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New derivatives of 4'-phenyl-2,2':6',2''-terpyridine as promising anticancer agents
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-11-23 , DOI: 10.1016/j.ejmech.2020.113032
Katarzyna Malarz , Dawid Zych , Robert Gawecki , Michał Kuczak , Robert Musioł , Anna Mrozek-Wilczkiewicz

Terpyridine derivatives are known from their broad application including anticancer properties. In this work we present the newly synthesised 4'-phenyl-2,2':6',2''-terpyridine group with high antiproliferative activity. We suggest that these compounds influence cellular redox homeostasis. Cancer cells are particularly susceptible to any changes in the redox balance because of their handicapped and inefficient antioxidant cellular systems. The antiproliferative activity of the studied compounds was tested on five different cell lines that represent several types of tumours; glioblastoma, leukaemia, breast, pancreatic and colon. Additionally, we also tested their selectivity towards normal cells. We performed molecular biology studies in order to detect the response of a cell to its treatment with the compounds that were tested. We looked at the in-depth changes in the proteins and cellular pathways that lead to cell cycle inhibition (G0/G1 and S), and consequently, death on the apoptosis and autophagy pathways. We proved that the studied compounds targeted DNA as well. Special attention was paid to the targets connected with ROS generation.



中文翻译:

4'-苯基-2,2':6',2''-吡啶的新衍生物有望用作抗癌药

特吡啶吡啶衍生物因其广泛的应用而广为人知,包括抗癌特性。在这项工作中,我们提出了新合成的具有高抗增殖活性的4'-苯基-2,2':6',2''-吡啶基。我们建议这些化合物影响细胞氧化还原稳态。癌细胞由于残障和低效的抗氧化剂细胞系统而特别容易受到氧化还原平衡变化的影响。在代表几种类型肿瘤的五种不同细胞系中测试了所研究化合物的抗增殖活性。胶质母细胞瘤,白血病,乳腺癌,胰腺癌和结肠癌。此外,我们还测试了它们对正常细胞的选择性。我们进行了分子生物学研究,以检测细胞对其受测试化合物处理的反应。我们研究了导致细胞周期抑制(G0 / G1和S)并因此导致细胞凋亡和自噬途径死亡的蛋白质和细胞途径的深入变化。我们证明了所研究的化合物也靶向DNA。特别关注与ROS产生有关的靶标。

更新日期:2020-11-23
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