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Most of
the epigenetic drugs suppress the level of DNA methylation and histone
acetylation. Their undeniable success leads to studying the regulation of other
epigenetic mechanisms such as hydroxymethylation of DNA. Number of recent works
demonstrated that hydroxymethyl cytosine similarly as methyl cytosine is
important for the regulation of gene expression. Disbalance in the
hydroxymethyl cytosine level is associated with pathogenesis of some serious
diseases such as acute myeloid leukemia; RET syndrome, Parkinson’s and
Alzheimer’s diseases and others.
Possible
way of modulation of hydroxymethyl cytosine level could be based on the
regulation of TET protein activity. Development and study of specific iron (II)
chelators for the inhibition of TET protein 1 can have high potential for the
clinical research and future medicinal applications.
It is well
known, that Fe(II) cation with lower charge density, prefers interaction with
binding groups containing ‘soft’ donor atom. One of the possible strategies for
the construction of chelator can be application of hydrazone motif in the
chelator design. In this work we studied modified hydrazones as inhibitors of
TET protein 1. Applicability of the heterocyclic hydrazones for the chelation
of Fe(II) was studied by absorption spectroscopy in aqueous media. Obtained
results showed affinity of tested chelators for Fe(II). Their inhibition
activity for the TET 1 protein was determined by fluorometric TET hydroxylase
activity quantification kit. Results of these studies proved correlation
between chelators’ affinity for Fe (II) ions and their inhibition activity.
Localization of compounds in 1 µM concentration was performed on fluorescent
microscope Leica SP8 FLIM. Cell viability was determined by MTT assay on
healthy (human fibroblasts) and cancer (A2058) cell lines. We established IC 50
and compared cytotoxicity of chelators on both cell lines.
Keywords: TET 1
protein, DNA methylation, Hydromethyl cytosine, Epigenetics, Cancer, Iron
chelators
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