Investigations of beta-lactams as novel bioactive compounds

Abstract

A natural stilbene product combretastatin A-4 (CA-4) is a known anti-cancer compound, which exerts its mechanism of action at the colchicine binding site on tubulin, a protein that is essential for the replication of cells. The synthesis and study of structure-activity relationships of a series of CA-4 analogues are described in which the four-member β-lactam heterocycle (azetidin-2-one) ring scaffold replaces the cis double bond in combretastatin A-4. A library of β-lactam compounds (CA-4 analogues) which are mimics of the substituted aryl ‘A’ ring and ‘B’ ring of CA-4 was synthesised using both Staudinger and Reformatsky reactions. Additional β-lactam compounds were prepared with diverse C-3 substitution at the β-lactam ring by Heck reaction, Diels-Alder reaction, aldol type reaction, alkylation and epoxidation reactions. A series of phosphate ester prodrugs and amino acid prodrugs were synthesised by suitable coupling reactions to improve the stability and solubility of the most active compounds.