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

Abstract

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 Friedländer 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>H∼Me>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).