Structure-activity relationships for binding of 4-substituted

Xiao, Zhangping and Fokkens, Marieke and Chen, Deng and Kok, Tjie and Proietti, Giordano and Merkerk, Ronald van and Poelarends, Gerrit J. and Dekker, Frank J. (2020) Structure-activity relationships for binding of 4-substituted. European Journal of Medicinal Chemistry, 186 (111849). pp. 1-13.

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Abstract

Macrophage migration inhibitory factor (MIF) is a versatile protein that plays a role in inflammation, autoimmune diseases and cancers. Development of novel inhibitors will enable further exploration of MIF as a drug target. In this study, we investigated structure-activity relationships of MIF inhibitors using a MIF tautomerase activity assay to measure binding. Importantly, we notified that transition metals such as copper (II) and zinc (II) interfere with the MIF tautomerase activity under the assay conditions applied. EDTA was added to the assay buffer to avoid interference of residual heavy metals with tautomerase activity measurements. Using these assay conditions the structure-activity relationships for MIF binding of a series of triazole-phenols was explored. The most potent inhibitors in this series provided activities in the low micromolar range. Enzyme kinetic analysis indicates competitive binding that proved reversible. Binding to the enzyme was confirmed using a microscale thermophoresis (MST) assay. Mo�lecular modelling was used to rationalize the observed structure-activity relationships. The most potent inhibitor 2d inhibited proliferation of A549 cells in a clonogenic assay. In addition, 2d attenuated MIF induced ERK phosphorylation in A549 cells. Altogether, this study provides insights in the structure�activity relationships for MIF binding of triazole-phenols and further validates this class of compounds as MIF binding agents in cell-based studies.

Item Type:	Article
Uncontrolled Keywords:	Microphage migration inhibitory factor (MIF), Transition metals, Triazole-phenols, Tautomerase activity, Clonogenic assay
Subjects:	T Technology > T Technology (General)
Divisions:	Faculty of Technobiology > Department of Biology
Depositing User:	Ester Sri W. 196039
Date Deposited:	10 Apr 2023 11:57
Last Modified:	07 Jul 2023 02:34
URI:	http://repository.ubaya.ac.id/id/eprint/43939

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