Łukowska-Chojnacka Edyta, Fedorov Egor, Kowalkowska Anna, Wielechowska Monika, Sobiepanek Anna, Koronkiewicz Mirosława, Wińska Patrycja
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego St. 3, 00-664 Warsaw, Poland.
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego St. 3, 00-664 Warsaw, Poland.
Bioorg Chem. 2024 Dec;153:107880. doi: 10.1016/j.bioorg.2024.107880. Epub 2024 Oct 10.
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 IC 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.
已开发出一种高效合成新型4,5,6,7-四溴-1H-苯并咪唑衍生物的方法。通过TBBi或2-Me-TBBi与各种苯甲酰卤进行N-烷基化反应得到新的酮，然后将其还原为相应的醇。所有化合物的产率均令人满意，在40-91%的范围内。合成的化合物表现出较弱的CK2和PIM-1抑制活性，但对癌细胞系，即MCF-7、PC-3、CCRF-CEM、K-562表现出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表现出最高的细胞毒性活性，对MCF-7的IC值为5.30μM，对CCRF-CEM的IC值为6.80μM。此外，该化合物对MCF-7和CCRF-CEM均表现出最高的选择性，其SI选择性系数（针对MRC-5和Vero细胞）对MCF-7分别为5.45和4.30，对CCRF-CEM分别为4.25和3.35。此外，研究表明化合物3aA通过诱导CCRF-CEM细胞中的线粒体凋亡途径表现出非常好的促凋亡特性。这些结果与显示3aA对CK2α蛋白细胞内水平和NF-κBp65中Ser529的CK2介导的磷酸化作用的数据相关。化合物3aA对CK2α和CK2α' mRNA水平影响的研究表明，对照CCRF-CEM细胞和用3aA处理的细胞的基因表达水平没有显著差异，表明3aA在蛋白质水平上起作用。
