Design and synthesis of dynemicin analogs

Dynemicin A is a member of the family of enediyne natural products. It is u nique in that it combines a ten-membered enediyne with an anthraquinone sub structure. These features stimulated the development of synthetic approache s to the natural product itself and of analogs thereof. This review summari zes the total syntheses of dynemicin A. In addition, an overview of the kno wn analogs is presented. The analogs can be classified according to the des igned trigger mechanism. Most of the analogs contain a removable carbamate on the nitrogen atom. Others are quite similar to the natural lead in that they contain a quinone substructure, which upon reduction causes opening of the oxirane ring. In addition, there are analogs that contain an aromatic sector, the enediyne, and the oxirane ring but lack the nitrogen heterocycl e. In these compounds the aryl ring assumes a different conformation from t hat in dynemicin A. Many of the simplified analogs proved to be quite activ e in vitro as well in vivo against murine tumor models. A highlight is comp ound 30 which is much more active than dynemicin A itself. However, looking at all analogs there is no clear-cut correlation between the DNA-cleaving ability at neutral pH and the in vitro results. From this one might conclud e that there are possibly two mechanisms for antitumor activity. One involv es diradical formation whereas the other might be due to a ligand-receptor interaction.