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Eur J Med Chem. 2014 Oct 6;85:191-206. doi: 10.1016/j.ejmech.2014.06.070. Epub 2014 Jul 5.

Development of quinone analogues as dynamin GTPase inhibitors.

Author information

1
Centre for Chemical Biology, Chemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia.
2
Centre for Chemical Biology, Chemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia; Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
3
Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
4
Centre for Chemical Biology, Chemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia. Electronic address: Adam.McCluskey@newcastle.edu.au.

Abstract

Virtual screening of the ChemDiversity and ChemBridge compound databases against dynamin I (dynI) GTPase activity identified 2,5-bis-(benzylamino)-1,4-benzoquinone 1 as a 273 ± 106 μM inhibitor. In silico lead optimization and focused library-led synthesis resulted in the development of four discrete benzoquinone/naphthoquinone based compound libraries comprising 54 compounds in total. Sixteen analogues were more potent than lead 1, with 2,5-bis-(4-hydroxyanilino)-1,4-benzoquinone (45) and 2,5-bis(4-carboxyanilino)-1,4-benzoquinone (49) the most active with IC50 values of 11.1 ± 3.6 and 10.6 ± 1.6 μM respectively. Molecular modelling suggested a number of hydrogen bonding and hydrophobic interactions were involved in stabilization of 49 within the dynI GTP binding site. Six of the most active inhibitors were evaluated for potential inhibition of clathrin-mediated endocytosis (CME). Quinone 45 was the most effective CME inhibitor with an IC50(CME) of 36 ± 16 μM.

KEYWORDS:

Dynamin; Dynamin inhibitors; Endocytosis; Modelling; Quinones

PMID:
25084145
DOI:
10.1016/j.ejmech.2014.06.070
[Indexed for MEDLINE]

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