Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 18, Pages -Publisher
MDPI
DOI: 10.3390/ijms231810850
Keywords
TET1 protein inhibitor; pyrrolo[3; 2-b]pyrrole; hydrazone; mitochondria
Funding
- Czech-BioImaging large RI projects - MEYS CR [LM2015062, CZ.02.1.01/0.0/0.0/16_013/0001775]
- MEYS CR [LM2018127]
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In this study, we synthesized a series of pyrrolopyrrole derivatives and found that the basic pyrrolo[3,2-b]pyrrole derivative 1 exhibited strong inhibitory activity against TET1 protein. Furthermore, derivative 1 showed potent anticancer activity and exclusive mitochondrial localization.
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 mu M), 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.
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