New Estrone Oxime Derivatives: Synthesis, Cytotoxic Evaluation and Docking Studies

Abstract

The interest in the introduction of the oxime group in molecules aiming to improve their biological effects is increasing. This work aimed to develop new steroidal oximes of the estrane series with potential antitumor interest. For this, several oximes were synthesized by reaction of hydroxylamine with the 17-ketone of estrone derivatives. Then, their cytotoxicity was evaluated in six cell lines. An estrogenicity assay, a cell cycle distribution analysis and a fluorescence microscopy study with Hoechst 3358 staining were performed with the most promising compound. In addition, molecular docking studies against estrogen receptor α, steroid sulfatase, 17β-hydroxysteroid dehydrogenase type 1 and β-tubulin were also accomplished. The 2-nitroestrone oxime showed higher cytotoxicity than the parent compound on MCF-7 cancer cells. Furthermore, the oximes bearing halogen groups in A-ring evidenced selectivity for HepaRG cells. Remarkably, the Δ9,11-estrone oxime was the most cytotoxic and arrested LNCaP cells in the G2/M phase. Fluorescence microscopy studies showed the presence of condensed DNA typical of prophase and condensed and fragmented nuclei characteristic of apoptosis. However, this oxime promoted the proliferation of T47-D cells. Interestingly, molecular docking studies estimated a strong interaction between Δ9,11-estrone oxime and estrogen receptor α and β-tubulin, which may account for the described effects.

The Structural Diversity and Biological Activity of Steroid Oximes

“…Aiming to develop new steroidal oximes with potential application in cancer treatment, a group of scientists designed and synthesized a series of estrone oxime derivatives and evaluated them in six cancer cell lines [ 57 ]. MTT results proved that compound 2r ( Figure 5 ) is the most active against all cell lines, being LNCaP cells the most sensitive to this molecule (IC 50 = 3.59 µM) ( Table 2 ).…”

“…Given this, the cytotoxicity of this steroidal oxime was mediated by a cell cycle arrest at G2/M phases accompanied by cell death by apoptosis, with evidence of condensed and fragmented nuclei. Moreover, the authors speculated that this compound might interfere with β-tubulin [ 57 ].…”

“…Necroptosis might also be a mechanism involved in the compounds’ cytotoxicity against cancer cells [ 34 ]. Oxime estrane derivatives induced cell death by apoptosis through cell cycle interference at G1 [ 53 ], S [ 54 ] and G2/M phases [ 57 ] and through activation of caspase-3 [ 53 ]. This class of compounds also interferes with microtubules by interfering with β-tubulin [ 55 , 57 ].…”

The Challenging Melanoma Landscape: From Early Drug Discovery to Clinical Approval

“…In general, prior to becoming available for commercialization, new drugs must pass through several steps, namely discovery and development, preclinical studies, clinical trials and review by regulatory entities [41][42][43]. Research and discovery of new antimelanoma molecules may start by preliminary selection of the most promising lead compounds through computational approaches (in silico) [44,45]. This strategy is usually followed by in vitro testing of hit compounds, selection of the most promising for further in vivo studies and, ultimately, clinical trials, as described in Figure 2 [46].…”

Discovery of Small Molecules as Membrane-Bound Catechol-O-methyltransferase Inhibitors with Interest in Parkinson’s Disease: Pharmacophore Modeling, Molecular Docking and In Vitro Experimental Validation Studies

“…The cytotoxicity was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay, performed as previously described [51]. For this, after adherence and growth, cells were exposed during 48 h to the compounds under study as well as 5-fluorouracil (5-FU; positive control) at different concentrations (0.1, 1, 10, 30, 50, and 100 µM) for dose-response studies.…”