Michael C. Pirrung

Department of Chemistry, University of California, Riverside, CA 92521-0403, USA

Abstract:

The utility of bioactive natural products as lead structures for drug development is highly dependent on chemistry’s ability to develop a practical yet versatile synthesis. To exploit the power of modern high-throughput synthesis methods, it is also important that the synthesis be highly modular, such that structural variation in the natural product analogs can be introduced via structurally variant modules. Modular syntheses of natural products and their application to the preparation of molecular libraries have been an important theme in our research. The novel proteasome inhibitor syringolin is an example. Our synthesis efficiently creates its α,b-unsaturated 12-membered macrolactam from amino acid, acetate, and unsaturated amine building blocks. Building block structures can be varied to create macrolactams with varied ring size and alkene positions. Attachment of side chains to the macrolactam enables the preparation of the natural products syringolin A and B. Application of this synthesis has generated structural variants that were subjected to biological evaluation against a range of leukemia and solid tumor lines. One shows unique activity against difficult-to-treat cancers they has moved it into drug development. Expanded data on the mode of action of these agents has emerged from cell biological studies.