title: Design, synthesis, and biological evaluation of diminutive forms of (+)-spongistatin 1: lessons learned.
abstract: 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 analogues, 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 of the ABEF analogue provide support for both the assigned solution conformation of (+)-spongistatin 1 and the validity of the design strategy.
authors.affiliation: Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, Department of Chemistry, University of Pennsylvania , Philadelphia, 19104, United States. smithab@sas.upenn.edu
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.forename: Christina A
authors.initials: CA
authors.lastname: Risatti
authors.forename: Onur
authors.initials: O
authors.lastname: Atasoylu
authors.forename: Clay S
authors.initials: CS
authors.lastname: Bennett
authors.forename: Junke
authors.initials: J
authors.lastname: Liu
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Cheng
authors.forename: Karen
authors.initials: K
authors.lastname: TenDyke
authors.forename: Qunli
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000095702:Polyether Toxins
chemical_list: D018942:Macrolides; D050257:Tubulin Modulators; C083856:spongistatin 1; D000095702:Polyether Toxins