Discovery of Potent Cell Migration Inhibitors through Total Synthesis: Lessons from Structure-Activity Studies of (+)-Migrastatin

摘要

The possibilities of enhancing the process of drug discovery through the use of nonpeptidal small-molecule natural products (secondary metabolites) are well established. In some instances, the natural products themselves (cf. steroids, -lactams, erythronolides, paclitaxel) are developed and ultimately registered as drugs. Perhaps more commonly, the natural product serves as a template for medicinal chemistry investigations, en route to eventual drugs. In other cases, natural products highlight substructural motifs which can be inserted as chemical cassettes in other molecular settings to produce valuable drugs (cf. Lipitor). By extension it could well be argued that tamoxifen, which does not per se carry a substructure found in a naturally occurring product, was clearly inspired by lessons learned from steroids and their binding to steroid receptors.