Synthesis of migrastatin analogues as inhibitors of tumour cell migration: exploring structural change in and on the macrocyclic ring
Murphy, Paul V.
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Lo Re D, Zhou Y;Mucha J;Jones LF;Leahy L;Santocanale C;Krol M;Murphy PV (2015) 'Synthesis of migrastatin analogues as inhibitors of tumour cell migration: exploring structural change in and on the macrocyclic ring'. Chemistry (Weinheim an der Bergstrasse, Germany), .
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..