Synthesis and evaluation of anticancer activity of new 4,5,6,7-tetrabromo-1H-benzimidazole derivatives.

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-10-10 DOI:10.1016/j.bioorg.2024.107880

Edyta Łukowska-Chojnacka, Egor Fedorov, Anna Kowalkowska, Monika Wielechowska, Anna Sobiepanek, Mirosława Koronkiewicz, Patrycja Wińska

{"title":"Synthesis and evaluation of anticancer activity of new 4,5,6,7-tetrabromo-1H-benzimidazole derivatives.","authors":"Edyta Łukowska-Chojnacka, Egor Fedorov, Anna Kowalkowska, Monika Wielechowska, Anna Sobiepanek, Mirosława Koronkiewicz, Patrycja Wińska","doi":"10.1016/j.bioorg.2024.107880","DOIUrl":null,"url":null,"abstract":"An efficient method for the synthesis of new 4,5,6,7-tetrabromo-1H-benzimidazole derivatives has been developed. New ketones were obtained by N-alkylation of TBBi or 2-Me-TBBi with various phenacyl halides and then reduced to the corresponding alcohols. All compounds were obtained with satisfactory yields in the range of 40-91 %. The synthesized compounds appeared a weak CK2 and PIM-1 inhibitors but exhibit an interesting cytotoxic activity against cancer cell lines, i.e. MCF-7, PC-3, CCRF-CEM, K-562. 1-Phenyl-2-(4,5,6,7-tetrabromo-1H-benzimidazol-1-yl)ethanone 3aA exhibits the highest cytotoxic activity with IC50 value of 5.30 µM for MCF-7 and 6.80 µM for CCRF-CEM. Moreover, this compound shows the highest selectivity against both MCF-7 and CCRF-CEM with SI selectivity coefficients (against MRC-5 and Vero cells) equal 5.45 and 4.30 for MCF-7 and 4.25 and 3.35 for CCRF-CEM, respectively. Furthermore, it was shown that compound 3aA exhibits very good pro-apoptotic properties, through induction of the mitochondrial apoptotic pathway in CCRF-CEM cells. These results correlate with data showing the effect of 3aA on intracellular level of CK2α protein and CK2-mediated phosphorylation of Ser529 in NF-κBp65. Study of the effect of compound 3aA on mRNA levels of CK2α and CK2α' showed no significant differences in gene expression levels in control CCRF-CEM and cells treated with 3aA, indicating 3aA action at the protein level.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107880"},"PeriodicalIF":4.5000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic Chemistry","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1016/j.bioorg.2024.107880","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/10 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

An efficient method for the synthesis of new 4,5,6,7-tetrabromo-1H-benzimidazole derivatives has been developed. New ketones were obtained by N-alkylation of TBBi or 2-Me-TBBi with various phenacyl halides and then reduced to the corresponding alcohols. All compounds were obtained with satisfactory yields in the range of 40-91 %. The synthesized compounds appeared a weak CK2 and PIM-1 inhibitors but exhibit an interesting cytotoxic activity against cancer cell lines, i.e. MCF-7, PC-3, CCRF-CEM, K-562. 1-Phenyl-2-(4,5,6,7-tetrabromo-1H-benzimidazol-1-yl)ethanone 3aA exhibits the highest cytotoxic activity with IC₅₀ value of 5.30 µM for MCF-7 and 6.80 µM for CCRF-CEM. Moreover, this compound shows the highest selectivity against both MCF-7 and CCRF-CEM with SI selectivity coefficients (against MRC-5 and Vero cells) equal 5.45 and 4.30 for MCF-7 and 4.25 and 3.35 for CCRF-CEM, respectively. Furthermore, it was shown that compound 3aA exhibits very good pro-apoptotic properties, through induction of the mitochondrial apoptotic pathway in CCRF-CEM cells. These results correlate with data showing the effect of 3aA on intracellular level of CK2α protein and CK2-mediated phosphorylation of Ser529 in NF-κBp65. Study of the effect of compound 3aA on mRNA levels of CK2α and CK2α' showed no significant differences in gene expression levels in control CCRF-CEM and cells treated with 3aA, indicating 3aA action at the protein level.

查看原文本刊更多论文

4,5,6,7-四溴-1H-苯并咪唑新衍生物的合成及抗癌活性评价。

我们开发了一种合成新的 4,5,6,7-四溴-1H-苯并咪唑衍生物的有效方法。通过 TBBi 或 2-Me-TBBi 与各种苯甲酰基卤的 N-烷基化反应，然后还原成相应的醇，得到了新的酮类化合物。所有化合物的产率都令人满意，在 40-91 % 之间。合成的化合物是一种弱的 CK2 和 PIM-1 抑制剂，但对 MCF-7、PC-3、CCRF-CEM、K-562 等癌细胞株具有有趣的细胞毒性活性。1-苯基-2-（4,5,6,7-四溴-1H-苯并咪唑-1-基）乙酮 3aA 的细胞毒性活性最高，对 MCF-7 的 IC50 值为 5.30 µM，对 CCRF-CEM 的 IC50 值为 6.80 µM。此外，该化合物对 MCF-7 和 CCRF-CEM 都表现出最高的选择性，SI 选择系数（对 MRC-5 和 Vero 细胞）分别为：对 MCF-7 为 5.45 和 4.30，对 CCRF-CEM 为 4.25 和 3.35。此外，研究表明，化合物 3aA 通过诱导 CCRF-CEM 细胞线粒体凋亡途径，具有很好的促凋亡特性。这些结果与 3aA 对细胞内 CK2α 蛋白水平和 CK2 介导的 NF-κBp65 Ser529 磷酸化的影响相关。化合物 3aA 对 CK2α 和 CK2α' mRNA 水平影响的研究表明，对照组 CCRF-CEM 和经 3aA 处理的细胞的基因表达水平没有显著差异，这表明 3aA 在蛋白质水平上发挥作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.