Development of quinone analogues as dynamin GTPase inhibitors.

Autor: MacGregor KA; Centre for Chemical Biology, Chemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia., Abdel-Hamid MK; 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., Odell LR; Centre for Chemical Biology, Chemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, NSW 2308, Australia., Chau N; Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia., Whiting A; Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia., Robinson PJ; Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia., McCluskey A; 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.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2014 Oct 06; Vol. 85, pp. 191-206. Date of Electronic Publication: 2014 Jul 05.
DOI: 10.1016/j.ejmech.2014.06.070
Abstrakt: 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.
(Crown Copyright © 2014. Published by Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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