Synthesis and DNA-cleaving activity of lactenediynes conjugated with DNA-complexing moieties

Lactenediynes are compounds characterized by the fusion of a β-lactam with a cyclodeca-3-ene-1,5-diyne. In this work the most promising members of this family have been activated by attaching a carbalkoxy or a carbamoyl group to the azetidinone nitrogen, and conjugated to various DNA-complexing moieties, either acting by intercalation or through groove binding. These conjugated artificial enediynes have been demonstrated to possess in vitro ability to produce single and double strand cleavage of plasmid DNA. As potency and capacity to induce double cut, they rank among the best simple enediyne analogues ever prepared. A thorough investigation was carried out in order to develop the best suited linkers for assembling these conjugates.

Lactenediynes activated as azetidinyl ureas and bearing DNA-complexing substructures R are able to afford single and double strand cleavage of plasmid DNA at sub-micromolar concentrations.Figure optionsDownload as PowerPoint slide