Synthesis, biochemical evaluation and structural studies of novel antiproliferative βeta-lactams

Abstract

The synthesis and antiproliferative evaluation of anti-cancer β-lactams targeting tubulin, heat shock protein 90 and the estrogen receptor is described. Compounds were planned to include relevant substituents known to confer target selectivity and included a diverse range in order to discern meaningful structure-activity relationships. The core β-lactam heterocycle was formed using established chemistry - the Staudinger and Reformatsky reactions. The Staudinger reaction was employed for the majority of analogues as the necessary synthetic precursors were readily available. All products were fully characterised. A library of over 100 combretastatin A-4 analogues containing the β-lactam core scaffold were prepared and evaluated for antiproliferative activity. Phenolic compound 181 was particularly potent, with activity in the picomolar range for a variety of cell types. Combretastatin A-4 is a known tubulin-targeting agent that binds at the colchicine-binding site, and selected β-lactam analogues including 181 inhibited the polymerisation of tubulin at low micromolar concentrations.