Sulfoxide-Containing Aromatic Nitrogen Mustards as Hypoxia-Directed Bioreductive Cytotoxins

Abstract

A series of diaryl and alkylaryl sulfoxide-containing nitrogen mustards were synthesized and evaluated for their hypoxia-selective cytotoxicity against V-79 cells in vitro as well as for their metabolism profiles with the rat S-9 fractions. In general, the diaryl sulfoxides (4, 5, and 7-9) showed much greater hypoxia selectivity (11-27-fold) than the alkylaryl sulfoxides (approximately 3-fold) (1 and 3). The fused diphenyl sulfoxides (10 and 11), on the other hand, showed very low hypoxia selectivity (1.3-3-fold). Compound 10 was highly cytotoxic under both aerobic and anaerobic conditions, while 11 showed low cytotoxicity under both conditions. The bioreduction of 8 by the rat S-9 fraction under anaerobic conditions was inhibited by menadione and enhanced by benzaldehyde, acetaldehyde, or 2-hydroxypyrimidine suggesting the involvement of aldehyde oxidase in the reduction of the sulfoxides. Bioreductive metabolism studies of selected model sulfoxides suggested that diaryl sulfoxides are better substrates for aldehyde oxidase than alkylaryl sulfoxides.

Photoredox Catalysis in Nickel-Catalyzed Cross-Coupling

“…This radical can enter the Ni cross-coupling cycle (Scheme 2) to complete this dual catalytic reaction. Thioethers are important structures found in many drugs for treatment of diseases such as cancer, HIV, and Alzheimer's disease [49]. The traditional transition metalcatalyzed synthesis of thioethers often requires strong bases, high temperatures, specially designed ligands, and high catalyst loading, limiting functional group tolerance [50,51].…”

Process development of clinical anti-HBV drug Y101: identification and synthesis of novel impurities

“…The reaction of benzoic acid with 8 gave the compound 9 [8][9][10][11][12]. Alkylation of the hydroxyl group of compound 9 with dimethylaminoethyl chloride and followed by hydrolysis of the ester bond with NaOH furnished impurity G. As shown in Scheme 3, impurity H was obtained by reaction of Y101 with mCPBA in CH 2 Cl 2 at 30°C [13,14].…”

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

“…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.…”