Novel Carbonyl Analogs of Tamoxifen: Design, Synthesis, and Biological Evaluation

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.

Recent Advances in the Synthesis of Tamoxifen and Analogues in Medicinal Chemistry

“…Arylboronic acid (73) was synthesized in 2 steps starting from threo-alkylation of p-bromophenol (75) with 76 under basic conditions to give 77 in 82% yield which was further converted to the desired intermediate 73 in 70% yield (Scheme 15).…”

“…Studer and co-workers reported the synthesis of tamoxifen by employing oxidative Heck arylation for conducting three arylation steps of methyl acrylate (92). [42] The first step involved the reaction of methyl acrylate (92) with 4-(2-dimethylaminoethoxy)phenylboronic acid (73) in the presence of TEMPO and [Pd(acac) 2 ] to give 93 in 81% yield as a single Eisomer. Compound 93 on oxidative arylation in the presence of phenyl boronic acid gave compound 94 in quantitative yield with selectivity towards Z-isomer.…”

“…[72] The synthesis involved with Friedel-Craft acylation of thioanisole 290 Kasiotis et al used palladium based synthetic methodology for ester substituted tamoxifen analogues with enhanced estrogen receptor binding affinity (Scheme 60). [73] The reaction involved desmethylation of compound 297 followed by benzylation to give ketone intermediate 298 in 80% yield. Compound 298 on reaction with tert-butyl-dimethyl-phenoxysilane lithium at À 78°C gave carbinol which on dehydration and deprotection under acidic condition gave 299 as a mixture of E-and Z-isomers with E/Z = 1/1 in 50% yield.…”

“…Kasiotis et al . used palladium based synthetic methodology for ester substituted tamoxifen analogues with enhanced estrogen receptor binding affinity (Scheme ) . The reaction involved desmethylation of compound 297 followed by benzylation to give ketone intermediate 298 in 80% yield.…”

Preparation and Characterization of MUC-30-Loaded Polymeric Micelles against MCF-7 Cell Lines Using Molecular Docking Methods and In Vitro Study

“…erefore, diminishing the expression of ER, PR, EGFR, HER2, Pgp, and NF-κB should be an important strategy to inhibit the growth and drug resistance of breast cancer cells. To determine protein inhibition, binding affinity of this compound to the mentioned proteins will be evaluated and compared to standard treatment such as tamoxifen [9]. MUC-30 (Figure 1), a semisynthetic analog of cleistanthin A from Phyllanthus taxodiifolius Beille, can be utilized to inhibit breast cancer [10].…”