Synthesis of migrastatin analogues as inhibitors of tumour cell migration: exploring structural change in and on the macrocyclic ring

�� 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. 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.This publication has emanated from research supported in part by a research grant from Science Foundation Ireland (SFI) and is co���funded under the European Regional Development Fund under Grant Number 14/SP/2710. The research leading to these results has also received funding in part from the People Programme (Marie Curie Actions) of the European Union���s Seventh Framework Programme FP7/2007���2013/ under REA grant agreement No. PIEF���GA���2011���299042 and the Poland National Science Council.Published versio