DESIGN SYNTHESIS AND BIOLOGICAL EVALUATION OF DIMUNITIVE FORMS OF (+)- SPONGISTATIN 1: LESSONS LEARNED

摘要

The design, synthesis, and biological evaluation of two diminutive forms of (+)-spongistatin 1, in conjunction with the development of a potentially general design strategy to simplify highly flexible macrocyclic molecules while maintaining biological activity, have been achieved. Examination of the solution conformations of (+)-spongistatin 1 revealed a common conformational preference along the western perimeter comprising the >ABEF rings. Exploiting the hypothesis that the small molecule recognition/binding domains are likely to comprise the conformationally less mobile portions of a ligand led to the design of analogs, incorporating tethers (blue) in place of the >CD and the >ABCD components of the (+)-spongistatin 1 macrolide, such that the conformation of the retained (+)-spongistatin 1 skeleton would mimic the assigned solution conformations of the natural product. The observed nanomolar cytotoxicity and microtubule destabilizing activity for the >ABEF analog provides support both for the assigned solution conformation of (+)-spongistatin 1 and the validity of the design strategy.