title: Synthesis of Migrastatin Analogues as Inhibitors of Tumour Cell Migration: Exploring Structural Change in and on the Macrocyclic Ring.
abstract: Migrastatin and isomigrastatin analogues have been synthesised in order to contribute to structure-activity studies on tumour cell migration inhibitors. These include macrocycles varying in ring size, functionality and alkene stereochemistry, as well as glucuronides. The synthesis work included application of the Saegusa-Ito reaction for regio- and stereoselective unsaturated macroketone formation, diastereoselective Brown allylation to generate 9-methylmigrastatin analogues and chelation-induced anomerisation to vary glucuronide configuration. Compounds were tested in vitro against both breast and pancreatic cancer cell lines and inhibition of tumour cell migration was observed in both wound-healing (scratch) and Boyden chamber assays. One unsaturated macroketone showed low affinity for a range of secondary drug targets, indicating it is at low risk of displaying adverse side effects.
authors.affiliation: School of Chemistry, National University of Ireland, Galway (Ireland).
authors.forename: Daniele
authors.initials: D
authors.lastname: Lo Re
authors.affiliation: School of Chemistry, National University of Ireland, Galway (Ireland).
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Science, Warsaw (Poland).
authors.forename: Joanna
authors.initials: J
authors.lastname: Mucha
authors.affiliation: School of Chemistry, National University of Ireland, Galway (Ireland).
authors.forename: Leigh F
authors.initials: LF
authors.lastname: Jones
authors.affiliation: Centre for Chromosome Biology, School of Natural SciencesNational University of Ireland, Galway(Ireland).
authors.forename: Lorraine
authors.initials: L
authors.lastname: Leahy
authors.affiliation: Centre for Chromosome Biology, School of Natural SciencesNational University of Ireland, Galway(Ireland).
authors.forename: Corrado
authors.initials: C
authors.lastname: Santocanale
authors.affiliation: Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Science, Warsaw (Poland).
authors.forename: Magdalena
authors.initials: M
authors.lastname: Krol
authors.affiliation: School of Chemistry, National University of Ireland, Galway (Ireland). paul.v.murphy@nuigalway.ie.
authors.forename: Paul V
authors.initials: PV
authors.lastname: Murphy
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D005260:Female; D020719:Glucuronides / Q000737:chemistry*; D006801:Humans; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D018942:Macrolides / Q000737:chemistry* / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000737:chemistry* / Q000188:drug therapy; D010881:Piperidones / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000608156:9-methylmigrastatin; D000475:Alkenes; D020719:Glucuronides; D047028:Macrocyclic Compounds; D018942:Macrolides; D010881:Piperidones; C455261:isomigrastatin; C418199:migrastatin
keywords: anomerization; glycosidation; natural products; stereoselective synthesis; tumour cell migration