Neuroblastoma represents 8-10 % of all malignant tumors in childhood and is responsible for 15 % of cancer deaths in the pediatric population. Aggressive neuroblastomas are often resistant to chemotherapy. Canonically, neuroblastomas can be classified according to the MYCN (N-myc proto-oncogene protein) gene amplification, a common marker of tumor aggressiveness and poor prognosis. It has been found that certain compounds with chelating properties may show anticancer activity, but there is little evidence for the effect of chelators on neuroblastoma. The effect of new chelators characterized by the same functional group, designated as HLZ (1-hydrazino phthalazine), on proliferation (WST-1 and methylene blue assay), cell cycle (flow cytometry), apoptosis (proliferation assay after use of specific pharmacological inhibitors and western blot analysis) and ROS production (fluorometric assay based on dichlorofluorescein diacetate metabolism) was studied in three neuroblastoma cell lines with different levels of MYCN amplification. The molecules were effective only on MYCN-non-amplified cells in which they arrested the cell cycle in the G0/G1 phase. We investigated the mechanism of action and identified the activation of cell signaling that involves protein kinase C.

• MeSH
• Apoptosis MeSH
• Chelating Agents pharmacology   therapeutic use   MeSH
• Child MeSH
• Nuclear Proteins genetics   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Neuroblastoma * drug therapy   MeSH
• Oncogene Proteins * genetics   metabolism   pharmacology   MeSH
• Cell Proliferation MeSH
• N-Myc Proto-Oncogene Protein genetics   metabolism   therapeutic use   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Chelating Agents MeSH
• Nuclear Proteins MeSH
• Oncogene Proteins * MeSH
• N-Myc Proto-Oncogene Protein MeSH

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.

• Keywords
• TET1 protein inhibitor, hydrazone, mitochondria, pyrrolo[3,2-b]pyrrole,
• MeSH
• Iron Chelating Agents MeSH
• Dioxygenases * metabolism   MeSH
• DNA MeSH
• Hydrazones chemistry   MeSH
• Mitochondrial Proteins MeSH
• Pyrroles * chemistry   pharmacology   MeSH
• Molecular Docking Simulation MeSH
• Iron MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Iron Chelating Agents MeSH
• Dioxygenases * MeSH
• DNA MeSH
• Hydrazones MeSH
• Mitochondrial Proteins MeSH
• Pyrroles * MeSH
• Iron MeSH