Benzothiepin-derived molecular scaffolds for estrogen receptor modulators: synthesis and antagonistic effects in breast cancer cells.
A series of novel benzothiepin-derived compounds are described as potent selective modulators of the human estrogen receptor (SERMs). The objective of the study is to evaluate the antiproliferative effects of the compounds on human MCF-7 breast tumor cells. These heterocyclic compounds contain the traditional triarylethylene arrangement exemplified by tamoxifen, conformationally restrained through the incorporation of the benzothiepin ring system. The compounds demonstrated potency at nanomolar concentrations in antiproliferative assays against an MCF-7 human breast cancer cell line with low cytotoxicity. The compounds exhibited low nanomolar binding affinity for the estrogen receptor (ER) with some specificity for ERbeta, and also demonstrate potent antiestrogenic properties in the human uterine Ishikawa cell line. The effect of a number of functional group substitutions on the ER binding properties of the benzothiepin molecular scaffold is explored through a brief computational structure-activity relationship investigation with molecular simulation.
School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Dublin 2, Ireland. mmeegan@tcd.ie
Mary J
MJ
Meegan
Irene
I
Barrett
Jochen
J
Zimmermann
Andrew J S
AJ
Knox
Daniela M
DM
Zisterer
David G
DG
Lloyd
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001582:Benzothiepins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D011960:Receptors, Estrogen / Q000737:chemistry / Q000187:drug effects*
D000970:Antineoplastic Agents; D001582:Benzothiepins; D020847:Estrogen Receptor Modulators; D011960:Receptors, Estrogen