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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
- 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.
- Subjects :
- 0301 basic medicine
Uterine Cervical Neoplasms
HeLa
0302 clinical medicine
dicarboximides
Biology (General)
Cytotoxicity
Spectroscopy
Cells, Cultured
Leukemia
biology
Kinase
Chemistry
apoptosis
General Medicine
MAP Kinase Kinase Kinases
Computer Science Applications
kinases
Biochemistry
gene profiling
030220 oncology & carcinogenesis
cytotoxicity
Female
Signal Transduction
SAR
Programmed cell death
QH301-705.5
p38 mitogen-activated protein kinases
Succinimides
Antineoplastic Agents
anticancer
Catalysis
Article
Inorganic Chemistry
03 medical and health sciences
medicine
Humans
Physical and Theoretical Chemistry
Molecular Biology
QD1-999
Organic Chemistry
Endothelial Cells
medicine.disease
biology.organism_classification
030104 developmental biology
Apoptosis
K562 Cells
Protein Kinases
chemical synthesis
K562 cells
HeLa Cells
Subjects
Details
- ISSN :
- 14220067
- Volume :
- 22
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- International journal of molecular sciences
- Accession number :
- edsair.doi.dedup.....fca3519be11bac87f9a9558c2688c5dc