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

Ivanov, А.А.; Koval, V. P.; Susova, Olga Yu.; Salyanov, V. I.; Oleinikov, Vladimir; Stomakhin, A. A.; Shalginskikh, Natalya; Kvasha, Margarita A.; Kirsanova, O. V.; Громова, Е. С.; Жузе, А. Л.

doi:10.1016/j.bmcl.2015.04.087

Cited by 13 publications

(11 citation statements)

References 29 publications

(33 reference statements)

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“…Four DBP(1–4) compounds were previously synthesized [ 10 ] ( Fig 1 ). To study the effects of DBP(1–4) on the oestrogen and progesterone receptor positive breast carcinoma cell MCF-7 sterile aqueous solutions of the compounds were added to the cultivation medium at a concentration of 7 to 80 μM and the cells were cultivated for 3 to 72 hours.…”

Section: Resultsmentioning

confidence: 99%

“…The fluorescent properties of the dimeric bisbenzimidazoles change significantly when the hydrophobicity surrounding the fluorophore is modified [ 11 ]. The addition of DBP(n) to DNA resulted in a shift of the emission band maximum from 468 to 475 nm and an increase in the fluorescence intensity [ 10 ]. The fluorescence properties of DBP in the hydrophobic environment with DNA were used to analyze the distribution of these compounds in the cells.…”

Section: Resultsmentioning

confidence: 99%

“…DBP(1–4) are unevenly distributed in the nuclei of MCF-7 ( Fig 3A ). DBP(1–4) interact with the DNA in the volume of the nucleus, as shown by the dark blue fluorescence which indicates DBP(1–4) complexes with DNA [ 10 ]. The compounds also accumulate in close proximity to the nucleoli.…”

Section: Resultsmentioning

confidence: 99%

“…Further research included the synthesis of the dimeric bisbenzimidazoles having a 1,4-piperazine cycle in the oligomethylene linker between bisbenzimidazole fragments, DBP(n) ( Fig 1 ). These compounds are water soluble, able to bind the DNA and relatively low toxic [ 10 ]. In experiments on the model systems it was shown that the DBP(n) in micromolar concentrations in vitro inhibit prokaryotic MTase M.SssI [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…These compounds are water soluble, able to bind the DNA and relatively low toxic [ 10 ]. In experiments on the model systems it was shown that the DBP(n) in micromolar concentrations in vitro inhibit prokaryotic MTase M.SssI [ 10 ]. It was also found that the DBP(n) produces a moderate effect on the activation of total gene expression in HeLa-TI population containing epigenetically repressed avian sarcoma genome [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Symmetric dimeric bisbenzimidazoles DBP(n) reduce methylation of RARB and PTEN while significantly increase methylation of rRNA genes in MCF-7 cancer cells

et al. 2018

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BackgroundHypermethylation is observed in the promoter regions of suppressor genes in the tumor cancer cells. Reactivation of these genes by demethylation of their promoters is a prospective strategy of the anticancer therapy. Previous experiments have shown that symmetric dimeric bisbenzimidazoles DBP(n) are able to block DNA methyltransferase activities. It was also found that DBP(n) produces a moderate effect on the activation of total gene expression in HeLa-TI population containing epigenetically repressed avian sarcoma genome.Principal findingsIt is shown that DBP(n) are able to penetrate the cellular membranes and accumulate in breast carcinoma cell MCF-7, mainly in the mitochondria and in the nucleus, excluding the nucleolus. The DBP(n) are non-toxic to the cells and have a weak overall demethylation effect on genomic DNA. DBP(n) demethylate the promoter regions of the tumor suppressor genes PTEN and RARB. DBP(n) promotes expression of the genes RARB, PTEN, CDKN2A, RUNX3, Apaf-1 and APC "silent" in the MCF-7 because of the hypermethylation of their promoter regions. Simultaneously with the demethylation of the DNA in the nucleus a significant increase in the methylation level of rRNA genes in the nucleolus was detected. Increased rDNA methylation correlated with a reduction of the rRNA amount in the cells by 20–30%. It is assumed that during DNA methyltransferase activity inhibition by the DBP(n) in the nucleus, the enzyme is sequestered in the nucleolus and provides additional methylation of the rDNA that are not shielded by DBP(n).Conclusions/SignificanceIt is concluded that DBP (n) are able to accumulate in the nucleus (excluding the nucleolus area) and in the mitochondria of cancer cells, reducing mitochondrial potential. The DBP (n) induce the demethylation of a cancer cell’s genome, including the demethylation of the promoters of tumor suppressor genes. DBP (n) significantly increase the methylation of ribosomal RNA genes in the nucleoli. Therefore the further study of these compounds is needed; it could lead to the creation of new anticancer agents.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Symmetric dimeric bisbenzimidazoles DBP(n) reduce methylation of RARB and PTEN while significantly increase methylation of rRNA genes in MCF-7 cancer cells

et al. 2018

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Synthesis and Structural Characterization of Macrocyclic Plasmin Inhibitors

Wiedemeyer

Pham

et al. 2023

ChemMedChem

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Two series of macrocyclic plasmin inhibitors with a C-terminal benzylamine group were synthesized. The substitution of the Nterminal phenylsulfonyl group of a previously described inhibitor provided two analogues with sub-nanomolar inhibition constants. Both compounds possess a high selectivity against all other tested trypsin-like serine proteases. Furthermore, a new approach was used to selectively introduce asymmetric linker segments. Two of these compounds inhibit plasmin with K i values close to 2 nM. For the first time, four crystal structures of these macrocyclic inhibitors could be determined in complex with a Ser195Ala microplasmin mutant. The macrocyclic core segment of the inhibitors binds to the open active site of plasmin without any steric hindrance. This binding mode is incompatible with other trypsin-like serine proteases containing a sterically demanding 99-hairpin loop. The crystal structures obtained experimentally explain the excellent selectivity of this inhibitor type as previously hypothesized.

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DNA sequence-specific ligands. XVII. Synthesis, spectral properties, virological and biochemical studies of fluorescent dimeric bisbenzimidazoles DBA(n)

Koval

Arutyunyan

Salyanov

et al. 2018

Bioorganic & Medicinal Chemistry

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

Cited by 13 publications

References 29 publications

Symmetric dimeric bisbenzimidazoles DBP(n) reduce methylation of RARB and PTEN while significantly increase methylation of rRNA genes in MCF-7 cancer cells

Symmetric dimeric bisbenzimidazoles DBP(n) reduce methylation of RARB and PTEN while significantly increase methylation of rRNA genes in MCF-7 cancer cells

Synthesis and Structural Characterization of Macrocyclic Plasmin Inhibitors

DNA sequence-specific ligands. XVII. Synthesis, spectral properties, virological and biochemical studies of fluorescent dimeric bisbenzimidazoles DBA(n)

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