Design, synthesis and biological evaluation of cobalt(II)-Schiff base complexes as ATP-noncompetitive MEK1 inhibitors

Hongyue Li; Dandan Xi; Yan Niu; Chao Wang; Fengrong Xu; Lei Liang; Ping Xu

doi:10.1016/j.jinorgbio.2019.03.022

Design, synthesis and biological evaluation of cobalt(II)-Schiff base complexes as ATP-noncompetitive MEK1 inhibitors

J Inorg Biochem. 2019 Jun:195:174-181. doi: 10.1016/j.jinorgbio.2019.03.022. Epub 2019 Mar 30.

Authors

Hongyue Li¹, Dandan Xi¹, Yan Niu¹, Chao Wang¹, Fengrong Xu¹, Lei Liang², Ping Xu³

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China.
² Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China. Electronic address: leiliang@bjmu.edu.cn.
³ Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China. Electronic address: pingxu@bjmu.edu.cn.

PMID: 30954694
DOI: 10.1016/j.jinorgbio.2019.03.022

Abstract

In this report, we designed and synthesized a series of cobalt(II)-Schiff base complexes (CoSBC) with competent MEK1 (mitogen-activated protein kinase kinase-1) inhibitory activity. Based on our previous report, the CoSBC exhibited high binding affinity with MEK1 protein. To further explore metal complexes as MEK1 inhibitors, a series of transition metals and ligands were employed to build a library of various metal Schiff base complexes. The MEK inhibition assays revealed that only CoSBC exhibited obvious inhibitory activity, complex 2b showed the best inhibition both in BRaf (B-rapidly accelerated fibrosarcoma)/MEK1 and MEK1/ERK2 (extracellular signal-regulated kinases-2) cascading (IC₅₀ is 1.988 ± 0.14 μM and 1.589 ± 0.054 μM respectively). In addition, homogeneous time-resolved fluorescence test method was used to prove that CoSBC as ATP-noncompetitive MEK1 inhibitor. MEK kinase selectivity assay indicated that CoSBC can selectively inhibit MEK1/2 kinases rather than other MAPKs (mitogen-activated protein kinases) family kinases. Moreover, the interaction mode of 2b with MEK1 protein has been demonstrated by computer aided drug design.

Keywords: ATP-noncompetitive MEK1 inhibitors; Cobalt(II)-Schiff base complexes; Molecular docking.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Coordination Complexes / chemistry*
Coordination Complexes / metabolism
Copper / chemistry
Drug Design
Humans
MAP Kinase Kinase 1 / antagonists & inhibitors*
MAP Kinase Kinase 1 / metabolism
Molecular Docking Simulation
Molecular Structure
Protein Binding
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / metabolism
Schiff Bases / chemistry*
Schiff Bases / metabolism
Structure-Activity Relationship

Substances

Coordination Complexes
Protein Kinase Inhibitors
Schiff Bases
Copper
MAP Kinase Kinase 1
MAP2K1 protein, human