_short New Succinimides with Potent Anticancer Activity: Synthesis, Activation of Stress Signaling Pathways and Characterization of Apoptosis in Leukemia and Cervical Cancer Cells
title_sort new succinimides with potent anticancer activity: synthesis, activation of stress signaling pathways and characterization of apoptosis in leukemia and cervical cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122671/
https://www.ncbi.nlm.nih.gov/pubmed/33919224
http://dx.doi.org/10.3390/ijms22094318
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