title: Synthesis of novel polybrominated benzimidazole derivatives-potential CK2 inhibitors with anticancer and proapoptotic activity.
abstract: The efficient method for the synthesis of novel cell permeable inhibitors of protein kinase CK2 with anticancer and proapoptotic activity has been developed. A series of polybrominated benzimiadazole derivatives substituted by various cyanoalkyl groups have been synthesized. Cyanoethyl derivatives were obtained by Michael type addition of 4,5,6,7-tetrabromo-1H-benzimidazole (TBBi) and 4,5,6,7-tetrabromo-2-methyl-1H-benzimidazole to acrylonitrile, whilst cyanomethyl, cyanopropyl and cyanobutyl analogs by N-alkylation of 4,5,6,7-tetrabromo-1H-benzimidazole and 4,5,6,7-tetrabromo-2-methyl-1H-benzimidazole with appropriate cyanoalkyl halides. The inhibitory activity against protein kinase rhCK2α catalytic subunit and cytotoxicity against two human cancer cell lines: acute lymphocytic leukemia (CCRF-CEM) and breast (MCF-7) were evaluated for all newly synthesized compounds. Additionally, the proapoptotic activity toward leukemia cells and intracellular inhibition of CK2 for the most cytotoxic derivatives have been performed, demonstrating 4,5,6,7-tetrabromo-2-methyl-1H-benzimidazole as a new selective inhibitor of rhCK2 with twenty-fold better proapoptotic activity than parental compound (TBBi).
authors.affiliation: Faculty of Chemistry, Institute of Biotechnology, Warsaw University of Technology, Noakowskiego St. 3, 00-664 Warsaw, Poland. Electronic address: elukowska@ch.pw.edu.pl.
authors.forename: Edyta
authors.initials: E
authors.lastname: Łukowska-Chojnacka
authors.affiliation: Faculty of Chemistry, Institute of Biotechnology, Warsaw University of Technology, Noakowskiego St. 3, 00-664 Warsaw, Poland.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Wińska
authors.affiliation: Faculty of Chemistry, Institute of Biotechnology, Warsaw University of Technology, Noakowskiego St. 3, 00-664 Warsaw, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Wielechowska
authors.affiliation: Faculty of Chemistry, Institute of Biotechnology, Warsaw University of Technology, Noakowskiego St. 3, 00-664 Warsaw, Poland.
authors.forename: Martyna
authors.initials: M
authors.lastname: Poprzeczko
authors.affiliation: Faculty of Chemistry, Institute of Biotechnology, Warsaw University of Technology, Noakowskiego St. 3, 00-664 Warsaw, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Bretner
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D054879:Halogenation; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D061986:MCF-7 Cells; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D047390:Casein Kinase II
keywords: 4,5,6,7-Tetrabromo-1H-benzimidazole derivatives; Apoptosis; Cytotoxicity; Inhibition; Kinase CK2