Azinomycin bisepoxides containing rigid aromatic linkers: synthesis, cytotoxicity and DNA interstrand cross-linking activity

The synthesis of a series of azinomycin bisepoxides containing rigid linkers is achieved through two different strategies. Double copper-mediated C–N bond formation under Buchwald-type conditions can be realised but yields are poor with fully intact epoxide substrates. The bisepoxides are made in improved yields through the simultaneous formation of two amide bonds. Bioassays reveal that 5, containing a 1,3-diaminobenzene linker, is a potent in vitro DNA interstrand cross-linking agent with significant cytotoxicity in the NCI 60-human cancer cell panel (GI50 = 0.15 μM).