Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inhibition of the TET1 protein (ten-eleven translocation methylcytosine dioxygenase 1) by specific iron chelators. Therefore, in the present work, we prepared a series of pyrrolopyrrole derivatives with hydrazide (1) or hydrazone (2-6) iron-binding groups. As a result, we determined that the basic pyrrolo[3,2-b]pyrrole derivative 1 was a strong inhibitor of the TET1 protein (IC50 = 1.33 μM), supported by microscale thermophoresis and molecular docking. Pyrrolo[3,2-b]pyrroles 2-6, bearing substituted 2-hydroxybenzylidene moieties, displayed no significant inhibitory activity. In addition, in vitro studies demonstrated that derivative 1 exhibits potent anticancer activity and an exclusive mitochondrial localization, confirmed by Pearson's correlation coefficient of 0.92.

• Klíčová slova
• TET1 protein inhibitor, hydrazone, mitochondria, pyrrolo[3,2-b]pyrrole,
• MeSH
• chelátory železa MeSH
• dioxygenasy * metabolismus   MeSH
• DNA MeSH
• hydrazony chemie   MeSH
• mitochondriální proteiny MeSH
• pyrroly * chemie   farmakologie   MeSH
• simulace molekulového dockingu MeSH
• železo MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chelátory železa MeSH
• dioxygenasy * MeSH
• DNA MeSH
• hydrazony MeSH
• mitochondriální proteiny MeSH
• pyrroly * MeSH
• železo MeSH

DNA methylation/demethylation pattern, determined by 5-methylcytosine (5-MeC) immunostaining, was evaluated in porcine "in vivo" produced embryos from zygote up to the blastocyst stage. In one-cell stage embryos, only the maternal pronucleus showed a positive labeling whilst the paternal pronucleus showed almost no labeling. The intensity of labeling is high until the late morula stage. Blastocysts containing less than 100 cells showed the same intensity of labeling in both the inner cell mass (ICM) nuclei and the trophectodermal (TE) cell nuclei. Interestingly, with further cell multiplication, cells of the ICM became more intensively labeled when compared to TE cells. This distinct methylation pattern is even more profound in blastocysts containing about 200-300 cells and is not caused by the difference in the cell volume of ICM and TE cells.

• MeSH
• blastocysta metabolismus   MeSH
• chromatin metabolismus   MeSH
• embryo savčí embryologie   metabolismus   MeSH
• metylace DNA * MeSH
• prasata MeSH
• zvířata MeSH
• zygota metabolismus   MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chromatin MeSH