Document Type

Article

Rights

This item is available under a Creative Commons License for non-commercial use only

Disciplines

1. NATURAL SCIENCES, 1.4 CHEMICAL SCIENCES, Organic Chemistry, Biochemistry and molecular biology, Medicinal chemistry

Publication Details

European Journal of Medicinal Chemistry, 2011, Vol. 46, Pages 4595 – 4607

DOI: http://dx.doi.org/10.1016/j.ejmech.2011.07.039

Abstract

The structure-activity relationships of antiproliferative β-lactams, focusing on modifications at the 4-position of the β-lactam ring, is described. Synthesis of this series of compounds was achieved utilizing the Staudinger and Reformatsky reactions. The antiproliferative activity was assessed in MCF-7 cells, where the 4-(4-ethoxy)phenyl substituted compound 26 displayed the most potent activity with an IC50 value of 0.22 μM. The mechanism of action was demonstrated to be by inhibition of tubulin. Cell exposure to combretastatin A-4 and 26 led to arrest of MCF-7 cells in the G2/M phase of the cell cycle and induction of apoptosis. Additionally, mitotic catastrophe for combretastatin A-4 and for 26 was demonstrated in breast cancer cells for the first time, as evidenced by the formation of giant, multinucleated cells.

DOI

10.1016/j.ejmech.2011.07.039