title: Stabilized cyclopropane analogs of the splicing inhibitor FD-895.
abstract: Targeting the spliceosome with small molecule inhibitors provides a new avenue to target cancer by intercepting alternate splicing pathways. Although our understanding of alternate mRNA splicing remains poorly understood, it provides an escape pathway for many cancers resistant to current therapeutics. These findings have encouraged recent academic and industrial efforts to develop natural product spliceosome inhibitors, including FD-895 (1a), pladienolide B (1b), and pladienolide D (1c), into next-generation anticancer drugs. The present study describes the application of semisynthesis and total synthesis to reveal key structure-activity relationships for the spliceosome inhibition by 1a. This information is applied to deliver new analogs with improved stability and potent activity at inhibiting splicing in patient derived cell lines.
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego , 9500 Gilman Drive, La Jolla, California 92093-0358, United States.
authors.forename: Reymundo
authors.initials: R
authors.lastname: Villa
authors.forename: Manoj Kumar
authors.initials: MK
authors.lastname: Kashyap
authors.forename: Deepak
authors.initials: D
authors.lastname: Kumar
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.forename: Januario E
authors.initials: JE
authors.lastname: Castro
authors.forename: James J
authors.initials: JJ
authors.lastname: La Clair
authors.forename: Michael D
authors.initials: MD
authors.lastname: Burkart
mesh_terms: D002853:Chromatography, Liquid; D003521:Cyclopropanes / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D018942:Macrolides / Q000494:pharmacology*; D013058:Mass Spectrometry; D016133:Polymerase Chain Reaction; D012326:RNA Splicing / Q000187:drug effects*
chemical_list: D003521:Cyclopropanes; C091810:FD 895; D018942:Macrolides; C030797:cyclopropane
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