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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

Authors :
Mariola Napiórkowska
Julia Kaźmierczak-Barańska
Barbara Nawrot
Karolina Królewska-Golińska
Iwona Wybrańska
Marcin Cieślak
Anna Hawrył
Source :
International Journal of Molecular Sciences, Volume 22, Issue 9, International Journal of Molecular Sciences, Vol 22, Iss 4318, p 4318 (2021)
Publication Year :
2021

Abstract

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.

Details

ISSN :
14220067
Volume :
22
Issue :
9
Database :
OpenAIRE
Journal :
International journal of molecular sciences
Accession number :
edsair.doi.dedup.....fca3519be11bac87f9a9558c2688c5dc