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Synthesis of Migrastatin Analogues as Inhibitors of Tumour Cell Migration: Exploring Structural Change in and on the Macrocyclic Ring
Author(s) -
Lo Re Daniele,
Zhou Ying,
Mucha Joanna,
Jones Leigh F.,
Leahy Lorraine,
Santocanale Corrado,
Krol Magdalena,
Murphy Paul V.
Publication year - 2015
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201502861
Subject(s) - chemistry , stereochemistry , stereoselectivity , ring (chemistry) , alkene , cell migration , in vitro , cell culture , chelation , side chain , cell growth , combinatorial chemistry , biochemistry , biology , organic chemistry , polymer , genetics , catalysis
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.