Sulfur-containing amsacrine analogues as potential anti-cancer agents

A series of sulfide-containing amsacrine analogs were synthesized and evaluated for their cytotoxicity against V-79 cells. The diol functionality appeared to be important for the cytotoxicity of both the diol-containing compounds (2a, 3), which were highly cytotoxic among these sulfides. A preliminary anticancer screening against P388 leukemia showed that 2a is the first sufide-containing amsacrine analog to be active in vivo. Topoisomerase II inhibitory activity appeared to be involved in the cytotoxicity of compound 2a. Compound 2b, which is 6–7 fold less cytotoxic than its potential metabolite, 2a, was considered as a potential bioreductive anti-cancer prodrug. Compound 2b was bioreduced by the rat liver S-9 fraction to its corresponding sulfide, 2a, only in the presence of the electron donors of aldehyde oxidase (e.g. benzaldehyde, 2-hydroxypyrimidine) under anaerobic condition. The bioreduction was inhibited in the presence of menadione. This metabolism study demonstrated that compound 2b is a specific substrate for aldehyde oxidase.*; *Please refer to dissertation for diagrams.