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  • Development of new steroidal oximes as possible anticancer drugs
    Publication . Canário, Catarina Sofia Simão; Alves, Gilberto Lourenço; Silvestre, Samuel Martins; Ferreira, Amílcar Celta Falcão Ramos
    Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. Therefore, it is urgent to find new anticancer treatments. This work aimed to develop new steroidal oximes of the estrane series with potential antitumor interest. For this, several intermediates and respective C17 oximes were synthesized by reaction of hydroxylamine with the 17-ketone of estrone derivatives. Then, their cytotoxicity was evaluated in six cell lines (MCF-7, T47-D, LNCaP, HepaRG, Caco-2 and NHDF) by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. Estrogenicity assays, cell cycle distribution analysis and fluorescence microscopy studies with Hoechst 33258 staining were also performed for the most promising compounds. In addition, molecular docking against estrogen receptor α (ERα), steroid sulfatase, 17β-hydroxysteroid dehydrogenase type 1 and β-tubulin were also accomplished. Computational predictions of their pharmacokinetics and toxicity properties were also performed. Δ9,11-estrone has been shown to be cytotoxic against HepaRG cancer cells (IC50 = 6.67 μM) and promoted a cell cycle arrest at G0/G1 phase. Estrogenic activity was also observed for this compound at 0.1 μM in T47-D cells and molecular docking studies estimated a marked interaction between this compound and ERα. The presence of a 16E-benzylidene group increased the antiproliferative effect on MCF-7 and T47-D cells. Moreover, the introduction of iodine in positions 2 and 4 of estrone seemed to induce a selective cytotoxicity for HepaRG cells. The 9α-hydroxy,11β-nitrooxyestrone derivative markedly reduced HepaRG cells viability (~92%) and 9α-hydroxyestrone acetate exhibited a selective antiproliferative effect on HepaRG cells, inducing a cell cycle arrest at G0/G1, and did not promote an estrogenic effect on T47-D cells. Docking studies estimated a generally lower affinity of C-ring oxidized compounds to ERα. Estrone p-quinol (10β-hydroxyestra-1,4-diene-3,17-dione) displayed marked cytotoxic activity, particularly against hormone-dependent cancer cells and the flow cytometry analysis revealed that this compound markedly reduced the viability of HepaRG cells. Molecular docking studies suggested a high affinity towards ERα and 17β-hydroxysteroid dehydrogenase type 1. Moreover, it was predicted that this molecule has a good oral bioavailability and a low maximum tolerated dose in humans. Concerning oximes, six steroidal oximes in estrane series were synthesized, five of which for the first time. The 2-nitroestrone oxime showed higher cytotoxicity than the parent compound on MCF-7 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 ERα and β-tubulin, which may account for the described effects. Thus, the presence of an oxime group at C17 in functionalized estrone scaffold showed to be a good strategy to obtain new molecules with potential anticancer effects.
    2022-11-15Doctoral thesis Open access Show more