Open Accessβ-Lactam Estrogen Receptor Antagonists and a Dual-Targeting Estrogen Receptor/Tubulin Ligand
Author(s) -
Niamh M. O’Boyle,
Jade K. Pollock,
M.J. Carr,
Andrew J. S. Knox,
Seema M. Nathwani,
Shu Wang,
Laura Caboni,
Daniela M. Zisterer,
Mary J. Meegan
Publication year - 2014
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/jm500670d
Subject(s) - chemistry , estrogen receptor , tubulin , ligand (biochemistry) , receptor , downregulation and upregulation , gene isoform , estrogen , ic50 , estrogen receptor alpha , estrogen receptor beta , in vitro , stereochemistry , biochemistry , microtubule , microbiology and biotechnology , cancer , medicine , endocrinology , breast cancer , biology , gene
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.
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