Peer-Reviewed Journal Details
Mandatory Fields
Fagan, V;Bonham, S;Carty, MP;Saenz-Mendez, P;Eriksson, LA;Aldabbagh, F
2012
May
Bioorganic And Medicinal Chemistry
COMPARE analysis of the toxicity of an iminoquinone derivative of the imidazo[5,4-f]benzimidazoles with NAD(P)H:quinone oxidoreductase 1 (NQO1) activity and computational docking of quinones as NQO1 substrates
Published
Altmetric: 1WOS: 16 ()
Optional Fields
DT-DIAPHORASE NAD(P)H-QUINONE OXIDOREDUCTASE-1 ANTITUMOR AGENTS RATIONAL DESIGN MITOMYCIN-C EXPRESSION MODEL INHIBITORS MECHANISM REDUCTASE
20
3223
3232
Synthesis and cytotoxicity of imidazo[5,4-f]benzimidazolequinones and iminoquinone derivatives is described, enabling structure-activity relationships to be obtained. The most promising compound (an iminoquinone derivative) has undergone National Cancer Institute (NCI) 60 cell line (single and five dose) screening, and using the NCI COMPARE program, has shown correlation to NQO1 activity and to other NQO1 substrates. Common structural features suggest that the iminoquinone moiety is significant with regard to NQO1 specificity. Computational docking into the active site of NQO1 was performed, and the first comprehensive mitomycin C (MMC)-NQO1 docking study is presented. Small distances for hydride reduction and high binding affinities are characteristic of MMC and of iminoquinones showing correlations with NQO1 via COMPARE analysis. Docking also indicated that the presence of a substituent capable of hydrogen bonding to the His194 residue is important in influencing the orientation of the substrate in the NQO1 active site, leading to more efficient reduction. (C) 2012 Elsevier Ltd. All rights reserved.
0968-0896
10.1016/j.bmc.2012.03.063
Grant Details
Publication Themes