Activation of prodrugs in hypoxia or anoxia by chemical reduction without fragmentation

2 Activation of prodrugs in hypoxia or anoxia by chemical reduction without fragmentation 

Alkylating agents have been of interest in cancer therapy for many years [113,114]. A typical aliphatic nitrogen mustard rapidly forms an aziridinium ion in aqueous solution, reactive towards nucleophiles such as DNA bases (and, in competition, water, thiols, etc.)  

The indolequinone moiety is of interest (i) as the activating nucleus of aziridine alkylating substituents and/or alkylating functionality through an iminium derivative produced in a C-3 elimination process [115-118], and (ii) as a vehicle for oxygen-sensitive, bioreductively-activated drug delivery [119,120] (see below). 

3 Nitroarenes forming reactive nitroso or hydroxyamino derivatives 

Most nitroarenes or nitroheteroarenes are reduced in a stepwise manner, forming nitroso (-(- 2 e ), hydroxyamino (-K 4 e ) or amino (+ 6 e ) derivatives through disproportionation reactions. Amine formation can be viewed as a detoxifying/excretion route, but the reduction intermediates are potentially cytotoxic because they can react with nucleophiles such as protein thiol groups and DNA bases. 

---