title: Diversity-oriented synthesis as a tool for identifying new modulators of mitosis.
abstract: The synthesis of diverse three-dimensional libraries has become of paramount importance for obtaining better leads for drug discovery. Such libraries are predicted to fare better than traditional compound collections in phenotypic screens and against difficult targets. Herein we report the diversity-oriented synthesis of a compound library using rhodium carbenoid chemistry to access structurally diverse three-dimensional molecules and show that they access biologically relevant areas of chemical space using cheminformatic analysis. High-content screening of this library for antimitotic activity followed by chemical modification identified 'Dosabulin', which causes mitotic arrest and cancer cell death by apoptosis. Its mechanism of action is determined to be microtubule depolymerization, and the compound is shown to not significantly affect vinblastine binding to tubulin; however, experiments suggest binding to a site vicinal or allosteric to Colchicine. This work validates the combination of diversity-oriented synthesis and phenotypic screening as a strategy for the discovery of biologically relevant chemical entities.
authors.affiliation: 1] Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK [2].
authors.forename: Brett M
authors.initials: BM
authors.lastname: Ibbeson
authors.affiliation: 1] Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK [2] Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK [3].
authors.forename: Luca
authors.initials: L
authors.lastname: Laraia
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Esther
authors.initials: E
authors.lastname: Alza
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Cornelius J
authors.initials: CJ
authors.lastname: O' Connor
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Yaw Sing
authors.initials: YS
authors.lastname: Tan
authors.affiliation: Department of Chemistry, Emory University, 440 Atwood Hall, 1515 Dickey Drive, Atlanta, Georgia 30322, USA.
authors.forename: Huw M L
authors.initials: HM
authors.lastname: Davies
authors.affiliation: Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.
authors.forename: Grahame
authors.initials: G
authors.lastname: McKenzie
authors.affiliation: Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.
authors.forename: Ashok R
authors.initials: AR
authors.lastname: Venkitaraman
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Spring
mesh_terms: D015195:Drug Design; D018613:Microscopy, Confocal; D008938:Mitosis / Q000187:drug effects*; D025341:Principal Component Analysis