Synthesis, structure, docking and cytotoxic studies of ferrocene–hormone conjugates for hormone-dependent breast cancer application

Conjugates of ferrocene with steroidal estrogens as selective antiproliferative agents against hormone‐dependent breast cancer cells are believed to be limited by the inherent estrogenicity of the conjugates. Motivated by a significant cytotoxicity of the ester of ferrocenecarboxylic acid and the phenolic group of estradiol toward such a cell line, we decided to explore other a‐ring‐tethered ferrocene–estra‐1,3,5(10)‐triene conjugates; in this study, ferrocenylmethylation of estradiol and estrone with (ferrocenylmethyl)trimethylammonium iodide in the presence of potassium carbonate yielded five new compounds (1–5). In dimethylformamide, only O‐alkylated products formed (1 and 3), while a mixture of O‐ and C‐alkylated products was obtained when methanol was used (2, 4, and 5 in addition to 1 and 3). All compounds were characterized using 1D and 2D NMR, IR, UV–Vis, and high‐resolution mass spectrometry. Two of the conjugates, a 3‐O‐ and a 4‐C‐alkylated derivative of estrone (3 and 4, respectively), were also analyzed using single‐crystal X‐ray diffraction. A cyclic voltammetric investigation of the electrochemical properties of 1–5 was performed. While some of the compounds were shown to have a slight‐to‐moderate antiproliferative activity against at least one of the six tested human tumor cell lines and were nontoxic to (the noncancerous) fetal human fibroblasts, compound 2 (4‐(ferrocenylmethyl)estra‐1,3,5(10)‐triene‐3,17β‐diol) with an IC50 value of 0.34 μM was found to be more active against the hormone‐dependent breast cancer cell line MCF‐7 than doxorubicin. These results suggest that a‐ring substitution of steroidal estrogens is a plausible strategy for preparing other ferrocene–steroid conjugates acting against tumor cells.

Section: Introductionsupporting

confidence: 56%

Ferrocenylmethylation of estrone and estradiol: Structure, electrochemistry, and antiproliferative activity of new ferrocene–steroid conjugates

Raičević

Radulović

Jovanović

et al. 2020

“…Previously, our group reported another crystal structure of II, [8] which was found to be composed of six independent molecules in the asymmetric unit. In both crystal structures, a substantial main difference arises on the C 16 -C 19 dihedral angle that connects the ferrocene and hormone moieties.…”

Section: Introductionmentioning

confidence: 99%

“…As a new approach to rationalize the metal‐based drug design, ferrocene has been incorporated into the principal structural component of natural and synthetic compounds with biological activity to develop more selective and effective metal‐based drugs . This approach has been applied in hormone‐dependent breast cancer, in which ferrocene has been vectorized with estrogen hormones in order to effectively deliver its moiety to cancer tissues . In this work, we aimed to explore position 16 of the estrogen hormone as part of the efforts to synthetize, characterize, and apply ferrocene–hormone conjugates in hormone‐dependent breast cancer.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, it has been found that the crystal structure is composed of four independent ferrocene–hormone conjugates in the unit cell. Previously, our group reported another crystal structure of II , which was found to be composed of six independent molecules in the asymmetric unit. In both crystal structures, a substantial main difference arises on the C 16 –C 19 dihedral angle that connects the ferrocene and hormone moieties.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4] This approach has been applied in hormone-dependent breast cancer, in which ferrocene has been vectorized with estrogen hormones in order to effectively deliver its moiety to cancer tissues. [5][6][7][8][9][10] In this work, we aimed to explore position 16 of the estrogen hormone as part of the efforts to synthetize, characterize, and apply ferrocene-hormone conjugates in hormone-dependent breast cancer.To establish the structural-biological activity relationship of each ferrocene-hormone conjugate, it is of paramount importance to understand the conformational arrangement aspects of each structure. In this context, the crystal structure of 16-ferrocenylmethyl-estra-1,3,5(10)-triene-3,17β-diol (II) is presented.…”

mentioning

confidence: 99%

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Synthesis and structural studies of 16‐ferrocenemethyl‐estra‐1,3,5(10)‐triene‐3,17β‐diol and its interaction with human serum albumin by fluorescence spectroscopy and in silico docking approaches

Carmona‐Negrón

Liboy-Lugo

Santana

et al. 2020

Self Cite

16‐Ferrocenylmethyl‐estra‐1,3,5(10)‐triene‐3,17β‐diol crystallizes in a triclinic unit cell and P1 space group. It contains four crystallographic independent molecules in the unit, representing four different conformers of the ferrocene–hormone conjugate. It provides evidence of a low rotational barrier around C19–C20 and the existence of alpha and beta conformers. The four conformers are interconnected by hydrogen bonds through hydroxyl groups of rings A and D. Density functional theory studies show the rotational barrier energy to be 4.96 Kcal/mol and the preferred conformer has a dihedral angle φ2 (defined as C16–C19–C20–C21) of 85.79°. This angle represents the conformer with the lowest steric strains. Docking studies between the subject compound and human serum albumin (HSA) showed that the most likely binding pocket of HSA is drug‐binding site 2. Quenching fluorescence spectroscopy was used to study HSA–ferrocene conjugate interaction and results showed that the complex formation was static and dominated by van der Waals and electrostatic/hydrogen bonding interactions.

Binding studies of ferrocene‐steroid conjugates with human serum albumin as potential drug carrier using fluorescence spectroscopy and in silico docking approach

Narváez-Pita

Meléndez

2021

Self Cite

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.