Abstract
Aim of this work was to provide tamoxifen analogs with enhanced estrogen receptor (ER) binding affinity. Hence, several derivatives were prepared using an efficient triarylethylenes synthetic protocol. The novel compounds bioactivity was evaluated through the determination of their receptor binding affinity and their agonist/antagonist activity against breast cancer tissue using a MCF-7 cell-based assay. Phenyl esters 6a,b and 8a,b exhibited binding affinity to both ERα and ERβ higher than 4-hydroxytamoxifen while compounds 13 and 14 have shown cellular antiestrogenic activity similar to 4-hydroxytamoxifen and the known ER inhibitor ICI182,780. Theoretical calculations and molecular modeling were applied to investigate, support and explain the biological profile of the new compounds. The relevant data indicated an agreement between calculations and demonstrated biological activity allowing to extract useful structure-activity relationships. Results herein underline that modifications of tamoxifen structure still provide molecules with substantial activity, as portrayed in the inhibition of MCF-7 cells proliferation.
Highlights
The assumption of Lacassagne that the utilization of estrogen antagonists for the treatment of breast cancers developed by an inherited sensitivity to estrogens is capable of averting the progress of the disease has attracted considerable interest (Lacassagne, 1936; Jordan, 1999)
TAM displays therapeutic indexes and features that are clearly distinguishable from the other anticancer agents (Morello et al, 2002; Singh et al, 2008; Peng et al, 2009) and as its significant estrogen like properties are observed on specific target tissues it is considered one of the first Selective Estrogen Receptor Modulators (SERMs)
The diastereomeric ratio of these compounds was determined by separating the E,Z isomers using a semi-preparative HPLC Their structures were confirmed by NOE experiments, which distinguished the E-isomer considering the absence of a correlation among the protons of the ethyl group and the unprotected phenol protons
Summary
The assumption of Lacassagne that the utilization of estrogen antagonists for the treatment of breast cancers developed by an inherited sensitivity to estrogens is capable of averting the progress of the disease has attracted considerable interest (Lacassagne, 1936; Jordan, 1999). Numerous estrogens antagonists (antiestrogens) have been synthesized and tested in respect to their binding affinity to the Estrogen Receptor (ER), a protein isolated and thoroughly studied (Toft and Gorski, 1966; Kuiper et al, 1996; Pettersson and Gustafsson, 2001) This campaign has afforded the discovery of various potent synthetic estrogens such as diethylstilbestrol (DES) (Lonning et al, 2001), and hexestrol (Figure 1), which have contributed greatly toward the development of a new philosophy for the design of antiestrogens (Dodds et al, 1938), which afforded the discovery of various novel stilbene derivatives with pronounced bioactivities, exemplified by the action of Tamoxifen (TAM) on hormone dependent breast cancers (Dellapasqua and Castiglione-Gertsch, 2005). TAM is extensively metabolized to (Z)-4-hydroxytamoxifen, (4OH-TAM, 1b, Figure 1), a TAM metabolite exhibiting an
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