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Estrogen receptor alpha (ERα) is a transcription factor that is activated by hormones, with 17β-estradiol being its most active agonist endogenous ligand. ERα is also activated or inactivated by exogenous ligands. ER is overexpressed in hormone-dependent breast cancer, and one of the treatments for this type of cancer is the use of an ER antagonist to halt cell proliferation. We have previously reported four steroid-functionalized titanocenes: pregnenolone, dehydroepiandrosterone (DHEA), trans-androsterone, and androsterone. These steroids have hormonal activity as well as moderate antiproliferative activity, thus these steroids could act as vectors for the titanocene dichloride to target hormone-dependent cancers. Also, these steroids could increase the antiproliferative activity of the resulting titanocenes based on synergism. In order to elucidate which factors contribute to the enhanced antiproliferative activity of these steroid-functionalized titanocenes, we performed docking studies between ERα and the titanocenes and the steroids. The binding affinities and type of bonding interactions of the steroid-functionalized titanocenes with ERα are herein discussed.

The interactions of 16-ferrocenylidene-3α-hydroxy androstan-17-one (1), 16-ferrocenylidene-3β-hydroxy androstan-17-one (2), 21-ferrocenylidene-3βhydroxy pregn-5-en-20-one (3), and 16-ferrocenylidene-3β-hydroxydehydro androstan-17-one (4) with human serum albumin (HSA) have been studied by fluorescence quenching spectroscopy and in silico docking calculations. The experimental results showed that the intrinsic fluorescence of HSA is quenched upon addition of the ferrocene-steroid conjugates and the quenching mechanism is static. Thermodynamic parameters demonstrated that the protein-ferrocene interactions are spontaneous, highly entropic, and hydrophobic. Protein-ligand docking studies were performed using AutoDock Vina Program. Docking studies corroborated the experimental data, and the binding interactions are hydrophobic. All ferrocene-steroid conjugates get engaged in hydrophobic interactions with LEU387, TYR411, LEU430, and ARG485 amino acid residues.