Centre of Molecular and Macromolecular Studies, Department of Bioorganic Chemistry, Polish Academy of Sciences, 112 Sienkiewicza, 90-363 Lodz, Poland.
Department of Biochemistry, Faculty of Medicine, Medical University of Warsaw, 1 Banacha, 02-097 Warsaw, Poland.
Int J Mol Sci. 2021 Apr 21;22(9):4318. doi: 10.3390/ijms22094318.
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.
基于先前具有显著抗癌和免疫调节活性的二酰亚胺，通过适当的二烯和马来酰亚胺或羟马来酰亚胺部分之间的 Diels-Alder 反应，设计并合成了一系列 26 种新衍生物。所得酰亚胺用烷醇胺或烷基胺侧链官能化，然后转化为其盐酸盐。通过 1H 和 13C NMR 以及 ESI MS 光谱分析确认了获得的化合物的结构。在人白血病（K562、MOLT4）、宫颈癌（HeLa）和正常内皮细胞（HUVEC）中评估了它们的细胞毒性。大多数衍生物表现出高至中等的细胞毒性，并诱导 K562 细胞凋亡。微阵列基因谱分析表明，与受体介导和线粒体细胞死亡途径相关的促凋亡基因以及与 NF-kB 信号转导相关的抗凋亡基因上调。选定的二酰亚胺在白血病细胞中激活 JNK 和 p38 激酶，表明 MAPK 可能参与细胞凋亡的调节。通过质粒 DNA 切割保护测定评估了测试的二酰亚胺与 DNA 的结合。选定的二酰亚胺为进一步开发作为抗癌药物提供了新的支架。
