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

Catarina Canário,Amílcar Falcão,Vanessa Brito,Adriana O Santos,Gilberto Alves,Samuel Silvestre,Mariana Matias

doi:10.3390/molecules26092687

Catarina Canário, Amílcar Falcão + Show 5 more

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https://doi.org/10.3390/molecules26092687

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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.

Highlights

Cancer is a major public health problem and is one of the leading causes of death worldwide [1]
In view of the therapeutic importance of steroidal oximes, and considering our interest in developing modified estrane derivatives as anticancer agents [7,28], the present study focuses on the synthesis and antiproliferative evaluation of new E1 derivatives bearing
Several E1 oxime derivatives were synthesized and revealed interesting effects against the proliferation of several tumor cell lines when compared with parent ketone compounds

Summary

Introduction

Cancer is a major public health problem and is one of the leading causes of death worldwide [1]. Over the years, medicinal chemists and other researchers have been working in the development of new drugs with antitumor activity—namely, starting from molecules that already exist in nature [2]. In this context, steroids are natural compounds that are usually involved in cell proliferation and in cancer development [3]. In the 90s, several steroids having very unusual and interesting structures were isolated from marine sponges. Steroidal oximes isolated by Rodriguez et al [4] from Cinachyrella sponges showed relevant antiproliferative activity against several types of cancer cells [5]. The oxime functional group is usually introduced by condensation of an aldehyde or a ketone, including of steroidal origin, with hydroxylamine affording, respectively, aldoximes and ketoximes [6]

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