title: 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.
abstract: 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.
authors.affiliation: School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Fagan
authors.forename: Sarah
authors.initials: S
authors.lastname: Bonham
authors.forename: Michael P
authors.initials: MP
authors.lastname: Carty
authors.forename: Patricia
authors.initials: P
authors.lastname: Saenz-Méndez
authors.forename: Leif A
authors.initials: LA
authors.lastname: Eriksson
authors.forename: Fawaz
authors.initials: F
authors.lastname: Aldabbagh
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity; D001562:Benzimidazoles / Q000633:toxicity*; D001665:Binding Sites; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000737:chemistry / Q000378:metabolism*; D011809:Quinones / Q000737:chemistry* / Q000633:toxicity; D012984:Software; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D011809:Quinones; C116897:iminoquinone; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human