Synthesis of Novel Estrogen Receptor Antagonists Using Metal-Catalyzed Coupling Reactions and Characterization of Their Biological Activity

Abstract

Estrogen receptor (ER) antagonists are valuable in the treatment of ER-positive human breast cancer. In this study, we designed and synthesized nine new derivatives of 17β-estradiol (E2) with a bulky side chain attached to its C-7α position, and determined their ER antagonistic activity using in vitro bioassays. Four of the derivatives showed a strong inhibition of ERα transactivation activity in a luciferase reporter assay and blocked ERα interactions with coactivators. Similarly, these derivatives also strongly inhibited the growth of the ERα-positive human breast cancer cells. Computational docking analysis was conducted to model the interaction of these antagonists with the human ERα, and showed that they could tightly bind to the ERα in a similar manner as ICI-182,780, a pure ER antagonist. These results provide an example that attachment of a bulky side chain to the C-7α position of E2 can produce ER antagonists with comparable ER affinity as ICI-182,780.

Finding a Potential Dipeptidyl Peptidase-4 (DPP-4) Inhibitor for Type-2 Diabetes Treatment Based on Molecular Docking, Pharmacophore Generation, and Molecular Dynamics Simulation

“…The total production time of 1000 ps simulations were performed with a type of run set as NVE (dynamics without temperature/pressure control). Default setting values were adopted for other parameters [ 37 ]. To analyze root mean square deviations (RMSDs) of protein-ligand complexes and ligands, we utilized the functions of Analyze Trajectory.…”

Site-Specific Fluorogenic Protein Labelling Agent for Bioconjugation

“…The crude was purified by flash chromatography using a gradient elution system of 0%-5% MeOH in DCM to obtain compound 1 as a pale-yellow solid in 7% yield. 1 Compound 7: The synthesis of compound 7 was done according to Jiang, et al [27]. A Finkelstein reaction was performed to synthesize 7 in which 6-chloro-1-hexyne (8.30 mmol, 1.00 mL) was added to dry acetone (100 mL) along with NaI (58.1 mmol, 8.71 g, 7 eq).…”

Bromodimethylsulfonium bromide: A novel reagent for the one pot synthesis of potent Nα-ureido peptides and study of molecular docking and antibacterial activities

“…The protein structures were downloaded from Protein Data Bank [46] and cleaned by deleting water molecules and any other heterogeneous molecules that came from crystallographic preparations [47]. Energy minimization of the targets was performed with the help of standard dynamics cascade protocol of Discovery Studio 3.5 (DS 3.5) by 20,000 steps of steepest descent minimization protocol and a standard relaxation procedure using restrained molecular dynamics [48]. The active sites were identied by receptor cavity method using DS 3.5 [49].…”