biostudies-literatureColucci MANCI NIH HHS5780-9https://www.ebi.ac.uk/biostudies/studies/S-EPMC2536657biostudies-literatureUnknown50(23)NAD(P)H:quinone oxidoreductase 1 is a proposed target in pancreatic cancer. We describe the synthesis of a series of indolequinones, based on the 5- and 6-methoxy-1,2-dimethylindole-4,7-dione chromophores with a range of phenolic leaving groups at the (indol-3-yl)methyl position. The ability of these indolequinones to function as mechanism-based inhibitors of purified recombinant human NQO1 was evaluated, as was their ability to inhibit both NQO1 and cell growth in human pancreatic MIA PaCa-2 tumor cells. The inhibition of rhNQO1 was related to the pKa of the leaving group: compounds with poorer phenolic leaving groups were poor inhibitors whereas those with more acidic leaving groups were more efficient inhibitors. These inhibition data also correlated with the inhibition NQO1 in MIA PaCaJournal of medicinal chemistrySynthesis and evaluation of 3-aryloxymethyl-1,2-dimethylindole-4,7-diones as mechanism-based inhibitors of NAD(P)H:quinone oxidoreductase 1 (NQO1) activity.PMC2536657R01 CA114441-03R01 CA114441Reigan PMoody CJSiegel DRoss DColucci MAChilloux AfalseSynthesis and evaluation of 3-aryloxymethyl-1,2-dimethylindole-4,7-diones as mechanism-based inhibitors of NAD(P)H:quinone oxidoreductase 1 (NQO1) activity.NAD(P)H:quinone oxidoreductase 1 is a proposed target in pancreatic cancer. We describe the synthesis of a series of indolequinones, based on the 5- and 6-methoxy-1,2-dimethylindole-4,7-dione chromophores with a range of phenolic leaving groups at the (indol-3-yl)methyl position. The ability of these indolequinones to function as mechanism-based inhibitors of purified recombinant human NQO1 was evaluated, as was their ability to inhibit both NQO1 and cell growth in human pancreatic MIA PaCa-2 tumor cells. The inhibition of rhNQO1 was related to the pKa of the leaving group: compounds with poorer phenolic leaving groups were poor inhibitors whereas those with more acidic leaving groups were more efficient inhibitors. These inhibition data also correlated with the inhibition NQO1 in MIA PaCa2007-01-01T00:00:00Z2007 Nov2025-04-18T15:36:14.713Z2019-03-27T00:16:35ZS-EPMC25366571794445110.1021/jm070396q