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Lo Re, D,Zhou, Y,Mucha, J,Jones, LF,Leahy, L,Santocanale, C,Krol, M,Murphy, PV
2015
December
Chemistry-A European Journal
Synthesis of Migrastatin Analogues as Inhibitors of Tumour Cell Migration: Exploring Structural Change in and on the Macrocyclic Ring
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anomerization glycosidation natural products stereoselective synthesis tumour cell migration WADSWORTH-EMMONS REACTION BREAST-CANCER CELLS MACROLIDE CORE IN-VIVO ETHYL (DIARYLPHOSPHONO)ACETATES CHEMICAL-SYNTHESIS POTENT INHIBITORS ISO-MIGRASTATIN GENE-EXPRESSION FASCIN
21
18109
18121
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.
10.1002/chem.201502861
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