Development of quinone analogues as dynamin GTPase inhibitors

作者：MacGregor Kylie A; Abdel Hamid Mohammed K; Odell Luke R; Chau Ngoc; Whiting Ainslie; Robinson Phillip J; McCluskey Adam^*

来源：European Journal of Medicinal Chemistry, 2014, 85: 191-206.

DOI：10.1016/j.ejmech.2014.06.070

• Dynamin
• Endocytosis
• Quinones
• Dynamin inhibitors
• Modelling

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 mu M inhibitor. In silica 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 mu M 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 mu M.

• 出版日期2014-10-6