β-Lactam type molecular scaffolds for antiproliferative activity: Synthesis and cytotoxic effects in breast cancer cells

Abstract

A series of novel β-lactam containing compounds are described as antiproliferative agents and potential selective modulators of the oestrogen receptor. The purpose of the study is to evaluate the antiproliferative effects of these compounds on human MCF-7 and MDA MB-231 breast cancer cells. The compounds are designed to contain three aryl ring substituents arranged on the heterocyclic azetidin-2-one (β-lactam), thus providing conformationally restrained analogues of the triarylethylene arrangement exemplified in the tamoxifen type structure. The compounds demonstrated potency in antiproliferative assays against MCF-7 human breast cancer cell line at low micromolar to nanomolar concentrations with low cytotoxicity and moderate binding affinity to the oestrogen receptor. The effect of a number of aryl and amine functional group substitutions on the antiproliferative activity of the β-lactam products was explored and a brief computational structure–activity relationship investigation with molecular simulation was investigated.

• β-Lactam
• azetidin-2-one
• SERMs
• antiproliferative activity

Acknowledgements

We are very grateful to Professor Richard Hochberg at Yale University Medical School, for kindly facilitating the alkaline phosphatase experiments and for the generous gift of the Ishikawa cells. We thank Dr. Ana Luisa Simplicio, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin for the capillary electrophoresis experiments. This work was supported through funding from the Trinity College IITAC research initiative (HEA PRTLI, Cycle 3), with additional support for computational facilities from the Wellcome Trust.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.