title: A "methyl extension" strategy for polyketide natural product linker site validation and its application to dictyostatin.
abstract: An approach to the validation of linker strategies for polyketide natural products with few or no obvious handles for linker attachment, and its application to dictyostatin, are described. Analogues in which the C(6)- and C(12)-methyl groups were replaced by 4-azidobutyl groups were prepared and shown to retain the low nanomolar potency of dictyostatin. Further, conjugation of the C(6) analogue with a cyclooctyne resulted in only minor attenuations in potency. Together, these results shed light on the binding of dictyostatin to β-tubulin, establish a validated linker strategy for dictyostatin, and set the stage for the synthesis and study of dictyostatin conjugates.
authors.affiliation: Department of Chemistry, Columbia University , New York, New York 10027, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Ho
authors.affiliation: Program in Physical Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Dan L
authors.initials: DL
authors.lastname: Sackett
authors.affiliation: Department of Chemistry, Columbia University , New York, New York 10027, United States.
authors.forename: James L
authors.initials: JL
authors.lastname: Leighton
mesh_terms: D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry*; D018942:Macrolides / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D061065:Polyketides / Q000737:chemistry*; D015203:Reproducibility of Results; D013237:Stereoisomerism; D014404:Tubulin / Q000737:chemistry
chemical_list: D001688:Biological Products; D018942:Macrolides; D061065:Polyketides; D014404:Tubulin; C470814:dictyostatin