| Abstract
| - Studies have shown that 4-(alkylamino)-5-nitroquinolines possesshigh selectivity (20−60-fold)for hypoxic tumor cells in vitro, but are not active ashypoxia-selective cytotoxins (HSCs) invivo. The compounds show inadequate rates of extravasculardiffusion, likely due both tosequestration of the bisbasic compounds into lysosomes and rapidnitroreduction. A furtherseries of analogues, designed to counteract these limitations, has beensynthesized andevaluated. Analogues bearing one to three electron-donatingsubstituents on the quinolinehave one-electron reduction potentials up to 100 mV lower than that ofthe unsubstitutedcompound (5), but do not have improved biological activity.The relationship between hypoxicselectivity and rates of metabolic reduction suggests at least twomechanisms of cytotoxicityfor this series of 5-nitroquinolines. Compounds with high rates ofreduction are toxic via oxygen-sensitive net bioreduction, while compounds which are poor substratesfor nitroreduction aretoxic through an oxygen-insensitive non-bioreductive mechanism. Asrates of metabolicreduction are lowered, the non-bioreductive mechanism of toxicitybecomes dominant andhypoxic selectivity is lost. A small series of analogues bearinghydrophilic but neutral sidechains were also prepared. Compounds with a dihydroxypropyl sidechain retained cytotoxicpotency and hypoxic cell selectivity in cell culture assays, and hadlowered uptake intolysosomes, but none of three analogues evaluated against KHT tumors inmice showed activityas an HSC in vivo.
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