Regioselective synthesis, physicochemical properties and anticancer activity of 2-aminomethylated estrone derivatives

Barnabás Molnár,Njangiru Isaac Kinyua,Gergő Mótyán,Péter Leits,István Zupkó,Renáta Minorics,György T Balogh,Éva Frank

doi:10.1016/j.jsbmb.2022.106064

Barnabás Molnár, Njangiru Isaac Kinyua + Show 6 more

Open Access

https://doi.org/10.1016/j.jsbmb.2022.106064

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Abstract

The unique estrogen receptor (ER)-independent antiproliferative and apoptotic activity of 2-methoxyestradiol (2ME2) is well known, however, its use has been limited because of its poor oral bioavailability. In this study, novel 2-aminomethylated estrone (E) and estradiol (E2) derivatives structurally related to 2ME2 were synthesized, and their physicochemical properties as well as their in vitro cytotoxic effects were investigated in the hope of finding more selective antiproliferative agents with improved pharmacokinetic profile. The target compounds were synthesized from 2-dimethylaminomethylated E obtained regioselectively by a three-component Mannich reaction. Quaternization with methyl iodide followed by reacting the ammonium salt with various dialkyl and alicyclic secondary amines afforded the desired products in good yields. The reactions proceeded via a 1,4-nucleophilic addition of the applied secondary amines to the ortho-quinone methide (o-QM) intermediates, generated in situ from the salt by base-promoted β-elimination. The compound library has been enlarged with structurally similar E2 analogues obtained by stereoselective reduction and with some 17β-benzylamino derivatives prepared by reductive amination. The potential values of the novel E and E2 derivatives were characterised by means of three different approaches. At the first step compounds were virtually screened using physicochemical parameters. Physicochemical characterization was completed by kinetic solubility and in vitro intestinal-specific permeability measurement. Antiproliferative effects were additionally determined on a panel of malignant and non-cancerous cell lines. The evaluation of the pharmacological profile of the novel E and E2 derivatives was completed with the calculation of lipophilic efficacy (LiPE).

Highlights

One of the most important tasks of medicinal chemistry is to create compound libraries that contain a large number of molecules with high structural diversity [1,2]
The amine and the aldehyde were used in excess, and the mixture was stirred in refluxing EtOH under regular thin-layer chromatography (TLC) control
Complete conversion was achieved within 2 h, and the transformation proved to be highly regioselective toward the formation of the 2-substituted product (1a), which was obtained in 85 % yield after chromatographic purification

Summary

Introduction

One of the most important tasks of medicinal chemistry is to create compound libraries that contain a large number of molecules with high structural diversity [1,2]. Multicomponent Mannich-type amino alkylation reactions in which a product can be formed by the simulta neous reaction of three reactants (an active hydrogen-containing agent, an aldehyde and an amine reagent) serve as an effective means of achieving this goal [3,4,5,6]. Their great advantage is that the order of addition of the components is arbitrary and their structure can be varied independently, vastly increasing the number of molecules that may be obtained in a short amount of time with minimal effort. In addition to their therapeutic po tential in many kinds of diseases, such as cancer (Fig. 1), improvements in the physicochemical and pharmacokinetic properties are

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