Flexible Estrogen Receptor Modulators:  Design, Synthesis, and Antagonistic Effects in Human MCF-7 Breast Cancer Cells

Abstract

Although many series of estrogen receptor antagonists continue to be produced, the majority are direct structural analogues of existing modulators. To examine the tolerance of the estrogen receptor toward flexible ligands, a series of novel flexible estrogen receptor antagonists were prepared and their antiproliferative effects on human MCF-7 breast tumor cells investigated. Each of these compounds deviated from the traditional triphenylethylene backbone associated with common tamoxifen analogues through the introduction of a flexible methylene (benzylic) spacing group between one of the aryl rings and the ethylene group and through variations in the basic side chain moiety. The compounds prepared, when assayed in conjunction with a tamoxifen standard, demonstrated high potency in antiproliferative assays against an MCF-7 human breast cancer cell line with low cytotoxicity and high binding affinity. A computational study was undertaken to investigate the compounds' potential interactions with specific residues within the human estrogen receptor alpha ligand-binding domain (ER-LBD), predicting these compounds bind in an antiestrogenic fashion within the ER-LBD and interact with those important residues previously identified in the structures of ER-LBD agonist/antagonist cocrystals. These compounds further illustrate the eclectic nature of the estrogen receptor in terms of ligand flexibility tolerance.

A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer

“…Selective estrogen receptor modulators (SERMs) are a new category of therapeutic agents that are used for the prevention and in the treatment of diseases such as osteoporosis and uterus and breast cancers [113,114]. They are known to have high affinity for ER, but no specific affinity for any other steroid hormone receptors.…”

The McMurry Coupling and Related Reactions

“…Higher yields are obtained from the mixed coupling reaction when one of the reactants is a diaryl ketone, because the latter undergoes a rapid twoelectron reduction and the resulting dianion then nucleophilically attacks the other ketone before it can be reduced; thus, 62 was isolated in 77% yield [80]. Such a reaction constitutes a classical route to the antitumor agent tamoxifen 63 [81] and many of its derivatives [82][83][84][85][86][87][88][89], including 64 and 65, and organometallic analogues such as 66 and 67 [90][91][92][93] (Figure 6.13).…”

An Efficient Preparation, Spectroscopic Properties, and Crystal Structure of 1,1-Bis(4-[2-(dimethylamino)ethoxy]phenyl)-2-(3-guaiazulenyl)ethylene

“…Furthermore, tamoxifen, which serves as a nonsteroidal antiestrogen [3], has become a widely used drug for a first-line endocrine therapy for all stages of breast cancer in pre-and postmenopausal women [5]. On the other hand, azulene, possessing a large dipole moment, is regarded as one of the representative examples of non-benzenoid aromatic hydrocarbons, and naturally occurring guaiazulene (7-isopropyl-1,4-dimethylazulene) (see Figure 1) [6] has been widely used clinically as an anti-inflammatory and antiulcer agent.…”