Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-b]pyrrole Chelators

Abstract

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.

Preparation of Tryptanthrin Derivates Bearing a Thiosemicarbazone Moiety to Inhibit SARS-CoV-2 Replication

“…Conditional constants (K values) were calculated from the absorbance changes (∆A) of tryptanthrin derivates and their complexes with Cu(II), Fe(II) and Fe(III) ions at their spectral maximum by regression analysis (Letagrop Spefo 2005 software). The details of computational model have been described and discussed by Silen et al [28], and the same method was used to analyse the binding affinity of the organic receptors for metal ions in aqueous media [29][30][31][32][33][34][35][36]. Solutions were mixed in the cuvette during the whole titration and after each addition of metal guests.…”

Strongly Polarized π-Extended 1,4-Dihydropyrrolo[3,2-b]pyrroles Fused with Tetrazolo[1,5-a]quinolines

“…3 The available facile synthesis of tetraaryl-1,4-dihydropyrrolo [3,2-b]pyrroles (TAPPs), combined with promising photophysical properties, is making TAPP scaffold-based organic chromophores attractive for many research applications. 4 Over the past decade, the versatility of 1,4-dihydropyrrolo- [3,2-b]pyrroles has been demonstrated in an expansive range of areas of research including two-photon absorption (2PA), 5 ground-and excited-state symmetry breaking, 6 solvatofluorochromism, 7 tunable single-molecule conductance, 8 targeting the mitochondrial TET1 protein, 9 direct solvent probing via H-bonding interactions, 10 photochromic analysis of halocarbons, 11 high-performance organic field-effect transistors, 12 dyesensitized solar cells, 13 and many others. 14−22 The exceptional feature of DHPPs is that a convenient onepot synthesis enables the assembly of the heterocyclic scaffold possessing four arenes linked via biaryl linkages.…”

“…Over the past decade, the versatility of 1,4-dihydropyrrolo­[3,2- b ]­pyrroles has been demonstrated in an expansive range of areas of research including two-photon absorption (2PA), ground- and excited-state symmetry breaking, solvatofluorochromism, tunable single-molecule conductance, targeting the mitochondrial TET1 protein, direct solvent probing via H-bonding interactions, photochromic analysis of halocarbons, high-performance organic field-effect transistors, dye-sensitized solar cells, and many others. − …”