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

Marcin Cieślak,Iwona Wybrańska,Barbara Nawrot,Julia Kaźmierczak-Barańska,Karolina Królewska-Golińska,Anna Hawrył,Mariola Napiórkowska

doi:10.3390/ijms22094318

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.

Highlights

Cancer diseases are an important problem in the clinical medicine and pharmacology of the 21st century
We have previously identified several lead dicarboximides structurally related to succinimides and phthalimides, which exhibited high cytotoxicity and selectivity toward leukemia cells
We found that they targeted the ABC50 protein, showed immunomodulatory activity, and induced apoptosis in leukemia cells [9,10,11]

Summary

Introduction

Cancer diseases are an important problem in the clinical medicine and pharmacology of the 21st century. More than eight million people die from cancer worldwide. In. Europe alone, three million new cases are diagnosed and 1.7 million people die from cancer. In Poland, cancer kills nearly 110,000 people, of which about 100,000 die from malignant tumors. It is estimated that the ongoing increase in the incidence of cancer will make it the main cause of death in Poland and worldwide in the coming decades [1,2]. Despite recent progress in cancer treatment (for example development of immune checkpoint inhibitors), chemotherapy (either alone or in combination with radiotherapy or biologic drugs) still remains the first-line treatment in the majority of cancers. New cytotoxic low molecular weight compounds are actively sought and developed because they may offer

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