Reductive heme-dependent activation of the n-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.
Nishida
Clinton R
CR
Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94158-2517, USA.
Ortiz de Montellano
Paul R
PR
D000693:Anaerobiosis; D000880:Anthraquinones / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D006418:Heme / Q000737:chemistry; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000378:metabolism*
D000880:Anthraquinones; D011355:Prodrugs; D006418:Heme; C094428:AQ4N; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human