title: An Orally Bioavailable, Indole-3-glyoxylamide Based Series of Tubulin Polymerization Inhibitors Showing Tumor Growth Inhibition in a Mouse Xenograft Model of Head and Neck Cancer.
abstract: A number of indole-3-glyoxylamides have previously been reported as tubulin polymerization inhibitors, although none has yet been successfully developed clinically. We report here a new series of related compounds, modified according to a strategy of reducing aromatic ring count and introducing a greater degree of saturation, which retain potent tubulin polymerization activity but with a distinct SAR from previously documented libraries. A subset of active compounds from the reported series is shown to interact with tubulin at the colchicine binding site, disrupt the cellular microtubule network, and exert a cytotoxic effect against multiple cancer cell lines. Two compounds demonstrated significant tumor growth inhibition in a mouse xenograft model of head and neck cancer, a type of the disease which often proves resistant to chemotherapy, supporting further development of the current series as potential new therapeutics.
authors.affiliation: School of Clinical Dentistry, University of Sheffield , 19 Claremont Crescent, Sheffield S10 2TA, U.K.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Colley
authors.affiliation: Department of Oncology, The University of Sheffield, Medical School , Beech Hill Road, Sheffield S10 2RX, U.K.
authors.forename: Munitta
authors.initials: M
authors.lastname: Muthana
authors.affiliation: Academic Unit of Clinical Oncology and Sheffield Experimental Medicine Centre, Weston Park Hospital , Whitham Road, Sheffield S10 2SJ, U.K.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Danson
authors.affiliation: Department of Chemistry, University of Sheffield , Brook Hill, Sheffield S3 7HF, U.K.
authors.forename: Lucinda V
authors.initials: LV
authors.lastname: Jackson
authors.affiliation: Department of Chemistry, University of Sheffield , Brook Hill, Sheffield S3 7HF, U.K.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Brett
authors.affiliation: Department of Chemistry, University of Sheffield , Brook Hill, Sheffield S3 7HF, U.K.
authors.forename: Joanne
authors.initials: J
authors.lastname: Harrison
authors.affiliation: Department of Chemistry, University of Sheffield , Brook Hill, Sheffield S3 7HF, U.K.
authors.forename: Sean F
authors.initials: SF
authors.lastname: Coole
authors.affiliation: Department of Chemistry, University of Sheffield , Brook Hill, Sheffield S3 7HF, U.K.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Mason
authors.affiliation: School of Clinical Dentistry, University of Sheffield , 19 Claremont Crescent, Sheffield S10 2TA, U.K.
authors.forename: Luke R
authors.initials: LR
authors.lastname: Jennings
authors.affiliation: Charles River , 8-9 Spire Green Centre, Harlow, Harlow, Essex CM19 5TR, U.K.
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.affiliation: Charles River , 8-9 Spire Green Centre, Harlow, Harlow, Essex CM19 5TR, U.K.
authors.forename: Vamshi
authors.initials: V
authors.lastname: Tulasi
authors.affiliation: Charles River , 8-9 Spire Green Centre, Harlow, Harlow, Essex CM19 5TR, U.K.
authors.forename: Dennis
authors.initials: D
authors.lastname: Norman
authors.affiliation: Charles River , 8-9 Spire Green Centre, Harlow, Harlow, Essex CM19 5TR, U.K.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Lockey
authors.affiliation: Department of Oncology, The University of Sheffield, Medical School , Beech Hill Road, Sheffield S10 2RX, U.K.
authors.forename: Lynne
authors.initials: L
authors.lastname: Williams
authors.affiliation: MedChemica Limited , Ebenezer House, Ryecroft, Newcastle-Under-Lyme, Staffordshire ST5 2BE, U.K.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Dossetter
authors.affiliation: MedChemica Limited , Ebenezer House, Ryecroft, Newcastle-Under-Lyme, Staffordshire ST5 2BE, U.K.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Griffen
authors.affiliation: Department of Chemistry, University of Sheffield , Brook Hill, Sheffield S3 7HF, U.K.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Thompson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D064593:Heterografts; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009368:Neoplasm Transplantation; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism / Q000648:ultrastructure; D050257:Tubulin Modulators / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D014404:Tubulin; D050257:Tubulin Modulators