Reductive Heme-Dependent Activation of theN-Oxide Prodrug AQ4N by Nitric Oxide Synthase

Anaerobic reduction of anticancer prodrugs is a promising route to achieve targeting and selectivity in anticancer drug design. Most reductive prodrug activations involve simple electron transfer from a flavoprotein and are not amenable to specific targeting. Here, we report that the N-oxide AQ4N is reduced by a nitric oxide synthase. This reduction involves interaction with the heme iron atom in the active site and is thus subject to specific protein constraints.