title: Hypoxia-selective antitumor agents. 15. Modification of rate of nitroreduction and extent of lysosomal uptake by polysubstitution of 4-(alkylamino)-5-nitroquinoline bioreductive drugs.
abstract: Studies have shown that 4-(alkylamino)-5-nitroquinolines possess high selectivity (20-60-fold) for hypoxic tumor cells in vitro, but are not active as hypoxia-selective cytotoxins (HSCs) in vivo. The compounds show inadequate rates of extravascular diffusion, likely due both to sequestration of the bisbasic compounds into lysosomes and rapid nitroreduction. A further series of analogues, designed to counteract these limitations, has been synthesized and evaluated. Analogues bearing one to three electron-donating substituents on the quinoline have one-electron reduction potentials up to 100 mV lower than that of the unsubstituted compound (5), but do not have improved biological activity. The relationship between hypoxic selectivity and rates of metabolic reduction suggests at least two mechanisms of cytotoxicity for this series of 5-nitroquinolines. Compounds with high rates of reduction are toxic via oxygen-sensitive net bioreduction, while compounds which are poor substrates for nitroreduction are toxic through an oxygen-insensitive non-bioreductive mechanism. As rates of metabolic reduction are lowered, the non-bioreductive mechanism of toxicity becomes dominant and hypoxic selectivity is lost. A small series of analogues bearing hydrophilic but neutral side chains were also prepared. Compounds with a dihydroxypropyl side chain retained cytotoxic potency and hypoxic cell selectivity in cell culture assays, and had lowered uptake into lysosomes, but none of three analogues evaluated against KHT tumors in mice showed activity as an HSC in vivo.
authors.affiliation: Department of Pathology, The University of Auckland, New Zealand.
authors.forename: B G
authors.initials: BG
authors.lastname: Siim
authors.forename: G J
authors.initials: GJ
authors.lastname: Atwell
authors.forename: R F
authors.initials: RF
authors.lastname: Anderson
authors.forename: P
authors.initials: P
authors.lastname: Wardman
authors.forename: S M
authors.initials: SM
authors.lastname: Pullen
authors.forename: W R
authors.initials: WR
authors.lastname: Wilson
authors.forename: W A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D015687:Cell Hypoxia; D002460:Cell Line; D004354:Drug Screening Assays, Antitumor; D007700:Kinetics; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009600:Nitroquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D009600:Nitroquinolines; D010100:Oxygen