Synthesis of Migrastatin Analogues as Inhibitors of Tumour Cell Migration: Exploring Structural Change in and on the Macrocyclic Ring. Issue 50 (4th November 2015)

• Record Type: Journal Article
• Authors: Lo Re, Daniele; Zhou, Ying; Mucha, Joanna; Jones, Leigh F.; Leahy, Lorraine; Santocanale, Corrado; Krol, Magdalena; Murphy, Paul V.
• Is Part Of: Chemistry. Volume 21:Issue 50(2015)
• Page Start: 18109
• Page End: 18121
• Publication Date: 2015-11-04
• Subjects: anomerization -- glycosidation -- natural products -- stereoselective synthesis -- tumour cell migration; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201502861
• Languages: English
• ISSNs: 0947-6539

Abstract

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. Abstract : Stop sign to cancer : Analogues of the migrastatin core macrocycle (see graphic) have been synthesised and evaluated as inhibitors of tumour cell migration.