title: Synthesis and Evaluation of a 2,11-Cembranoid-Inspired Library.
abstract: The 2,11-cembranoid family of natural products has been used as inspiration for the synthesis of a structurally simplified, functionally diverse library of octahydroisobenzofuran-based compounds designed to augment a typical medicinal chemistry library screen. Ring-closing metathesis, lactonisation and SmI2 -mediated methods were exemplified and applied to the installation of a third ring to mimic the nine-membered ring of the 2,11-cembranoids. The library was assessed for aqueous solubility and permeability, with a chemical-space analysis performed for comparison to the family of cembranoid natural products and a sample set of a screening library. Preliminary investigations in cancer cells showed that the simpler scaffolds could recapitulate the reported anti-migratory activity of the natural products.
authors.affiliation: Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, UK.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Welford
authors.affiliation: Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, UK. john.caldwell@icr.ac.uk.
authors.forename: John J
authors.initials: JJ
authors.lastname: Caldwell
authors.affiliation: Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, UK.
authors.forename: Manjuan
authors.initials: M
authors.lastname: Liu
authors.affiliation: Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, UK.
authors.forename: Meirion
authors.initials: M
authors.lastname: Richards
authors.affiliation: Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, UK.
authors.forename: Nathan
authors.initials: N
authors.lastname: Brown
authors.affiliation: Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, UK.
authors.forename: Cara
authors.initials: C
authors.lastname: Lomas
authors.affiliation: UK National Crystallography Service, University of Southampton, Southampton, SO17 1BJ, UK.
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Tizzard
authors.affiliation: UK National Crystallography Service, University of Southampton, Southampton, SO17 1BJ, UK.
authors.forename: Mateusz B
authors.initials: MB
authors.lastname: Pitak
authors.affiliation: UK National Crystallography Service, University of Southampton, Southampton, SO17 1BJ, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Coles
authors.affiliation: Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, UK.
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.affiliation: Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, UK.
authors.forename: Florence I
authors.initials: FI
authors.lastname: Raynaud
authors.affiliation: Division of Cancer Therapeutics, The Institute of Cancer Research, London, SM2 5NG, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Collins
mesh_terms: D001572:Benzofurans / Q000737:chemistry*; D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D004224:Diterpenes / Q000138:chemical synthesis* / Q000737:chemistry; D007783:Lactones / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000737:chemistry*
chemical_list: D001572:Benzofurans; D001688:Biological Products; D004224:Diterpenes; D007783:Lactones; D054852:Small Molecule Libraries
keywords: medicinal chemistry; medium-ring compounds; molecular diversity; oxygen heterocycles; synthesis design