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.
Subject(s)
Alkenes/chemistry , Cell Movement/drug effects , Glucuronides/chemistry , Macrocyclic Compounds/chemistry , Macrocyclic Compounds/pharmacology , Macrolides/chemistry , Macrolides/pharmacology , Pancreatic Neoplasms/chemistry , Piperidones/chemistry , Piperidones/pharmacology , Cell Line, Tumor , Female , Humans , Pancreatic Neoplasms/drug therapy , Structure-Activity RelationshipABSTRACT
Invited for the cover of this issue are Paulâ V. Murphy and co-workers at the National University of Ireland Galway (NUI Galway) and Warsaw University. The image depicts MGSTA-6 giving a stop signal to tumour cells that are on the move. Read the full text of the article at 10.1002/chem.201502861.
