Total synthesis and functional analysis of non-ribosomal peptides.

Antillatoxin and polytheonamide B are cytotoxic non-ribosomal peptides, both isolated from marine sources. These molecules possess unique biological activities that relate to ion channel proteins. Antillatoxin binds and activates voltage-gated sodium channels, while polytheonamide mimics functions of an ion channel protein. The goal of this research program is to control the function and behavior of ion channels in a desired fashion by exploiting structural motifs of these natural products. In the opening phase of this program, we first developed general and efficient synthetic routes to antillatoxin and polytheonamide B. The strategies for the total syntheses were then applied to the preparation of structurally varied derivatives for studies of structure-function relationships, which resulted in deciphering important structural elements for the potent biological activities of these natural products.