Design and discovery of new pyrimidine coupled nitrogen aromatic rings as chelating groups of JMJD3 inhibitors

Bioorganic & Medicinal Chemistry Letters
Jianping HuBing Xiong

Abstract

The histone methylation on lysine residues is one of the most studied post-translational modifications, and its aberrant states have been associated with many human diseases. In 2012, Kruidenier et al. reported GSK-J1 as a selective Jumonji H3K27 demethylase (JMJD3 and UTX) inhibitor. However, there is limited information on the structure-activity relationship of this series of compounds. Moreover, there are few scaffolds reported as chelating groups for Fe(II) ion in Jumonji demethylase inhibitors development. To further elaborate the structure-activity relationship of selective JMJD3 inhibitors and to explore the novel chelating groups for Fe(II) ion, we initialized a medicinal chemistry modification based on the GSK-J1 structure. Finally, we found that several compounds bearing different chelating groups showed similar activities with respect to GSK-J1 and excellent metabolic stability in liver microsomes. The ethyl ester prodrugs of these inhibitors also showed a better activity than GSK-J4 for inhibition of TNF-α production in LPS-stimulated murine macrophage cell line Raw 264.7 cells. Taking together, the current study not only discovered alternative potent JMJD3 inhibitors, but also can benefit other researchers to desig...Continue Reading

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Citations

Oct 23, 2016·Drug Discovery Today. Technologies·Srikanth AppikondaMichelle Craig Barton
Mar 25, 2017·Chemical Reviews·H Ümit KaniskanJian Jin
Apr 14, 2018·Journal of Enzyme Inhibition and Medicinal Chemistry·Hongzhi LinHaopeng Sun
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Jun 12, 2020·Frontiers in Chemistry·José A SoutoÁngel R de Lera
Feb 14, 2021·Biochimie·Francisco Alejandro Lagunas-Rangel
Apr 1, 2019·Bioorganic & Medicinal Chemistry Letters·Pattaporn JaikhanTakayoshi Suzuki
Apr 19, 2019·ACS Medicinal Chemistry Letters·Assunta GiordanoSimone Di Micco
Sep 19, 2018·Journal of Chemical Information and Modeling·C EspositoA Caflisch

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