migrastatin and Pancreatic-Neoplasms

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.

Topics: Alkenes; Cell Line, Tumor; Cell Movement; Female; Glucuronides; Humans; Macrocyclic Compounds; Macrolides; Pancreatic Neoplasms; Piperidones; Structure-Activity Relationship

An efficient and scalable synthesis of a key acyclic intermediate used for the preparation of migrastatin and its macroketone analogue is described; Brown alkoxyallylation is the key step for this synthesis. The macroketone was prepared on 100 mg scale by this route. Treatment of invasive pancreatic cancer cells grown on a cell-derived matrix or as subcutaneous tumours in nude mice with the macroketone inhibited E-cadherin dynamics in a manner consistent with increased cell adhesion and reduced invasive potential.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cadherins; Cell Adhesion; Cell Movement; Fluorescence Recovery After Photobleaching; Humans; Macrolides; Mice, Nude; Pancreatic Neoplasms; Piperidones; Tumor Cells, Cultured