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