Novel quinolinequinone antitumor agents: structure-metabolism studies with NAD(P)H:quinone oxidoreductase (NQO1).

A series of quinolinequinones bearing various substituents has been synthesized, and the effects of substituents on the metabolism of the quinones by recombinant human NAD(P)H:quinone oxidoreductase (hNQO1) was studied. A range of quinolinequinones were selected for study, and were specifically designed to probe the effects of aryl substituents at C-2. A range of 28 quinolinequinones 2-29 was prepared using three general strategies: the palladium(0) catalyzed coupling of 2-chloroquinolines, the classical Friedlander synthesis and the double-Vilsmeier reaction of acetanilides. One example of an isoquinolinequinone 30 was also prepared, and the reduction potentials of the quinones were measured by cyclic voltammetry. For simple substituents R-2 at the quinoline 2-position, the rates of quinone metabolism by hNQO1 decrease for R-2 = Cl>Hsimilar toMe>Ph. For aromatic substituents, the rate of reduction decreases dramatically for R-2 = Ph > 1-naphthyl > 2-naphthyl > 4-biphenyl. Compounds containing a pyridine substituent are the best substrates, and the rates decrease as R-2 4-pyridyl > 3-pyridyl > 2-pyridyl > 4-methyl-2-pyridyl > 5-methyl-2-pyridyl. The toxicity toward human colon carcinoma cells with either no detectable activity (H596 or BE-WT) or high NQO1 activity (H460 or BE-NQ) was also studied in representative quinones. Quinones that are good substrates for hNQO1 are more toxic to the NQO1 containing or expressing cell lines (H460 and BE-NQ) than the NQO1 deficient cell lines (H596 and BE-WT). (C) 2004 Elsevier Ltd. All rights reserved.