β-Lactam estrogen receptor antagonists and a dual-targeting estrogen receptor/tubulin ligand

Niamh M O'Boyle; Jade K Pollock; Miriam Carr; Andrew J S Knox; Seema M Nathwani; Shu Wang; Laura Caboni; Daniela M Zisterer; Mary J Meegan

doi:10.1021/jm500670d

β-Lactam estrogen receptor antagonists and a dual-targeting estrogen receptor/tubulin ligand

J Med Chem. 2014 Nov 26;57(22):9370-82. doi: 10.1021/jm500670d. Epub 2014 Nov 17.

Authors

Niamh M O'Boyle¹, Jade K Pollock, Miriam Carr, Andrew J S Knox, Seema M Nathwani, Shu Wang, Laura Caboni, Daniela M Zisterer, Mary J Meegan

Affiliation

¹ School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology and ‡School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College , 152-160 Pearse Street, Dublin 2, Ireland.

PMID: 25369367
DOI: 10.1021/jm500670d

Abstract

Twelve novel β-lactams were synthesized and their antiproliferative effects and binding affinity for the predominant isoforms of the estrogen receptor (ER), ERα and ERβ, were determined. β-Lactams 23 and 26 had the strongest binding affinities for ERα (IC50 values: 40 and 8 nM, respectively) and ERβ (IC50 values: 19 and 15 nM). β-Lactam 26 was the most potent in antiproliferative assays using MCF-7 breast cancer cells, and further biochemical analysis showed that it caused accumulation of cells in G2/M phase (mitotic blockade) and depolymerization of tubulin in MCF-7 cells. Compound 26 also induced apoptosis and downregulation of the expression of pro-survival proteins Bcl-2 and Mcl-1. Computational modeling predicted binding preferences for the dual ER/tubulin ligand 26. This series is an important addition to the known pool of ER antagonists and β-lactam 26 is the first reported compound that has dual-targeting properties for both the ER and tubulin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Cell Division
Chemistry, Pharmaceutical / methods
Computer Simulation
Estrogen Receptor Antagonists / chemistry*
Estrogen Receptor alpha / antagonists & inhibitors
Estrogen Receptor alpha / chemistry
Estrogen Receptor beta / antagonists & inhibitors
Estrogen Receptor beta / chemistry
Estrogens / chemistry
G2 Phase
Humans
Inhibitory Concentration 50
L-Lactate Dehydrogenase / chemistry
Ligands
MCF-7 Cells
Models, Molecular
Myeloid Cell Leukemia Sequence 1 Protein / chemistry
Protein Binding
Proto-Oncogene Proteins c-bcl-2 / chemistry
Software
Tetrazolium Salts / chemistry
Thiazoles / chemistry
Tubulin / chemistry*
beta-Lactams / chemistry*

Substances

ESR1 protein, human
Estrogen Receptor Antagonists
Estrogen Receptor alpha
Estrogen Receptor beta
Estrogens
Ligands
MCL1 protein, human
Myeloid Cell Leukemia Sequence 1 Protein
Proto-Oncogene Proteins c-bcl-2
Tetrazolium Salts
Thiazoles
Tubulin
beta-Lactams
L-Lactate Dehydrogenase
thiazolyl blue