Synthesis 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 PaCa-2 cells. However, the data demonstrate that NQO1 inhibition does not correlate with growth inhibitory activity, at least in the MIA PaCa-2 cell line, suggesting that targets in addition to NQO1 need to be considered to explain the potent growth inhibitory activity of this series of indolequinones in human pancreatic cancer cells.
Colucci
Marie A
MA
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom.
Reigan
Philip
P
Siegel
David
D
Chilloux
Aurélie
A
Ross
David
D
Moody
Christopher J
CJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D010190:Pancreatic Neoplasms; D011809:Quinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D007211:Indoles; D011809:Quinones; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human