The proposal describes a complementary approach to uncover the chemical origins of the bioactivity of a potent new antitumor antibiotic, Leinamycin (1), and related dithiolanone oxides (2-4). Leinamycin is thought to exert its bioactivity by binding and subsequently cleaving DNA in a thiol-dependent reaction. The mechanisms for these processes are not known. By separation of the cleaving ability from the DNA binding properties, it may be possible to gain valuable insights into each of these aspects. An affinity cleaving agent (5) with predictable binding specificity is proposed as an advanced model for the thiol-dependent DNA cleavage reaction. Predictable binding specificity combined with analysis of reaction products should provide powerful clues about the mechanism of DNA cleavage. Leinamycin and inactive analogs will be used to study the binding properties of the marcrocycle.
