p-(Methylsulfinyl)phenyl nitrogen mustard as a novel bioreductive prodrug selective against hypoxic tumors

Designing Prodrugs and Bioprecursors

“…However, solid tumors possess a few unique and important microenvironmental properties such as localized hypoxia, nutrient deprivation, and low pH [156]. Taking advantage of these findings, Kwon et al [158] devised a hypoxia-selective alkylating bioprecursor prodrug (Figure 28.46a). The oxidation to the sulfone is the dominant process under normal physiological conditions, but the reduction to the sulfide becomes significant under anaerobiotic conditions [157].…”

Designing Prodrugs and Bioprecursors

“…Electrophilic species ϩ FIGURE 36.32 Bioactivation of cyclophosphamide. 139 Taking advantage of these fi ndings, Kwon et al 140 devised a hypoxia-selective alkylating bioprecursor prodrug ( Figure 36.33a ). 138 On the other hand, as shown above for sulindac, sulfoxides can undergo two major biotransformations: reversible reduction to the sulfi de and irreversible oxidation to the sulfone.…”

“…33 (a) and (b): Hypoxia-selective nitrogen mustard140 and bioactivated TP inhibitors 141. 33 (a) and (b): Hypoxia-selective nitrogen mustard140 and bioactivated TP inhibitors 141.…”

F‐18 labelled N,N‐bis‐haloethylamino‐phenylsulfoxides — a new class of compounds for the imaging of hypoxic tissue

“…1 H Nuclear magnetic resonance spectra were recorded at 400 MHz and 19 F spectra were recorded at 375 MHz using a JOEL GX-400 spectrometer. 13 C nuclear magnetic resonance spectra were recorded at 100 MHz using a JOEL GX-400 spectrometer.…”

“…13,14 It is believed that this class of compounds undergoes bioreduction to the corresponding thioether in hypoxic cells, which activates the nitrogen mustard moiety. 15 This process results in the formation of an aziridinium ion intermediate, which binds in an irreversible manner to reductases in the cell and is responsible for the cytotoxic effect of these compounds.…”