Evofosfamide radical anion (TH-302 radical anion)

The evofosfamide radical anion is a transient, reactive intermediate formed during the bioreductive activation of the prodrug evofosfamide (TH-302) (Sun et al., 2012). Evofosfamide is designed to target the hypoxic regions of solid tumors, which are often resistant to conventional radiotherapy and chemotherapy (Duan et al., 2008). Under low-oxygen conditions, intracellular one-electron reductases, such as NADPH-cytochrome P450 reductase, reduce the 2-nitroimidazole moiety of evofosfamide to form this radical anion (Hunter et al., 2015). In the presence of oxygen, the radical anion is rapidly re-oxidized to the parent compound; however, in hypoxia, it undergoes fragmentation to release the potent DNA-alkylating agent bromo-isophosphoramide mustard (Br-IPM) (Meng et al., 2012). This mechanism ensures that the cytotoxic payload is selectively released within the tumor microenvironment, leading to DNA cross-linking and subsequent cell death (Weiss et al., 2011). Consequently, the formation and stability of this radical anion are the primary determinants of the drug's hypoxia-selective therapeutic index.

Other names

TH-302 radical anionReduced evofosfamide intermediateNitro-radical anion of evofosfamide

Hypoxia-activated bioreductive fragmentation leading to the release of bromo-isophosphoramide mustard (Br-IPM) and subsequent DNA cross-linking