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

Alzheimer's disease (AD) is a disabling neurodegenerative disorder that leads to long-term functional and cognitive impairment and greatly reduces life expectancy. Early genetic studies focused on tracking variations in genome-wide DNA sequences discovered several polymorphisms and novel susceptibility genes associated with AD. However, despite the numerous risk factors already identified, there is still no fully satisfactory explanation for the mechanisms underlying the onset of the disease. Also, as with other complex human diseases, the causes of low heritability are unclear. Epigenetic mechanisms, in which changes in gene expression do not depend on changes in genotype, have attracted considerable attention in recent years and are key to understanding the processes that influence age-related changes and various neurological diseases. With the recent use of massive sequencing techniques, methods for studying epigenome variations in AD have also evolved tremendously, allowing the discovery of differentially expressed disease traits under different conditions and experimental settings. This is important for understanding disease development and for unlocking new potential AD therapies. In this work, we outline the genomic and epigenomic components involved in the initiation and development of AD and identify potentially effective therapeutic targets for disease control.

• Klíčová slova
• Alzheimer’s disease, dementia, epigenetic mechanisms, genetic risk factors, genome-wide association study (GWAS), missing heritability, older adults,
• MeSH
• Alzheimerova nemoc genetika   patologie   MeSH
• epigeneze genetická * MeSH
• genetická predispozice k nemoci * MeSH
• genomika metody   MeSH
• lidé MeSH
• metylace DNA * MeSH
• regulace genové exprese * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH