title: Pharmacological and biological evaluation of a series of substituted 1,4-naphthoquinone bioreductive drugs.
abstract: The indolequinone compound EO9 has good pharmacodynamic properties in terms of bioreductive activation and selectivity for either NAD(P)H:quinone oxidoreductase-1 (NQO1)-rich aerobic or NQO1-deficient hypoxic cells. However, its pharmacokinetic properties are poor and this fact is believed to be a major reason for EO9's lack of clinical efficacy. The purpose of this study was to develop quinone-based bioreductive drugs that retained EO9's good properties, in terms of bioreductive activation, but have improved pharmacokinetic properties. Out of 11 naphthoquinone compounds evaluated, 2-aziridinyl-5-hydroxy-1,4-naphthoquinone (compound 2), 2,3-bis(aziridinyl)-5-hydroxy-1,4-naphthoquinone (compound 3), and 2-aziridinyl-6-hydroxymethyl-1,4-naphthoquinone (compound 11) were selected for further evaluation based on good substrate specificity for NQO1 and selectivity towards NQO1-rich cells in vitro. Compound 3 was of particular interest as it also demonstrated selectivity for NQO1-rich cells under hypoxic conditions. Compound 3 was not metabolised by murine whole blood in vitro (in contrast to compounds 2, 11 and EO9) and pharmacokinetic studies in non-tumour-bearing mice in vivo (at the maximum soluble dose of 60 mg kg(-1) administered intraperitoneally) demonstrated significant improvements in plasma half-life (16.2 min) and AUC values (22.5 microM h) compared to EO9 (T(1/2) = 1.8 min, AUC = 0.184 microM h). Compound 3 also demonstrated significant anti-tumour activity against H460 and HCT-116 human tumour xenografts in vivo, whereas EO9 was inactive against these tumours. In conclusion, compound 3 is a promising lead compound that may target both aerobic and hypoxic fractions of NQO1-rich tumours and further studies to elucidate its mechanism of action and improve solubility are warranted.
authors.affiliation: Cancer Research Unit, Tom Connors Cancer Research Centre, University of Bradford, Bradford BD71DP, UK. r.m.phillips@bradford.ac.uk
authors.forename: Roger M
authors.initials: RM
authors.lastname: Phillips
authors.forename: Mohammed
authors.initials: M
authors.lastname: Jaffar
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Maitland
authors.forename: Paul M
authors.initials: PM
authors.lastname: Loadman
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shnyder
authors.forename: Gillian
authors.initials: G
authors.lastname: Steans
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Cooper
authors.forename: Amanda
authors.initials: A
authors.lastname: Race
authors.forename: Adam V
authors.initials: AV
authors.lastname: Patterson
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Stratford
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001388:Aziridines / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D045563:Indolequinones / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D009285:Naphthoquinones / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001388:Aziridines; D045563:Indolequinones; D009285:Naphthoquinones; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C060817:apaziquone