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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-methylmigras-tatin 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. We acknowledge networking support and a short term scientific mission funded by the COST Action CM1106. We thank Dr. A. Calon and Dr. E. Lonardo (Institute for Research in Biomedicine, IRB Barcelona) for helpful discussion. peer-reviewed

An efficient and scalable synthesis of a key acyclic intermediate used for the preparation of migrastatin and its macroketone analogue is described; Brown alkoxyallylation is the key step for this synthesis. The macroketone was prepared on 100 mg scale by this route. Treatment of invasive pancreatic cancer cells grown on a cell-derived matrix or as subcutaneous tumours in nude mice with the macroketone inhibited E-cadherin dynamics in a manner consistent with increased cell adhesion and reduced invasive potential. Science Foundation Ireland (Grant Nos. 07/IN.1/B966 and 11/TIDA/B2047), People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA grant agreement number PIEF-GA-2011-299042 peer-reviewed