DNA specific fluorescent symmetric dimeric bisbenzimidazoles DBP(n): the synthesis, spectral properties, and biological activity

Alexander A Ivanov; Vasiliy S Koval; Olga Yu Susova; Victor I Salyanov; Vladimir A Oleinikov; Andrey A Stomakhin; Natalya A Shalginskikh; Margarita A Kvasha; Olga V Kirsanova; Elizaveta S Gromova; Alexei L Zhuze

doi:10.1016/j.bmcl.2015.04.087

DNA specific fluorescent symmetric dimeric bisbenzimidazoles DBP(n): the synthesis, spectral properties, and biological activity

Bioorg Med Chem Lett. 2015 Jul 1;25(13):2634-8. doi: 10.1016/j.bmcl.2015.04.087. Epub 2015 May 5.

Affiliations

¹ Institute of Carcinogenesis, Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Kashirskoye Shosse 24, Moscow 115478, Russia.
² Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow 117997, Russia.
³ Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova St. 32, Moscow 119991, Russia.
⁴ Chemistry Department, Moscow State University, Moscow 119991, Russia.
⁵ Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova St. 32, Moscow 119991, Russia. Electronic address: zhuze@eimb.ru.

PMID: 25987376
DOI: 10.1016/j.bmcl.2015.04.087

Abstract

A series of new fluorescent symmetric dimeric bisbenzimidazoles DBP(n) bearing bisbenzimidazole fragments joined by oligomethylene linkers with a central 1,4-piperazine residue were synthesized. The complex formation of DBP(n) in the DNA minor groove was demonstrated. The DBP(n) at micromolar concentrations inhibit in vitro eukaryotic DNA topoisomerase I and prokaryotic DNA methyltransferase (MTase) M.SssI. The DBP(n) were soluble well in aqueous solutions and could penetrate cell and nuclear membranes and stain DNA in live cells. The DBP(n) displayed a moderate effect on the reactivation of gene expression.

Keywords: DNA methyltransferase; DNA topoisomerase-I; Dimeric bisbenzimidazoles; Inhibitors; Minor groove binders.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Bisbenzimidazole / analogs & derivatives*
Bisbenzimidazole / chemical synthesis
Bisbenzimidazole / pharmacology
Cell Line
DNA / chemistry*
DNA / drug effects*
DNA / genetics
DNA-Cytosine Methylases / antagonists & inhibitors
Dimerization
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Fluorescent Dyes / chemical synthesis*
Fluorescent Dyes / chemistry
Fluorescent Dyes / pharmacology*
Gene Expression / drug effects
Humans
MCF-7 Cells
Mice
Microscopy, Fluorescence
Structure-Activity Relationship
Topoisomerase I Inhibitors / chemical synthesis
Topoisomerase I Inhibitors / chemistry
Topoisomerase I Inhibitors / pharmacology

Substances

Antineoplastic Agents
Enzyme Inhibitors
Fluorescent Dyes
Topoisomerase I Inhibitors
DNA
DNA modification methylase SssI
DNA-Cytosine Methylases
Bisbenzimidazole