Indolequinone inhibitors of NRH:quinone oxidoreductase 2. Further structure-activity relationships

An improved route to the indolequinone pharmacophore is described based on the reaction of bromobenzoquinones with enamines. Through the implementation of small changes in the reaction conditions, the reaction conditions were much improved with quantities of copper salt, base, and acetonitrile solvent all reduced compared with the original method. The resulting indolequinone-3-carboxylates were subsequently converted into novel indolequinones as potential inhibitors of the quinone reductase enzyme NQO2. A number of potent, mechanism-based inhibitors were identified, increasing our understanding of structure-activity relationships for inhibition of this enzyme.